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"Following the success of the Lendy Finance Challenge in 2018, Sunsail, the Official Charter Sailing Partner of Lendy Cowes Week, is once again delighted to host the Lendy Finance Challenge in 2019.\nThe Challenge will be held over the five days of Monday 10th – Friday 17th August. The Finance Challenge uses Sunsail's identical fleet of 28 Sunsail Match First 40s to race, making the competition fair, fast-paced and challenging. A daily prize giving for all participants in the Finance Challenge will be held in Sunsail's exclusive hospitality area in Cowes Yacht Haven and the overall Finance Challenge champions will be awarded the Lendy Finance Challenge Trophy on Friday 10th August.\nAll finance companies racing in the Sunsail Match First 40 class will be eligible to enter and Sunsail has pre-reserved a portion of its 28 strong fleet for finance companies wishing to participate.\nNo previous sailing experience is necessary, as your entry includes a high-quality Match First 40 yacht and professional skipper and mate to ensure that even first-timers will have the best possible time on the water."

"Our Friends at TasPorts Invite You to Come Stay The Weekend\nWe're Back! Introducing the Parade Of Sail 2021!\nDo you remember Tassie Too?\nSullivans Cove\nTasPorts\nThe Australian Wooden Boat Festival has grown dramatically over the last 26 years. Not only have we seen a constant increase in the number of participating wooden boats, but have also seen significant growth in the festival site, which now stretches from Princes Wharf One right across to Hunter Street. This great expansion of the AWBF has only been possible through a solid partnership with TasPorts. Our site is largely owned by TasPorts and we work very closely with them in the lead up to the Festival, during the Festival and after the Festival to ensure we can provide our participants with the best experience possible.\nSince the early 1800's the waterfront has been a thriving trading and working port. Convict workers adapted the shape of the shoreline in order to accommodate the trading vessels and the port became the heart of Hobart. Constitution Dock, the heart of the waterfront, also become the heart of the Australian Wooden Boat Festival — from the very first Festival, hundreds of wooden boats were berthed in 'Con Dock' for the AWBF.\nTasPorts is a state-owned company responsible for eleven Tasmanian Ports and even one airport. Its ports are located alongside some of the most beautiful places in Tasmania, including our AWBF site – Sullivan's Cove. TasPorts proudly sponsors several charitable organisations, events and activities around Tasmania through financial and in-kind support. Each year TasPorts partners with iconic Tasmania events and festivals including the Sydney to Hobart Yacht Race, Dark Mofo and the AWBF.\nIn keeping with appreciating and maintaining good relationships, TasPorts and the AWBF are inviting you, as a loyal wooden boat owner and newsletter subscriber to come and stay in Constitution Dock for 2 nights for the price of 1. For just $64.90 you will have access to a berth in Constitution Dock, on these three weekends: 18-20th December 2020, 8-10th January 2021 and 22-24th January 2021 (Mona Foma weekend). Why not come into town for the weekend and enjoy the summer festivities?\nWant to book? Simply return the completed booking form below to sponsorship@tasports.com.au\nTasPorts-AWBF-Special-Offer-Booking-Form-1BOOKING FORM HERE\nWhen: 18-20th December 2020, 8-10th January 2021 and 22-24th January 2021.\nTerms & Conditions: Bridge openings available at 1500 Friday and departure on Sunday at 1100 or 1300. Bookings must be received a minimum of 7 days prior to arrival date. A full list of T&C's available on the booking form."

"In August of 2014, the FDA approved ELELYSO for long-term enzyme replacement therapy (ERT) for pediatric subjects with a confirmed diagnosis of Type 1 Gaucher disease. The recommended dosage for treatment-naïve adult and pediatric subjects 4 years of age and older is 60 units per kg of body weight administered every other week as a 60 to 120 minute intravenous infusion. As a postmarketing commitment, the Sponsor agreed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of Elelyso (taliglucerase alfa) in pediatric subjects with Type 1 Gaucher Disease. in at least 5 subjects with body weight less than 15 kg; at least 5 subjects with body weight 15 to less than 20 kg; and at least 5 subjects with body weight of 20-25 kg with Type 1 Gaucher disease dosed at 60 units/kg every other week.\nWhen applicable, PD measurements for children enrolled in the PK study may be obtained through the taliglucerase alfa registry (PMR 1895-5) and will include organ volumes (spleen and liver), hematological values (hemoglobin and platelets) as well as growth (height and weight) data. Safety data, including any serious hypersensitivity reactions, such as anaphylaxis, as well as changes in antibody status (ie, detection and titers of binding and neutralizing antibodies, and detection of IgE antibodies), will also be collected through the taliglucerase alfa registry.\nless than 20 kg or 20-25 kg.\nGaucher disease diagnosis history documented in advance of treatment start.\nan infusion rate of 1 mL/min.\nassent must also be obtained.\nscheduled visits, treatment plan, laboratory tests and other study procedures.\nharm to the subject or decrease compliance with the study requirements.\nsymptoms characteristic of Type 2 or 3 Gaucher disease.\nmedication (ie, switch from taliglucerase alfa to a different ERT).\nstudy would not be in the study candidate's best interest.\n6. A hemoglobin level of the PK sample visit.\nonly if heparin lock or flush is to be used on the day of the PK sample visit).\nPfizer employees directly involved in the conduct of the study."

"Bayer's oral anticoagulant Xarelto has been submitted for EU marketing authorisation for the treatment of pulmonary embolism and the prevention of recurrent deep vein thrombosis.\nXarelto has already been approved by the European Commission for the treatment of DVT and the prevention of recurrent DVT and PE following an acute DVT in adults.\nThe submission is supported by data from the pivotal, global Phase III Einstein-PE study, which compared the oral single drug approach of Xarelto (rivaroxaban) 15mg twice daily for three weeks followed by 20mg once daily with the current standard of care, subcutaneous enoxaparin followed by a VKA.\nAccording to the study, Xarelto demonstrated efficacy comparable to that of the current standard therapy in reducing the primary end point of recurrent symptomatic VTE, a composite of symptomatic deep vein thrombosis and non-fatal or fatal PE. Xarelto was associated with a significant 50% relative risk reduction in major bleeding events.\n\"Pulmonary embolism is one of the most severe events in thrombotic medicine. The EMA submission of rivaroxaban for the treatment of PE and the prevention of recurrent DVT represents another step towards providing patients and the NHS with a single drug solution in this indication,\" said Luis Felipe Graterol, medical director at Bayer HealthCare UK.\nEinstein-PE is one of three Phase III studies in the global Einstein programme that evaluated the safety and efficacy of Xarelto in the treatment of venous thromboembolism in almost 10,000 patients."

"Xarelto 20mg film-coated tablets\nBayer plc contact details\nB01AF01\nRisk Materials\nLast updated on emc: 17 Jan 2022\nThis medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.\nXarelto 20 mg film-coated tablets\nEach film-coated tablet contains 20 mg rivaroxaban.\nExcipient with known effect\nEach film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4.\nFilm-coated tablet (tablet)\nBrown-red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the BAYER-cross on one side and \"20\" and a triangle on the other side.\nPrevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.\nTreatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)\nPaediatric population\nTreatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initial parenteral anticoagulation treatment.\nPrevention of stroke and systemic embolism in adults\nThe recommended dose is 20 mg once daily, which is also the recommended maximum dose.\nTherapy with Xarelto should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).\nIf a dose is missed the patient should take Xarelto immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.\nTreatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults\nThe recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.\nShort duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.\nWhen extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a dose of Xarelto 20 mg once daily should be considered.\nThe duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).\nDosing schedule\nTotal daily dose\nTreatment and prevention of recurrent DVT and PE\nDay 1 - 21\n15 mg twice daily\nDay 22 onwards\n20 mg once daily\nPrevention of recurrent DVT and PE\nFollowing completion of at least 6 months therapy for DVT or PE\n10 mg once daily or\nor 20 mg\nTo support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack of Xarelto for treatment of DVT/PE is available.\nIf a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.\nIf a dose is missed during the once daily treatment phase, the patient should take Xarelto immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.\nTreatment of VTE and prevention of VTE recurrence in children and adolescents\nXarelto treatment in children and adolescents aged less than 18 years should be initiated following at least 5 days of initial parenteral anticoagulation treatment (see section 5.1).\nThe dose for children and adolescent is calculated based on body weight.\n- Body weight of 50 kg or more:\na once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.\n- Body weight from 30 to 50 kg:\n- For patients with body weight less 30 kg refer to the Summary of Product Characteristics of Xarelto granules for oral suspension.\nThe weight of a child should be monitored and the dose reviewed regularly. This is to ensure a therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight only.\nTreatment should be continued for at least 3 months in children and adolescents. Treatment can be extended up to 12 months when clinically necessary. There is no data available in children to support a dose reduction after 6 months treatment. The benefit-risk of continued therapy after 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential bleeding risk.\nIf a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose.\nConverting from Vitamin K Antagonists (VKA) to Xarelto\n- Prevention of stroke and systemic embolism:\nVKA treatment should be stopped and Xarelto therapy should be initiated when the International Normalised Ratio (INR) is ≤ 3.0.\n- Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE and prevention of recurrence in paediatric patients:\nVKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.\nWhen converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see section 4.5).\nConverting from Xarelto to Vitamin K antagonists (VKA)\nThere is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.\nIn patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).\nPaediatric patients:\nChildren who convert from Xarelto to VKA need to continue Xarelto for 48 hours after the first dose of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose of Xarelto. Co-administration of Xarelto and VKA is advised to continue until the INR is ≥ 2.0. Once Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see above and section 4.5).\nConverting from parenteral anticoagulants to Xarelto\nFor adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).\nConverting from Xarelto to parenteral anticoagulants\nDiscontinue Xarelto and give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.\nRenal impairment\nLimited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).\nIn patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15 - 29 ml/min) renal impairment the following dose recommendations apply:\n- For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).\n- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).\nWhen the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary.\nNo dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) (see section 5.2).\n- Children and adolescents with mild renal impairment (glomerular filtration rate 50 - 80 mL/min/1.73 m2): no dose adjustment is required, based on data in adults and limited data in paediatric patients (see section 5.2).\n- Children and adolescents with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2): Xarelto is not recommended as no clinical data is available (see section 4.4).\nXarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).\nNo clinical data is available in children with hepatic impairment.\nElderly population\nNo dose adjustment (see section 5.2)\nNo dose adjustment for adults (see section 5.2)\nFor paediatric patients the dose is determined based on body weight.\nPatients undergoing cardioversion\nXarelto can be initiated or continued in patients who may require cardioversion.\nFor transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.\nPatients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement\nThere is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once daily for patients with moderate renal impairment [creatinine clearance 30 - 49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement (see sections 4.4 and 5.1).\nThe safety and efficacy of Xarelto in children aged 0 to < 18 years have not been established in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. No data are available. Therefore, it is not recommended for use in children below 18 years of age in indications other than the treatment of VTE and prevention of VTE recurrence.\nMethod of administration\nXarelto is for oral use.\nThe tablets are to be taken with food (see section 5.2).\nCrushing of tablets\nFor patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.\nThe crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6).\nChildren and adolescents weighing more than 50 kg\nThe patient should be advised to swallow the tablet with liquid. It should also be taken with food (see section 5.2). The tablets should be taken approximately 24 hours apart.\nIn case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the dose should not be re-administered and the next dose should be taken as scheduled.\nThe tablet must not be split in an attempt to provide a fraction of a tablet dose.\nFor patients who are unable to swallow whole tablets, Xarelto granules for oral suspension should be used. If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban are prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water or apple puree immediately prior to use and administering orally.\nThe crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 and 6.6).\nHypersensitivity to the active substance or to any of the excipients listed in section 6.1.\nActive clinically significant bleeding.\nLesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.\nConcomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).\nHepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).\nPregnancy and breast-feeding (see section 4.6).\nClinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.\nHaemorrhagic risk\nAs with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto administration should be discontinued if severe haemorrhage occurs (see section 4.9).\nIn the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.\nSeveral sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8).\nAny unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.\nAlthough treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2).\nThere is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection (see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with rivaroxaban.\nIn adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).\nXarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).\nXarelto is not recommended in children and adolescents with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2), as no clinical data is available.\nInteraction with other medicinal products\nThe use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk. No clinical data is available in children receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp (see section 4.5).\nCare is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).\nOther haemorrhagic risk factors\nAs with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as:\n• congenital or acquired bleeding disorders\n• uncontrolled severe arterial hypertension\n• other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)\n• vascular retinopathy\n• bronchiectasis or history of pulmonary bleeding\nPatients with cancer\nPatients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban therapy.\nIn patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated (see section 4.3).\nPatients with prosthetic valves\nRivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for these patients.\nPatients with antiphospholipid syndrome\nDirect acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.\nPatients with non-valvular atrial fibrillation who undergo PCI with stent placement\nClinical data are available from an interventional study with the primary objective to assess safety in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1). No data are available for such patients with a history of stroke/transient ischaemic attack (TIA).\nHaemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy\nXarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Xarelto have not been established in these clinical situations.\nSpinal/epidural anaesthesia or puncture\nWhen neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of 20 mg rivaroxaban in these situations.\nTo reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known and should be weighed against the urgency of a diagnostic procedure.\nFor the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.\nIf traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.\nNo data is available on the timing of the placement or removal of neuraxial catheter in children while on Xarelto. In such cases, discontinue rivaroxaban and consider a short acting parenteral anticoagulant.\nDosing recommendations before and after invasive procedures and surgical intervention\nIf an invasive procedure or surgical intervention is required, Xarelto 20 mg should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician.\nIf the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.\nXarelto should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician (see section 5.2).\nIncreasing age may increase haemorrhagic risk (see section 5.2).\nDermatological reactions\nSerious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.\nInformation about excipients\nXarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.\nThis medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially \"sodium-free\".\nThe extent of interactions in the paediatric population is not known. The below mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.\nCYP3A4 and P-gp inhibitors\nCo-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4).\nActive substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).\nErythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.\nIn subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).\nFluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).\nGiven the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.\nAfter combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.\nDue to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants (see sections 4.3 and 4.4).\nNSAIDs/platelet aggregation inhibitors\nNo clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response.\nNo clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.\nClopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.\nCare is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).\nSSRIs/SNRIs\nAs with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.\nConverting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.\nIf it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.\nIf it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.\nNo pharmacokinetic interaction was observed between warfarin and rivaroxaban.\nCYP3A4 inducers\nCo-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.\nOther concomitant therapies\nNo clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.\nLaboratory parameters\nClotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see section 5.1).\nSafety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated during pregnancy (see section 4.3).\nWomen of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.\nSafety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.\nNo specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).\nXarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.\nSummary of the safety profile\nThe safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).\nOverall, 69,608 adult patients in nineteen phase III studies and 412 paediatric patients in two phase II and one phase III studies were exposed to rivaroxaban.\nTable 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies\nNumber of patients*\nMaximum treatment duration\nPrevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery\nPrevention of VTE in medically ill patients\nTreatment of deep vein thrombosis (DVT), pulmonary embolism (PE) and prevention of recurrence\nDay 1 - 21: 30 mg\nDay 22 and onwards: 20 mg\nAfter at least 6 months: 10 mg or 20 mg\nTreatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment\nBody weight-adjusted dose to achieve a similar exposure as that observed in adults treated for DVT with 20 mg rivaroxaban once daily\nPrevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation\nPrevention of atherothrombotic events in patients after an ACS\n5 mg or 10 mg respectively, co-administered with either ASA or ASA plus clopidogrel or ticlopidine\nPrevention of atherothrombotic events in patients with CAD/PAD\n5 mg co-administered with ASA or 10 mg alone\n3,256**\n5 mg co-administered with ASA\n* Patients exposed to at least one dose of rivaroxaban\n**\tFrom the VOYAGER PAD study\nThe most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4. and 'Description of selected adverse reactions' below) (Table 2). The most commonly reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).\nTable 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies\nAny bleeding\n6.8% of patients\nPrevention of venous thromboembolism in medically ill patients\n12.6% of patients\nTreatment of DVT, PE and prevention of recurrence\n23% of patients\n28 per 100 patient years\n2.5 per 100 patient years\n0.15 per 100 patient years**\n8.38 per 100 patient years #\n0.74 per 100 patient years*** #\n* For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.\n** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied\n***\tA selective approach to adverse event collection was applied\n#\tFrom the VOYAGER PAD study\nTabulated list of adverse reactions\nThe frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.\nFrequencies are defined as:\nvery common (≥ 1/10)\ncommon (≥ 1/100 to < 1/10)\nuncommon (≥ 1/1,000 to < 1/100)\nrare (≥ 1/10,000 to < 1/1,000)\nvery rare (< 1/10,000)\nnot known (cannot be estimated from the available data)\nTable 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and one phase III studies in paediatric patients\nBlood and lymphatic system disorders\nAnaemia (incl. respective laboratory parameters)\nThrombocytosis (incl. platelet count increased)A, thrombocytopenia\nAllergic reaction, dermatitis allergic, angioedema and allergic oedema\nAnaphylactic reactions including anaphylactic shock\nDizziness, headache\nCerebral and intracranial haemorrhage, syncope\nEye haemorrhage (incl. conjunctival haemorrhage)\nHypotension, haematoma\nRespiratory, thoracic and mediastinal disorders\nEpistaxis, haemoptysis\nGingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA\nHepatobiliary disorders\nIncrease in transaminases\nHepatic impairment, increased bilirubin, increased blood alkaline phosphataseA, increased GGTA\nJaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)\nPruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage\nStevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome\nPain in extremityA\nHaemarthrosis\nMuscle haemorrhage\nCompartment syndrome secondary to a bleeding\nRenal and urinary disorders\nUrogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)\nRenal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion\nFeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)\nFeeling unwell (incl. malaise)\nLocalised oedemaA\nIncreased LDHA, increased lipaseA, increased amylaseA\nInjury, poisoning and procedural complications\nPostprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA\nVascular pseudoaneurysmC\nA: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery\nB: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years\nC: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)\n* A pre-specified selective approach to adverse event collection was applied in selected phase III studies. The incidence of adverse reactions did not increase and no new adverse drug reaction was identified after analysis of these studies.\nDescription of selected adverse reactions\nDue to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 \"Management of bleeding\"). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4 \"Haemorrhagic risk\"). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.\nKnown complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.\nThe safety assessment in children and adolescents is based on the safety data from two phase II and one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years. The safety findings were generally similar between rivaroxaban and comparator in the various paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, although assessment is limited by the small number of patients.\nIn paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin (common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% (common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug reactions in paediatric patients were primarily mild to moderate in severity.\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.\nIn adults, rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patient should be observed carefully for bleeding complications or other adverse reactions (see section \"Management of bleeding\"). There is limited data available in children. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic doses in children.\nA specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is available for adults, but not established in children (refer to the Summary of Product Characteristics of andexanet alfa).\nThe use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.\nManagement of bleeding\nShould a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours in adults. The half life in children estimated using population pharmacokinetic (popPK) modelling approaches is shorter (see section 5.2). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.\nIf bleeding cannot be controlled by the above measures, either the administration of a specific factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should be considered. However, there is currently very limited clinical experience with the use of these medicinal products in adults and in children receiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings (see section 5.1).\nProtamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in children receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.\nPharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01\nRivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.\nPharmacodynamic effects\nDose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.\nIn patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.\nIn patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.\nIn a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).\nThe activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see section 5.2).\nPT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close correlation to plasma concentrations in children. The correlation between anti-Xa to plasma concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa values as compared to the corresponding plasma concentrations may occur. There is no need for routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti-Factor Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasma concentrations in children). The lower limit of quantifications must be considered when the anti-Xa test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or safety events has been established.\nClinical efficacy and safety\nThe rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.\nIn the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban 20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or to warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment was 19 months and overall treatment duration was up to 41 months.\n34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class III antiarrhythmic including amiodarone.\nRivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79; 95% CI, 0.66 - 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% per year) (HR 0.88; 95% CI, 0.74 - 1.03; P<0.001 for non-inferiority; P=0.117 for superiority). Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 4.\nAmong patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ratio (HR) with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).\nThe incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding events) were similar for both treatment groups (see Table 5).\nTable 4: Efficacy results from phase III ROCKET AF\nITT analyses of efficacy in patients with non-valvular atrial fibrillation\nTreatment dose\nRivaroxaban 20 mg once daily\n(15 mg once daily in patients with moderate renal impairment)\nEvent rate (100 pt-yr)\nWarfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0)\np-value, test for superiority\nStroke and non-CNS systemic embolism\n0.88 (0.74 - 1.03)\nStroke, non-CNS systemic embolism and vascular death\nStroke, non-CNS systemic embolism, vascular death and myocardial infarction\nNon-CNS systemic embolism\nTable 5: Safety results from phase III ROCKET AF\nPatients with non-valvular atrial fibrillationa)\nMajor and non-major clinically relevant bleeding events\nMajor bleeding events\nDeath due to bleeding*\nCritical organ bleeding*\nIntracranial haemorrhage*\nHaemoglobin drop*\nTransfusion of 2 or more units of packed red blood cells or whole blood*\nNon-major clinically relevant bleeding events\nAll-cause mortality\na) Safety population, on treatment\n* Nominally significant\nIn addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorisation, non-interventional, open-label cohort study (XANTUS) with central outcome adjudication including thromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) systemic embolism in clinical practice. The mean CHADS2 and HAS-BLED scores were both 2.0 in XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET AF, respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in 0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS systemic embolism was recorded in 0.8 per 100 patient years.\nThese observations in clinical practice are consistent with the established safety profile in this indication.\nA prospective, randomised, open-label, multicentre, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemic embolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n = 978) and 5 (1.0%) patients in the VKA group (n = 492; RR 0.50; 95% CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.\nA randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patients with non-valvular atrial fibrillation who underwent PCI with stent placement for primary atherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen. Patients were randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history of stroke or TIA were excluded.\nGroup 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinine clearance 30 - 49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low-dose acetylsalicylic acid [ASA]) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for subjects with creatinine clearance 30 - 49 ml/min) once daily plus low-dose ASA. Group 3 received dose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low-dose ASA.\nThe primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7%), 117 (16.6%), and 167 (24.0%) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI 0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint (composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) subjects in the group 1, group 2 and group 3, respectively. Each of the rivaroxaban regimens showed a significant reduction in clinically significant bleeding events compared to the VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCI with stent placement.\nThe primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (including thromboembolic events) in this population are limited.\nTreatment of DVT, PE and prevention of recurrent DVT and PE\nThe rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the initial and continued treatment of acute DVT and PE and prevention of recurrence.\nOver 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooled analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment duration in all studies was up to 21 months.\nIn Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.\nFor the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This was followed by 20 mg rivaroxaban once daily.\nIn Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.\nFor the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. This was followed by 20 mg rivaroxaban once daily.\nIn both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until the PT/INR was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonist dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.\nIn Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.\nEinstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent DVT, non-fatal PE and all-cause mortality.\nIn Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12 months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed anticoagulation were excluded from the study. The treatment duration was up to 12 months depending on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and Rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.\nThe primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE.\nIn the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); HR: 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a HR of 0.67 ((95% CI: 0.47 - 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).\nThe incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) as well as the secondary safety outcome (major bleeding events) were similar for both treatment groups.\nTable 6: Efficacy and safety results from phase III Einstein DVT\n3,449 patients with symptomatic acute deep vein thrombosis\nTreatment dose and duration\nRivaroxaban a)\n3, 6 or 12 months\nN=1,731\nEnoxaparin/VKAb)\nSymptomatic recurrent VTE*\nSymptomatic recurrent PE\nSymptomatic recurrent DVT\nSymptomatic PE and DVT\nFatal PE/death where PE cannot be ruled out\nMajor or clinically relevant non-major bleeding\na) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily\nb) Enoxaparin for at least 5 days, overlapped with and followed by VKA\n* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076 (superiority)\nIn the Einstein PE study (see Table 7) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 (0.749 - 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484).\nThe incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789).\nTable 7: Efficacy and safety results from phase III Einstein PE\n4,832 patients with an acute symptomatic PE\n(<0.1%)\n* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 - 1.684)\nA prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see Table 8).\nTable 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein PE\n8,281 patients with an acute symptomatic DVT or PE\n* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 - 1.186)\nThe prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 - 0.967), nominal p value p = 0.0244).\nIn the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary and secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.\nTable 9: Efficacy and safety results from phase III Einstein Extension\n1,197 patients continued treatment and prevention of recurrent venous thromboembolism\n6 or 12 months\nN=602\nClinically relevant non-major bleeding\na) Rivaroxaban 20 mg once daily\n* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393)\nIn the Einstein Choice study (see Table 10) rivaroxaban 20 mg and 10 mg were both superior to 100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid.\nTable 10: Efficacy and safety results from phase III Einstein Choice\n3,396 patients continued prevention of recurrent venous thromboembolism\nASA 100 mg once daily\nTreatment duration median [interquartile range]\n349 [189-362] days\nSymptomatic recurrent VTE\n(1.5%)*\n(1.2%)**\nSymptomatic recurrent VTE, MI, stroke, or non-CNS systemic embolism\nSymptomatic recurrent VTE or major bleeding (net clinical benefit)\n(2.1%)+\n(1.5%)++\n* p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20-0.59)\n** p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14-0.47)\n+ Rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.44 (0.27-0.71), p=0.0009 (nominal)\n++ Rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.32 (0.18-0.55), p<0.0001 (nominal)\nIn addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.\nThese results in clinical practice are consistent with the established safety profile in this indication.\nTreatment of VTE and prevention of VTE recurrence in paediatric patients\nA total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).\nThe EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE. There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 to < 6 years, and 54 children aged < 2 years.\nIndex VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis (CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 84/165 patients in the comparator group). The most common presentation of index thrombosis in children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged < 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban group and 9 patients in comparator group).\nVTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) children.\nPatients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months (for children <2 years with CVC-VTE up to 3 months) in total.\nThe primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and safety outcomes were centrally adjudicated by an independent committee blinded for treatment allocation. The efficacy and safety results are shown in Tables 11 and 12 below.\nRecurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients (3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 43 of 165 patients in the comparator group. These findings were generally similar among age groups. There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 45 (27.8%) children in the comparator group.\nTable 11: Efficacy results at the end of the main treatment period\nN=335*\nRecurrent VTE (primary efficacy outcome)\n(1.2%, 95% CI 0.4% – 3.0%)\n(3.0%, 95% CI 1.2% - 6.6%)\nComposite: Symptomatic recurrent VTE + asymptomatic deterioration on repeat imaging\nComposite: Symptomatic recurrent VTE + asymptomatic deterioration + no change on repeat imaging\n(11.5%, 95% CI 7.3% – 17.4%)\nNormalisation on repeat imaging\n(38.2%, 95% CI 33.0% - 43.5%)\nComposite: Symptomatic recurrent VTE + major bleeding (net clinical benefit)\nFatal or non-fatal pulmonary embolism\n* FAS= full analysis set, all children who were randomised\nTable 12: Safety results at the end of the main treatment period\nComposite: Major bleeding + CRNMB (primary safety outcome)\nMajor bleeding\nAny treatment-emergent bleedings\n* SAF = safety analysis set, all children who were randomised and received at least 1 dose of study medicinal product\nThe efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE population and the DVT/PE adult population, however, the proportion of subjects with any bleeding was higher in the paediatric VTE population as compared to the DVT/PE adult population.\nPatients with high risk triple positive antiphospholipid syndrome\nIn an investigator sponsored, randomised open-label multicentre study with blinded endpoint adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2 patients (3%) of the warfarin group.\nThe European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see section 4.2 for information on paediatric use).\nThe following information is based on the data obtained in adults.\nRivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake.\nOral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.\nDue to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg are to be taken with food (see section 4.2).\nRivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose.\nVariability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.\nAbsorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.\nBioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.\nChildren received rivaroxaban tablet or oral suspension during or closely after feeding or food intake and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is readily absorbed after oral administration as tablet or granules for oral suspension formulation in children. No difference in the absorption rate nor in the extent of absorption between the tablet and granules for oral suspension formulation was observed. No PK data following intravenous administration to children are available so that the absolute bioavailability of rivaroxaban in children is unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was found, suggesting absorption limitations for higher doses, even when taken together with food.\nRivaroxaban 20 mg tablets should be taken with feeding or with food (see section 4.2).\nPlasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.\nNo data on rivaroxaban plasma protein binding specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. Vss estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 113 L for a subject with a body weight of 82.8 kg.\nBiotransformation and elimination\nIn adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.\nRivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).\nUnchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.\nNo metabolism data specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. CL estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 8 L/h for a subject with body weight of 82.8 kg. The geometric mean values for disposition half-lives (t1/2) estimated via population PK modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, respectively.\nIn adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients. An exploratory analysis did not reveal relevant differences in rivaroxaban exposure between male and female children.\nElderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.\nDifferent weight categories\nIn adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%). No dose adjustment is necessary.\nIn children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal a relevant impact of underweight or obesity on rivaroxaban exposure in children.\nInter-ethnic differences\nIn adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.\nAn exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among Japanese, Chinese or Asian children outside Japan and China compared to the respective overall paediatric population.\nCirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.\nThe inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.\nRivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).\nIn adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no data in patients with creatinine clearance < 15 ml/min.\nDue to the high plasma protein binding rivaroxaban is not expected to be dialysable.\nUse is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).\nNo clinical data is available in children 1 year or older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2).\nPharmacokinetic data in patients\nIn patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 32 (6 - 239) mcg/l, respectively.\nIn paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum concentrations during the dose interval are summarised in Table 13.\nTable 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state plasma concentrations (mcg/L) by dosing regimen and age\nTime intervals\n12 -< 18 years\n6 -< 12 years\n2.5-4h post\n(105-484)\n(91.5-777)\n20-24h post\n(5.69-66.5)\nb.i.d.\n2 -< 6 years\n0.5 -< 2 years\n(0.25-127)\n(n.c.-n.c.)\nt.i.d.\nBirth -< 2 years\nBirth -< 0.5 years\n7-8h post\n(18.7-99.7)\no.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated\nValues below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation of statistics (LLOQ = 0.5 mcg/L).\nPharmacokinetic/pharmacodynamic relationship\nThe pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.\nSafety and efficacy have not been established in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.\nNon-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile toxicity.\nEffects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant exposure levels.\nIn rats, no effects on male or female fertility were seen. Animal studies have shown reproductive toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, hepatic multiple light coloured spots) and an increased incidence of common malformations as well as placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.\nRivaroxaban was tested in juvenile rats up to 3-month treatment duration starting at postnatal day 4 showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specific toxicity was seen.\nTablet core\nCroscarmellose sodium\nHypromellose (2910)\nSodium laurilsulfate\nFilm-coat\nMacrogol (3350)\nTitanium dioxide (E 171)\nIron oxide red (E 172)\nCrushed tablets\nCrushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours.\nThis medicinal product does not require any special storage conditions.\nCartons containing 10, 14, 28 or 98 film-coated tablets in PP/Alu foil blisters.\nCartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.\nMultipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose blisters.\nCartons containing 14 film-coated tablets in PVC/PVDC/Alu foil blisters .\nHDPE bottles with a PP screw cap containing 100 film-coated tablets.\nAny unused medicinal product or waste material should be disposed of in accordance with local requirements.\nRivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can result in reduced absorption and thereby, reduced active substance exposure. After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.\nBayer plc, 400 South Oak Way, Reading, RG2 6AD\nPLGB 00010/0709\nBayer plc\n400 South Oak Way, Reading, Berkshire, RG2 6AD\nhttp://www.bayer.co.uk"

"Roche today announced that the EU Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Hemlibra (emicizumab) for routine prophylaxis of bleeding episodes in adults and children with severe haemophilia A (congenital factor VIII deficiency, FVIII <1%) without factor VIII inhibitors. The CHMP has also recommended that Hemlibra can be used at multiple dosing options (once weekly, every two weeks, or every four weeks) for all indicated people with haemophilia A, including those with factor VIII inhibitors.\nThe positive CHMP opinion is based on results from the pivotal HAVEN 3 and HAVEN 4 studies. In the HAVEN 3 study in people with haemophilia A without factor VIII inhibitors, Hemlibra prophylaxis led to statistically significant and clinically meaningful reductions in treated bleeds compared to no prophylaxis, and compared to prior treatment with factor VIII prophylaxis in a prospective intra-patient comparison. In the HAVEN 4 study in people with haemophilia A with and without factor VIII inhibitors, Hemlibra showed a clinically meaningful control of bleeding when dosed every four weeks. Based on this opinion, a final decision regarding the approval of Hemlibra for people without factor VIII inhibitors is expected from the European Commission in the near future.\nIn the phase III HAVEN 3 study, adults and adolescents aged 12 years or older with haemophilia A without factor VIII inhibitors who received Hemlibra prophylaxis once weekly (n=36) or every two weeks (n=35) experienced a 96% (rate ratio [RR]=0.04; p<0.0001) and 97% (RR= 0.03; p<0.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis (n=18). Hemlibra is the first medicine to significantly reduce treated bleeds compared to prior factor VIII prophylaxis, the standard of care for people with haemophilia A without factor VIII inhibitors, as demonstrated by a statistically significant reduction of 68% (RR=0.32; p<0.0001) in treated bleeds in an intra-patient comparison (n=48) of people who previously received factor VIII prophylaxis in a prospective non-interventional study and switched to Hemlibra prophylaxis.\nIn the single-arm phase III HAVEN 4 study, Hemlibra prophylaxis every four weeks led to clinically meaningful control of bleeding in adults and adolescents aged 12 years or older with haemophilia A with factor VIII inhibitors (n=5) and without factor VIII inhibitors (n=36).\nThe most common adverse reactions occurring in 10% or more of people treated with Hemlibra in pooled studies (n=373) were injection site reactions (20%), joint pain (arthralgia; 15%) and headache (14%).\nOn 4 October 2018, Hemlibra was approved by the US Food and Drug Administration (FDA) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children, ages newborn and older, with haemophilia A without factor VIII inhibitors, following Priority Review. Hemlibra was also previously granted Breakthrough Therapy Designation by the FDA for haemophilia A without factor VIII inhibitors. Priority Review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a serious disease. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat a serious condition with preliminary evidence that indicates they may demonstrate substantial improvement over existing therapies. Submissions to other regulatory authorities around the world are ongoing.\nHemlibra has been approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people with haemophilia A with factor VIII inhibitors in over 50 countries worldwide, including the US in November 2017, EU member states in February 2018 and Japan in March 2018. It has been studied in one of the largest pivotal clinical trial programmes in people with haemophilia A with and without factor VIII inhibitors, including four phase III studies (HAVEN 1, HAVEN 2, HAVEN 3 and HAVEN 4).\nHAVEN 3 is a randomised, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics of Hemlibra prophylaxis versus no prophylaxis (episodic/on-demand factor VIII treatment) in people with haemophilia A without factor VIII inhibitors. The study included 152 patients with haemophilia A (12 years of age or older) who were previously treated with factor VIII therapy either on-demand or as prophylaxis. Patients previously treated with on-demand factor VIII were randomised in a 2:2:1 fashion to receive subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 1.5 mg/kg/wk for at least 24 weeks (Arm A), subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 3 mg/kg/2wks (Arm B) for at least 24 weeks or no prophylaxis (Arm C) for at least 24 weeks.\nPatients previously treated with factor VIII prophylaxis received subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 1.5 mg/kg/wk until the end of study (Arm D). Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.\nHemlibra prophylaxis every week or every two weeks resulted in a 96% (RR=0.04; p<0.0001) and 97% (RR= 0.03; p<0.0001) reduction in treated bleeds, respectively, compared to no prophylaxis.\n55.6% (95% CI: 38.1, 72.1) of people treated with Hemlibra every week and 60% (95% CI: 42.1, 76.1) of people treated with Hemlibra every two weeks experienced zero treated bleeds, compared to 0% (95% CI: 0.0; 18.5) of people treated with no prophylaxis.\nHemlibra prophylaxis every week or every two weeks resulted in a 95% (RR=0.05; p<0.0001) and 95% (RR=0.05; p<0.0001) reduction in treated target joint bleeds, respectively, compared to no prophylaxis.\nHemlibra prophylaxis every week or every two weeks resulted in a 95% (RR=0.05; p<0.0001) and 94% (RR=0.06; p<0.0001) reduction in all bleeds, respectively, compared to no prophylaxis.\nHemlibra prophylaxis every week demonstrated a statistically significant reduction of 68% (RR=0.32; p<0.0001) in treated bleeds compared to prior factor VIII prophylaxis based on an intra-patient comparison of people who were previously enrolled in a prospective non-interventional study.\nIn pooled data from the phase III HAVEN programme (n=373), the most common adverse reactions occurring in 10% or more of people treated with Hemlibra were injection site reactions (20%), joint pain (arthralgia; 15%) and headache (14%).\nHAVEN 4 is a single-arm, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics (PK) of subcutaneous administration of Hemlibra dosed every four weeks. The study included 48 patients (12 years of age or older) with haemophilia A with or without factor VIII inhibitors who were previously treated with either factor VIII or bypassing agents, on-demand or as prophylaxis. The study was conducted in two parts: a PK run-in and an expansion cohort. All patients in the PK run-in (n=7) were previously treated on-demand and received subcutaneous Hemlibra at 6 mg/kg to fully characterise the PK profile after a single dose during four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Patients in the expansion cohort (n=41), patients with haemophilia A with factor VIII inhibitors (n=5) and without factor VIII inhibitors (n=36), received subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Episodic treatment of breakthrough bleeds with factor VIII therapy or bypassing agents, depending on a patient's factor VIII inhibitor status, was allowed per study protocol.\nIn the HAVEN 4 study, 56.1% (95% CI: 39.7; 71.5) of people with or without factor VIII inhibitors treated with Hemlibra prophylaxis every four weeks experienced zero treated bleeds.\nHaemophilia A is an inherited, serious disorder in which a person's blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Haemophilia A affects around 320,000 people worldwide,[1, 2] approximately 50-60% of whom have a severe form of the disorder. People with haemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with haemophilia A can bleed frequently, especially into their joints or muscles. These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility, and long-term joint damage. A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body's immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible to obtain a level of factor VIII sufficient to control bleeding."

"EU Panel Backs Damoctocog Alfa Pegol for Hemophilia A\nEU Panel Backs Damoctocog Alfa…\nThe Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) voted to recommend damoctocog alfa pegol (Jivi, Bayer AG) for the treatment and prophylaxis of bleeding in patients aged 12 years and older who have been previously treated for hemophilia A, a congenital factor VIII deficiency.\nJivi will be available as powder and solvent for solution for injection (250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU). The active substance of Jivi is damoctocog alfa pegol, a recombinant human factor VIII (ATC code: B02BD02), which replaces the missing coagulation factor VIII needed for effective hemostasis.\nThe benefits with Jivi are its ability to prevent and control bleeding when used on demand and during surgical procedures, as seen in clinical trials in adult and pediatric patients with hemophilia A.\nThe most common side effects are hypersensitivity, insomnia, headache, dizziness, cough, abdominal pain, nausea, vomiting, erythema, rash, infusion site reactions, and pyrexia.\nThe full indication is: \"Treatment and prophylaxis of bleeding in previously treated patients ≥ 12 years of age with hemophilia A (congenital factor VIII deficiency).\" It is proposed that Jivi is prescribed by physicians experienced in the treatment of hemophilia.\nThe European Commission granted orphan medicinal product designation to damoctocog alfa pegol on February 23, 2011. Damoctocog alfa pegol is a recombinant human factor VIII, which replaces the missing coagulation factor VIII necessary to stop bleeding. It will be marketed as powder and solvent for an injectable solution (250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU).\nThe US Food and Drug Administration (FDA) approved damoctocog alfa pegol for the same indication on August 30, 2018. \"The initial recommended prophylactic regimen for Jivi is twice weekly with the ability to dose every 5 days and further individually adjust to less or more frequent dosing based on bleeding episodes,\" Bayer said.\n\"The FDA also approved Jivi for on-demand treatment and the perioperative management of bleeding in the same population,\" Bayer said in its news release about the FDA approval.\nHemophilia A\nAccording to the EMA summary of opinion, clinical trials that showed damoctocog alfa pegol prevented and controlled bleeding \"when used on demand and during surgical procedures\" in adults and children with hemophilia A.\nThe most frequently seen adverse effects are hypersensitivity, insomnia, headache, dizziness, cough, abdominal pain, nausea, vomiting, skin redness, rash, infusion site reactions, and fever. Only physicians experienced in treating hemophilia should prescribe damoctocog alfa pegol, according to the EMA.\nThe summary of product characteristics will include detailed recommendations for the use of the product and will be published in the European public assessment report, which will be made available in all official European Union languages after the European Commission grants the marketing authorization.\nPreviousPrevious post:Combination Therapy of Prostatectomy Plus RadiotherapyNextNext post:Blood Test Predicts The Time Of Internal Body Clock"

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"RussianPatents.com\nNew! → US patents search\nThe method of producing sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone from acridone\nC07D219/06 - Oxygen atoms\nA61P31/12 - Antivirals\nA61K31/473 -\n(57) Abstract:\nThe invention relates to an improved method for obtaining 10-methylanthracene-9-acridone or 10-metrocable-9-acridone intended for the synthesis of drug substances or preparation of dosage forms (sodium 10-methylanthracene-9-acridone) used in medical and veterinary practice as antiviral agents. Offered technologically acceptable method of obtaining sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone by alkylation of acridine ethylparathion in the presence of carbonates of sodium or potassium in conditions allowing to obtain technical ester 10-metrocable-9-acridone with high yield and high content of basic substance, and translate it by alkaline hydrolysis and separation of the original product in the target products of high purity. The technical result consists in increasing the yield and purity of the target product. 9 C.p. f-crystals, 1 table.\nThe present invention relates to chemistry acridone, in particular, to an improved method for the synthesis of sodium 10-methylanthracene-9-acridone and 10-metrocable-9-acridone, the General formula\n< / BR>\nwhere R = Na, (I is prigotovleniya dosage forms, salt (I) is used in medical and veterinary practice as antiviral agents: the inducer of interferon has antiviral activity against both DNA-and RNA-containing viruses that due to its ability to dramatically stimulate the formation of interferon. Proposed as an anti-plague funds for animals (Patent 2031650, the Russian Federation, 1995, Szule And B. at al.//Arch. Immun. Therapie.. 1985. Vol. 33. P. 287-297).\nAll known methods of obtaining products (I, Ia) based on alkaline hydrolysis of the ester 10-metrocable-9-acridone (II) when they are processed with caustic soda or sodium alcoholate in the alcohol and subsequent selection of salt (I) as the target product or the acidification of its solution with acid secretion (Ia). Because the last stage is the selection of the acid (Ia) is quite simple, the decisive stages of the chain are getting ether (II) and its hydrolysis with the formation of the salt (I).\nEther (II) is usually synthesized in the alkylation of 10-methoxyacridine [Lyakhov S. A. at al.//Pharmazie. 1994. Vol. 45. N 5. P. 367-3683] or alkaline salts acridone (III) esters of chloro - or bromoxynil acid, using in the case of acridone the overall scheme of [U.S. Pat. 3681360. USA, 1972, Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Patent 2033413. The Russian Federation, 1995, Inglot F. D. et al. //Arch. Immun. Therapie E1977. Bd. 319. N 2. S. 347-352. Patent 2029764. Of the Russian Federation. 1995].\nThe method of obtaining the product (I) through 9-methoxyacridine is heated (120oC) last methylbromide in nitrobenzene. In this embodiment, instead of substitution in position 10 with the formation of O-methylated analogue ether (II) took place N9-alkylation by heteroatom cycle with the formation of the intermediate Quaternary salt, which upon basic hydrolysis with sodium methylate in methanol gave the target salt (I) /60%/ [S. A. Lyakhov, etc. // Pharmazie. 1994. Vol. 45. N 5. P. 367-3683], this method is not practically feasible due to inaccessible 9-ethoxyaniline and use of nitrobenzene, sodium methylate and methanol.\nMore promising in terms of technology, the methods based on the alkylation of acridine (III) acylhalogenides when heated in a solvent in the presence of bases.\nThe method of obtaining the target salt (I) of the ester (II) is described in [Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Inglot F. D. etc. // Arch. Immun. Therapie.. 1985. Vol. 33. P. 275-285. Patent 2029764. Of the Russian Federation. 1995] . In the last two papers of the previous stage - alkylation, is not considered at all, although, as experience shows, it is the quality of the product of this stage determines the way of its transformation into zelenoy acid with the release of >90%.\nMethods of synthesis of salt (I) on the basis of the ether (II) [//J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352 7] close: a hot solution of ester (II) in absolute alcohol is treated with excess concentrated aqueous solution of caustic soda, the output of technical substance 85%, recrystallized from a mixture of DMF/methanol - 70%.\nThe disadvantages of this method:\n1) the use of absolute ethanol in a large number of /on 1 g of salt (I) to 35 ml/.\n2) the need to use purified ether, free from acridone as the last in the accepted conditions of alkaline hydrolysis go into target products (I, Ia) almost completely;\n3) low yield of purified substances.\nThe Way [The Patent 2029764. Of the Russian Federation. 1995] uses alkaline hydrolysis of the ester (II) by boiling the latter in aqueous alkali, which is easier and more economical, but the authors make use of the catalysts, porous aluminosilicates (zeolites, molecular sieves with pore size 3-9 (A); target salt (I) after evaporation of the filtered solution discharges acetone, yield >90%. 10-Metrocable-9-acridone (Ia), if necessary, isolated by acidification neuverennogo solution of salt (I) dilute hydrochloric acid.\nThe disadvantages of this option:\n1) primesearchteam synthesis of regeneration or recycling of the catalyst;\n3) synthesis of ester (II) in the patent is not considered, but it is assumed the application of the product to be of high quality (so pl. 176-178oC); the transformation of a technical product, the content of acridone which significantly above 2% for this option is not available; note that even in the case of a positive return unreacted acridone in the cycle will be problematic and, as a minimum, will require the development of methods of separation from the catalyst. Pre-target - synthesis of ester (II), considered by the same authors separately in the patent [Patent 2033413. Of the Russian Federation. 1995].\nHere esters 10-metrocable-9-acridone received by boiling acridone with esters of monochloracetic acid in the environment dimethylacetamide (DMAA) in the presence of phase transfer catalyst (Quaternary ammonium salt), and the use of only 0.5 to 4 equivalents of anhydrous carbonate of an alkali metal. Pre-mix acridone, carbonate and catalyst were heated (165oC) followed by distillation of part of the solvent, and then spent the dosage of ethylchloride and gave an extract by boiling; the reaction mass is cooled to 60-70oC, poured into water with ice, fallen target product was washed on the had been no higher than 2%, he did not require, according to the authors, additional cleaning, and its output was 82-88%.\nThe disadvantages of this method include:\n1) introduction preliminary boiling of the base and catalyst in a solvent and distillation 1/3 DMAA; this is an additional operation that ethnologica, with the safety of the catalyst at this stage dubious;\n2) use very harsh reaction conditions, in particular high-temperature synthesis 165oC, which requires extra energy, but most importantly, promotes the decomposition of metastability catalyst and ethylchloride and leads to partial resinification mass. It should be noted that in other cases the alkylation of acridine other alkylating agents when using potassium carbonate was carried out under relatively mild conditions by introducing Quaternary ammonium salts; in this case, however, with the introduction of the catalyst applied unreasonably harsh conditions of alkylation - DMF changed to the higher boiling DMAA, and the reaction is carried out at boiling last (165oC);\n3) use very high for technological purposes in the concentration of reagents (1.43 g of reagent to 1 ml of the solvent at the start, more than 0.7 g of the target ester in 1 ml of DMAA s of acridone (or its salt) in a small amount of solvent at the start, but it is important for faster and target consumption, metastabile at such high temperatures of ethylchloride; b/ reaction mass is mixed and difficult very quickly thickens when cooled, making it drain even when 70oC; this leads to significant mechanical losses at the end of the synthesis;\n4) the low quality of ether (II); and the product is very dark, due to the high concentration reagent and the extremely high (165oC, boiling DMAA) the reaction temperature at that are used insufficiently thermally stable catalyst and ethylchloride; the resulting product requires repeated cleaning with the use of activated carbon.y.), that leads to more and greater losses; washing the product on the filter with ethanol, as proposed in the patent, does not give a significant increase quality, but leads to a considerable drop in output; b/ ether includes an appreciable amount of unreacted acridone when technical product 85%, it contains more than 10% of acridone (1. TLC; 2. hydrolysis of the alkali in the water 58% salt (I). UV spectroscopy); the output from acridone in terms of the target substance when it is less than 50%;\n5) the number of soda, introduced in the synthesis of ester (II) in particular PTSA.\nA prototype of the proposed solution is the synthesis of the sodium salt of 10-metallocarborane-9-acridone (I) and 10-metrocable-9-acridone (Ia) from acridone (III) through the ether (II) [. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352].\nIn this embodiment, the synthesis of salt (I) was carried out at alkylation of acridine (III) ethylparathion boiling reagents in DMF and the use of KOH as base, with subsequent transfer of the resulting ester (II) in the target product (I) in the processing of his warm solution in absolute alcohol conc. the alkali solution; Sol (I) stood out, was dissolved in water, and its solution upon acidification gave the acid (Ia); however, in the synthesis of ester (II):\n1) pre-prepared K-salt acridone in DMF (10 minutes in boiling DMF of acridone with a 2.5-fold amount of KOH, followed by distillation of the water in the form of its azeotrope with DMF);\n2) to a cooled suspension of salt was dotirovala ethylchloride, the reaction mass was heated to the boil, boiled 20 min, poured into ice water, the product was filtered off;\n3) after drying, the residue was twice extracted with chloroform, after evaporation which received technical ether with a yield of 79% (product quality not assessed); most likely it is the introduction of this time-consuming operation pozvoliali of alcohol with very high so pl. (182.5-183oC); at the stage of synthesis of the target product (I): received broadcast (II) was dissolved in absolute alcohol and treated with a concentrated solution of alkali; to obtain the product (Ia) Sol (I) was dissolved in water and acidified with 5% HCl.\nThe disadvantages of the method include:\n1. the use of KOH under alkylation, leading to the formation of water during the synthesis of K-salts acridone, the removal of which is necessary and is accomplished by distillation in the form of its azeotrope with DMF; controlled distillation of part of the solvent - reception, significantly complicating technology; used in the synthesis of 2.5 times the amount of alkali - its large surplus remaining in the reaction mass, inevitably causing adverse reactions: the conversion of ethylchloride and ether (II) into the corresponding salt (RCOOOEt + KOJ ---> RCOOK + EtOH), which contaminates the product of this stage /ether (II)/ and reduces its output; when testing option marked foaming of the reaction mixture with a threat of release, the development side of the process, and impurities due to the use of KOH, complicated isolation and purification of the ester (II), which dramatically reduced its output (about 50%);\n2. a noticeable admixture of acridone technical ester (II) 30%;\n3. introduction to advanced operations - extraction is here applied only purified ether (II) when translating it into the target salt (I) and then acid (Ia);\n5. the use of absolute alcohol at high module on the operation of the hydrolysis of ester (II) in the target salt (I).\nAll this makes the technology is complex, time consuming and ineffective.\n1. received the prototype for the alkylation of acridine technical ester (II) is not useful to translate it into the target products (I, Ia) according to the method proposed in the prototype; therefore, it requires treatment with chloroform, and then repeated crystallization obtained after distillation of the chloroform the product with the corresponding loss in yield, and the high cost of solvents and their regeneration;\n2. the proposed option of alkaline hydrolysis in alcohol consuming absolute alcohol, and therefore, its regeneration, but it does not solve the problem of application of the technical product (II) to obtain the target substance (I, Ia).\nAs follows from the above, the defining stage of the multistep synthesis of compounds (I, Ia) from acridone (III) is receiving ether (II), the quality of which determines the yield and purity of Pharmacopoeia drugs (I, Ia). Despite the seeming simplicity of the scheme of application accepted for NH-acids options - alkylation of acrida ether - all these methods have drawbacks: they are not always feasible and the results are often difficult reproducible (first of all, it concerns the quality of the intermediate product (II)).\nThe task to be solved by the invention is to remedy these disadvantages and to develop technologically acceptable method of obtaining sodium salt of 10-metrocable-9-acridone (I) or a 10-metrocable-9-acridone (Ia) from acridone (III) to synthesize the target drugs (I, Ia) Pharmacopoeia purity with high yield.\nThe task can be solved with:\n1) finalization phase alkylation of acridine to ensure a high yield (>90%) technical ester (II) with a low content of acridone (not >10%);\n2) develop ways of translating technical ester (II) sodium salt of 10-metrocable-9-acridone for removing residual acridone from it and the synthesis of the target drugs (I, Ia) high quality.\nThe essence of the decision is that\nat the stage of alkylation of acridine ethylparathion in DMF is proposed to use the carbonates of potassium or sodium, conducting the process with a ratio of acridan-DMF and the temperature of the dosage of these is isharesoft at a temperature of 100-130oC), and using the reagents, the ratio of acridan:carbonate:ethylchloride = 1:2-3:2-3 (mol), followed by exposure at temperatures below the boiling point of DMF (130-140oC) and the allocation of broadcast 10-metrocable-9-acridone in the usual way;\nat the stage of alkaline hydrolysis of the resulting ester 10-metrocable-9-acridone (II) is proposed to handle technical ether aqueous alkali and separating the resulting solution of the target sodium salt from unreacted acridone, for example, be filtered; the filtrate is a solution of the target product, further processed sorbent, such as activated carbon, followed by filtration, the filtrate is proposed to be used for preparation of aqueous solutions of the desired product, the desired concentration (and in this form it is used as a substance in the drug [1]), and on its basis:\na/ to obtain sodium 10-methylanthracene-9-acridone in crystalline form by adding alcohols (ethyl, isopropyl) to its concentrated aqueous solution;\nb/ extract the 10-methylanthracene-9-acridone upon acidification with mineral acid.\nThe proposed solution when SUB>):\nand/ carbonate, in particular potassium carbonate, unlike KOH, in the formation of salts acridone and its alkylation turns into MeHCO3and MeCl (KHCO3, KCl), i.e., does not produce water, and the stage of the azeotropic distillation of water with the solvent is removed altogether;\nb/ potassium carbonate is a good drying agent, and the application of its surplus (III: K2CO3= 1:2-3) provides the removal of water, the introduction of which is possible with the original products or solvent.\nAt the same time, the use of even a large excess of potassium carbonate in the absence of water does not cause unlike KOH intensive translation available in the reaction mixture of the target and alkylating esters in salt even when a prolonged stay in a high temperature environment (salt at the final stage in the application of KOH certainly go with the spent aqueous solvent, but it will significantly affect the output stage alkylation).\nT. O. application of potassium carbonate in excess provides a synthesis of K-salts acridone, removing the moisture binding HCl and provides the reduced alkalinity of the environment and, consequently, the degree of transmission of adverse reactions, which together leads to increase in the yield and purity of products alkilirovan is ethylchloride at elevated temperature (up to 37oC) and the application of its surplus (III: ClCH2COOEt = 1:2-3) achieved the highest salt concentration of acridine in solution by the time the dosage that provides fast flow metastabile at an elevated temperature of ethylchloride mainly on the target direction and almost for the time, with no need for prolonged boiling of the reaction mixture, which usually leads to its partial resinification; but the introduction of the phase transfer catalyst does not accelerate or increase in the yield or quality of the broadcast.\nThese techniques provide a fast and high conversion acridone in ether (II), and therefore, its high output and sufficient purity of the technical product (yield ether (II) >90%, the content of acridone (III) it is <10%).\nHence it is necessary to work out the conditions of hydrolysis technical ester, which provides separation of acridone and education pure sodium salt.\nWhen spirit and alkaline hydrolysis technical ester (II) acridan (III) enters the target salt actually completely. And this stage should provide Pharmacopoeia purity of the target drugs. Therefore alcoholic version of the hydrolysis of the prototype is not acceptable for technical aired at all.\nAcridan, as it turned out, noticeably soluble in alcohol and practically insoluble in aqueous alkali.\nIn this decision, the Department of acridone are encouraged to migrate to the stage of hydrolysis of the ester, holding the latter in an aqueous-alkaline medium: process ether aqueous alkali or soda when heated and filter unreacted acridan, and the resulting filtrate or acidified with filtration of the precipitated target acid (Ia), or to reach the desired concentration of salt in the water, or give the target product (I) in crystalline form.\nIt is proposed conditions for the stages of the alkylation and hydrolysis of the complex allow you to use Si and remaining technical broadcast acridan, to clean an aqueous solution of sodium salt sorbent, to exclude the application of absolute alcohol, to reduce the amount of solvent in the cleaning operations, and selection and get clean target drugs with high output.\nFor a better understanding of the essence of the present invention is an example of its specific implementation.\nExample 1. Synthesis of ethyl ether 10 metrocable-9-acridone (II). To 150-180 ml DMF sprinkled 15 g (0.077 mol) of acridone (III) and 21-32 g (0.154-0.231 mol) of potassium carbonate (or 0.154-0.231 mol soda), the mixture is heated with stirring to boiling, boil for 15-20 minutes, cool and add 16-24 ml (0.15-0.23 mol) of ethylchloride so that the temperature in the reactor was maintained at the level 100-130oC. after dosing the reaction mass is maintained at 130-140oC for 0.5-1 h and control the content of the original acridone /TLC, the system chloroform:methanol = 95:5). If necessary, give additional exposure. The reaction mass is then cooled, poured with stirring into water, the precipitated product is filtered and washed on the filter with water. On stage alkaline hydrolysis product arrives without purification.\nSynthesis of sodium salt of 10-metrocable-9-acridone (I).\nthe stage maintained at 95-100oC 0.5-1 h, cooled, filtered unreacted acridan and washed it with distilled water. After drying, acridan return to the stage alkylation. The resulting filtrate is treated with activated carbon.W.) when heated, cooled, and filtered from.. and washed on the filter with distilled water; the resulting filtrate is A solution of the desired product (I) in water; output 90-94% (UV-spectroscopy filtrate); if necessary, clean up operation.. I repeat; the solution is evaporated under vacuum, fending off the main part of water to the residue add the alcohol, the resulting suspension is brought to a boil, soak in boiling 0.5 h, filtered and leave the filtrate to crystallize. The precipitated product is filtered off, washed on the filter with alcohol and dried; the yield of the product (I) 90-94% (including residual product in the mother liquor). Water uterine solvent may be partially recycled to the extraction of salt, the remainder is subject to regeneration. Selection 10-metrocable-9-acridone (Ia). Cooled to 5-10oC the filtrate a solution of salt (I) acidified with 5% sulfuric (hydrochloric) acid to pH 1, then maintained under stirring at this temperature for 0.5 h, the precipitated yellow Timoti the product is crystallized (DMF - water = 1/3); product characteristics identical to those described in [5].\nThe structure and personality of the obtained sodium salt of 10-metrocable-9-acridone confirmed by TLC, elemental analysis, IR and UV spectroscopy.\nUV-spectrum (0.02 R-R in a solution of 0.01 mol/l sodium hydroxide), l, nm, (Ig E): 257 (4.68), 388 (3.88), 407 (3.91);\nIR, cm-1: 760, 940, 1180, 1270, 1290, 1395 (COO-), 1460, 1490, 1595 (COar, COO-), 3020;\nRange of PMR, B., M. D.: 4.83 (CH2, 2H), 7.26-7.68 mm (ArH, 4H), 7.70-7.80 m (2H, 4H, and 5H), 8.30 (2H, J = 8 Hz, 1H and 8H), D2O; NMR C13, B., M. D.: 50.9 (1C), 116.2, 124.4, 122.9, 127.2, 135.9 (12C - aromatics), 175.8, 180.1 (2C - carbonyl),2O + 0.01% dioxane.\nTLC (Silufol UV-254): Rf0.34-0.36 (IPA: ethyl acetate: NH4OH = 59:25:16).\nFound, %: C, 65.12, 65.32; H, 4.01, 3.88; N, 5.23, 5.11\nC15H10NO3Na\nCalculated, %: C, 65.46; H, 3.66; N, 5.09\nSimilarly carried out the alkylation of acridine when the variation of the process parameters with the subsequent transfer of technical product in the target salt according to the above method; the results are shown in the table.\n1. The method of producing sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone by alkylation of acridine ethylparathion in dimethylformamide (DMF) PR is the selection of target products, characterized in that the alkylation is carried out in the presence of potassium carbonate or sodium when the ratio acridan-DMF and temperature dosage ethylchloride providing solubility of acridine using the reactants in a molar ratio acridan : potassium carbonate or sodium : ethylchloride= 1 : 2 - 3 : 2 - 3, followed by exposure at temperatures below the boiling point of DMF, the allocation of technical ester 10-metrocable-9-acridone, processed aqueous alkali, separating the solution of the resulting sodium 10-methylanthracene-9-acridone from acridone and selection of target products.\n2. A way of getting under item 1, characterized in that acridan-DMF used in the ratio of 1 : 10 to 12 (the weight.h. : about.h.).\n3. A way of getting under item 1, characterized in that the dosage of ethylchloride carried out at a temperature of 100 - 130oC.\n4. A way of getting under item 1, characterized in that the exposure is performed at a temperature of 130 - 140oC.\n5. A way of getting under item 1, characterized in that acridan from a solution of sodium 10-methyltyrosine-9-acridone after alkaline hydrolysis is separated by filtration.\n6. A way of getting under item 1, characterized in that a solution of sodium 10-methylanthranilate for PP.1, 6, characterized in that the sodium 10-methylanthracene-9-acridone isolated in the form of an aqueous solution of the desired concentration.\n8. The way of getting PP.1, 6, characterized in that the sodium 10-methylanthracene-9-acridone isolated in crystalline form.\n9. The way of getting PP.1, 7, characterized in that the sodium 10-methylanthracene-9-acridone separated from the concentrated aqueous solution by the addition of alcohol.\n10. The way of getting PP.1, 7, characterized in that 10-metrocable-9-acridone allocate acidification of a solution of its sodium salt.\nSame patents:\nSalts of 1-deoxy-1-n-methyliminodiacetic with n - greenexpo acid having immunomodulatory activity, and the drug based on them // 2135474\nThe invention relates to medicine, namely to synthetic biologically active compounds derived class 1 detoxi-1-N - methylaminoethanol and N-greenexpo acid\nQuinolone and acridinone compounds, methods for their preparation and pharmaceutical composition based on them // 2124006\nThe invention relates to quinolone and acridinium compounds of the formula I or their pharmaceutically acceptable salts, where R2- H, (C1-C6)alkyl (C1-C4)foralkyl; R3IS H, CN, (C1-C6)alkyl, (C1-C6)foralkyl, ethanol or R2and R3form 1,4-butandiol; R4means a group of formula II; R7- H, R8- H, (C1-C4)alkoxy, NO2CN, (C1-C4)foralkyl, halogen, (C1-C4)alkyl; R9- H, halogen, (C1-C4)alkyl or (C1-C4)foralkyl or R8and R9taken together form a (C1-C3)alkylenedioxy; R10and R11- H, (C1-C4)alkyl\nDerivatives of acridine synthesis method, pharmaceutical composition and method of treatment of malignant tumors // 2119482\nSalts of 2-deoxy-2-amino (or 2-methylamino)-d-glucose with n - greenexpo acid having antimicrobial activity // 2093510\nDerivatives tetrahydrouridine, methods for their production (options), derivatives of tetrahydrouridine, derived dihydroisoxazole and pharmaceutical composition exhibiting the ability to ease or eliminate memory dysfunction // 2083564\nThe invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I\nin which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer\nDerivative of 1,8-acridinone, the pharmaceutical composition for relaxation of the bladder, substance, relaxing the bladder, methods of obtaining (options) // 2079492\nThe method of obtaining esters of n-metrocable-9-acridone // 2033413\nThe invention relates to organic chemistry and relates to an improved method of producing esters of N-metrocable-9-acridone different structures that exhibit intense biological properties, for example, are low-molecular inducers of interferons\nThe method of obtaining n-metrocable-9-acridone or its sodium salt // 2029764\nThe invention relates to an improved method for producing N-metrocable-9-acridone and its salts, which are low-molecular inducers of interferons and have immunomodulatory effects\nScopoli and monodisperse water-soluble oligomer, the method of its production, pharmaceutical product, the method of inhibiting the activity of viruses // 2160746\nDerivatives piron and their pharmaceutically acceptable salts, intermediate compounds for their production, pharmaceutical composition with anti-virus and antibacterial activity based on them, the method of treatment caused by rotavirus infection or disease // 2160733\nAntiviral agent and method thereof // 2160105\nThe invention relates to medicine, in particular to pharmacology relates to antiviral agents in the form of solid dosage forms containing acyclovir, microcrystalline cellulose, salt of stearic acid, low molecular weight polyvinylpyrrolidone, and, optionally, a dye in a certain ratio, and method of its production\nAntiviral agent in ointment form-based interferon-alpha-2 // 2159609\nThe invention relates to pharmaceutical industry, production of medicines intended to treat herpes infections of the skin and mucous membranes\nMethod for selective destruction of cells (options) // 2158139\nThe invention relates to medicine and can be used for selective destruction of cells infected with RNA of hepatitis C virus(HCV)\nA method of obtaining a medicinal product, which has antiviral, hepatoprotective and immunostimulatory activity // 2155051\nThe invention relates to medicine\nDerivatives piron, a pharmaceutical composition with anti-virus and antibacterial activity based on them and the method of treatment caused by rotavirus infection or disease // 2153497\nOral suspension containing a high dose of mofetil of mycophenolate // 2150942\nThe method of treatment of chronic hepatitis in children // 2149019\nThe invention relates to medicine, namely to the treatment of infectious diseases in children\nThe method of obtaining enantiomerically pure compounds of imidazolyl, enantiomerically pure acid additive salt of imidazoline and d - or l-pyroglutamic acid, monohydrate hydrochloride enantiomerically pure compounds of imidazolyl // 2162085\n9 benzylideneamino-1,2,3,4-tetrahydropyridine exhibiting analgesic and antimicrobial activity against staph. aureus. // 2161606\nMethod for preparing (+)-glaucine hydrochloride (variants) // 2259829\nFIELD: pharmaceutical technology.\nSUBSTANCE: method involves extraction of the above-ground part of yellow poppy (Glaucium flavum Crantz.) with an organic solvent, the following filtration, alkalization of an aqueous-acid solution, extraction of alkaloids with an organic solvent, removing an organic solvent under vacuum, treatment of prepared glaucine base with hydrochloric acid and purifying the product. Extraction of vegetable raw is carried out with 60% aqueous alcohol solution in the presence or tribasic mineral acid, for example, phosphoric acid. Organic solvent is removed under vacuum, an aqueous vat residue is neutralized with mixture of calcium carbonate and calcium chloride, or calcium carbonate and aluminum chloride followed by filtration. Filtrate is alkalinized to obtain alkaloid bases that are extracted from an aqueous phase with an organic solvent, preferably, with aromatic solvent, for example, with benzene or toluene. Organic phase is evaporated under vacuum, residue is treated with hydrochloric acid and product is subjected for purification, or after filtration alkaloid hydrochlorides formed are extracted with chloroform. Organic phase is evaporated under vacuum and product is subjected for purification. Invention provides simplifying the process.\nEFFECT: improved preparing method.\n2 cl, 5 ex\nAcridine derivatives, method for their preparing and pharmaceutical composition based on thereof // 2267488\nFIELD: organic chemistry, medicine, oncology, pharmacy.\nSUBSTANCE: invention relates to new derivatives of acridine of the formula (1):\nwherein R, R1, R2 and R3 mean hydrogen atom; Z means oxygen or sulfur atom; X means nitrogen atom or C-R5 wherein R5 means hydrogen atom; n = 2; m = 0; R4 means (C1-C3)-alkyl residue that can be substituted with aryl, (C4-C10)-heteroaryl and other substitutes, (C6-C10)-aryl and others, and to their pharmaceutically acceptable salts. Compounds of the formula (1) possess an anti-tumor activity and can be used as an active component of the medicinal agent.\nEFFECT: improved preparing method, valuable medicinal properties of compounds and composition.\n9 cl, 1 tbl, 20 ex\n© Patent search, search for pacenow for inventions - russianpatents.com 2012-2019"

"KEY ISSUES FOR CLINICIANS CONCERNING ANTIVIRAL TREATMENTS FOR 2009 H1N1\nThe Delaware Division of Public Health is forwarding this Health Advisory from the Centers for Disease Control and Prevention.\nAlthough use of influenza antiviral drugs in the United States has increased during the 2009-2010 flu season, not all people recommended for antiviral treatment are getting treated. Listed below are important facts to consider when deciding whether a patient needs to be treated with antiviral medication.\nIt is critical to remember that it is not too late to treat, even if symptoms began more than 48 hours ago. Although antiviral treatment is most effective when begun within 48 hours of influenza illness onset, studies have shown that hospitalized patients still benefit when treatment with oseltamivir is started more than 48 hours after illness onset. Outpatients, particularly those with risk factors for severe illness who are not improving, might also benefit from treatment initiated more than 48 hours after illness onset.\nRecommendations for Clinicians:\nMany 2009 H1N1 patients can benefit from antiviral treatment, and all hospitalized patients with suspected or confirmed 2009 H1N1 should receive antiviral treatment with a neuraminidase inhibitor – either oseltamivir or zanamivir – as early as possible after illness onset. Moderately ill patients, especially those with risk factors for severe illness, and those who appear to be getting worse, can also benefit from treatment with neuraminidase inhibitors. A full listing of risk factors for severe influenza is available at: http://www.cdc.gov/h1n1flu/highrisk.htm\nAlthough antiviral medications are recommended for treatment of 2009 H1N1 in patients with risk factors for severe disease, some people without risk factors may also benefit from antivirals. To date, 40% of children and 20% of adults hospitalized with complications of 2009 H1N1 did not have risk factors. Clinical judgment is always an essential part of treatment decisions.\nWhen treatment of persons with suspected 2009 H1N1 influenza is indicated, it should be started empirically. If a decision is made to test for influenza, treatment should not be delayed while waiting for laboratory confirmation. The earlier antiviral treatment is given, the more effective it is for the patient. Also, rapid influenza tests often can give false negative results. If you suspect flu and feel antiviral treatment is warranted, treat even if the results of a rapid test are negative. Obtaining more accurate testing results can take more than one day, so treatment should not be delayed while waiting for these test results. For more information on influenza testing, please see: http://www.cdc.gov/h1n1flu/guidance/diagnostic_tests.htm.\nAlthough commercially produced pediatric oseltamivir suspension is in short supply, there are ample supplies of children's oseltamivir capsules, which can be mixed with syrup at home. In addition, pharmacies can compound adult oseltamivir capsules into a suspension for treatment of ill infants and children. Additional information on compounding can be found at: http://www.cdc.gov/H1N1flu/pharmacist/.\nUpdated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season: http://www.cdc.gov/H1N1flu/recommendations.htm\nAntiviral Drugs, 2009-2010 Flu Season: http://www.cdc.gov/h1n1flu/antiviral.htm\nInfluenza Diagnostic Testing: http://www.cdc.gov/h1n1flu/diagnostic_testing_clinicians_qa.htm\nUpdated Interim Recommendations for Obstetric Health Care Providers Related to Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season: http://www.cdc.gov/H1N1flu/pregnancy/antiviral_messages.htm\nAntiviral Drugs: Summary of Side Effects: http://www.cdc.gov/flu/protect/antiviral/sideeffects.htm\nGeneral information for the public on antiviral drugs is available in \"2009 H1N1 and Seasonal Flu: What You Should Know About Flu Antiviral Drugs\" at http://www.cdc.gov/H1N1flu/antivirals/geninfo.htm\nDownloadable brochures and informational flyers, including one on antiviral drugs, are available at http://www.cdc.gov/h1n1flu/flyers.htm\nFor the FDA page on antiviral influenza drugs:\nhttp://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm100228.htm\nFor additional information, you can also call CDC's toll-free hotline, 800-CDC-INFO (800-232-4636) TTY: (888) 232-6348, which is available 24 hours a day, every day."

"In July 2000, Glaxo Wellcome sent a letter to physicians warning them to be especially careful when restarting abacavir after it has been discontinued. It has long been known that abacavir must never be re-started after it has been stopped due to a hypersensitivity reaction to this drug. The new warning resulted from cases where a previous hypersensitivity reaction might or might not have occurred, but had not been recognized.\n1. This warning about re-starting does not apply if a patient has only missed one or two doses.\n2. Before re-starting abacavir, patients should call their physician. If the patient had symptoms consistent with hypersensitivity when they stopped the drug, they should never use abacavir again. It is important to check the latest medical information on how to recognize these symptoms.\n3. When re-starting abacavir, patients and physicians should have a plan for emergency care in case problems develop. The drug should not be re-started if the patient will be out of reach of medical care -- in a remote area, for example. The dangerous reaction often occurs within hours, but can occur days or a few weeks after re-starting.\n4. The initial hypersensitivity reaction happens in 3-5% of patients started on abacavir. If the drug is then permanently discontinued, the reaction goes away on its own without further problems, but if abacavir is ever re-started after the reaction has occurred, the hypersensitivity can become much worse, and can be fatal. So far the overall death rate from abacavir has been 2-4 patients per 10,000.\nThe most important point is that patients must check with their physician before re-starting Ziagen (abacavir) after it has been discontinued for any reason.\nGlaxo Wellcome Inc. is writing to inform you of important new safety information about hypersensitivity reactions to abacavir, a nucleoside analogue reverse transcriptase inhibitor which, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. Fatal hypersensitivity reactions are a described risk associated with the use of abacavir (Ziagen); patients who have developed hypersensitivity reactions upon abacavir rechallenge are at an increased risk of a severe hypersensitivity reaction, which may result in death.\nHypersensitivity to abacavir was not recognized before abacavir therapy was interrupted.\nMost of these hypersensitivity reactions were indistinguishable from hypersensitivity reactions associated with abacavir rechallenge: short time to onset, increased severity of symptoms, and poor outcome (including death).\nSevere or fatal hypersensitivity reactions occurred upon reintroduction when abacavir was discontinued for reasons unrelated to symptoms of hypersensitivity. In some cases, symptoms consistent with hypersensitivity may have been present before abacavir was discontinued, but may have been attributed to other medical conditions (for example, acute onset respiratory diseases, gastroenteritis or reactions to other medications).\nHypersensitivity reactions occurred days to weeks following abacavir reintroduction in a minority of reports.\nThe reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If hypersensitivity is suspected, abacavir should NOT be reintroduced.\nIf symptoms consistent with hypersensitivity are not identified, reintroduction should be undertaken with caution. Patients should be made aware that a hypersensitivity reaction can occur upon reintroduction of abacavir, and that reintroduction should be undertaken only if medical care can be readily accessed by the patient and others.\nPlease read the enclosed package insert for revisions in the BOXED WARNING, WARNINGS ADVERSE REACTIONS, PRECAUTIONS: Information for Patients and patient Medication Guide. This information is provided to help you in the management of patients prescribed Ziagen Tablets or Ziagen Oral Solution.\nGlaxo Wellcome is committed to providing you with the current product information for the management of your patients being treated with ZIAGEN. You can assist us in monitoring the safety of ZIAGEN by reporting adverse reactions to the Glaxo Wellcome Product Surveillance Department at 1-888-825-5249 or to the FDA MedWatch program by telephone at 1-800-332-1088, by FAX at 1-800-332-0178, via http://www.fda.gov/medwatch or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.\nPlease refer to the enclosed revised prescribing information for ZIAGEN. If you have questions about the new information or want additional medical information about ZIAGEN, please contact the Glaxo Wellcome Customer Response Center at 1-888-TALK2GW (1-888-825-5249)."

"Home > Drugs A-Z > Abacavir\nAbacavir (Aurobindo Pharma Limited)\nTABLET, FILM COATED 60 TABLET, FILM COATED in 1 BOTTLE (65862-073-60) Label Information\nComplete Abacavir Information\nBOXED WARNING(What is this?)\nWARNING: HYPERSENSITIVITY REACTIONS\nSerious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir.\nPatients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see Warnings and Precautions (5.1)].\nAbacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)].\nFollowing a hypersensitivity reaction to abacavir, NEVER restart abacavir or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)].\nThese highlights do not include all the information needed to use ABACAVIR TABLETS safely and effectively. See full prescribing information for ABACAVIR TABLETS.\nABACAVIR tablets, for oral use\nSee full prescribing information for complete boxed warning.\nSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir. (5.1)\nHypersensitivity to abacavir is a multi-organ clinical syndrome. (5.1)\nPatients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. (5.1)\nAbacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. (4)\nDiscontinue abacavir as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue abacavir if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1)\nFollowing a hypersensitivity reaction to abacavir, NEVER restart abacavir or any other abacavir-containing product. (5.1)\nBoxed Warning 05/2018\nWarnings and Precautions, Lactic Acidosis and Severe 05/2018\nHepatomegaly with Steatosis (5.2)\nWarnings and Precautions, Fat Redistribution (previous 5.4) Removed\nWarnings and Precautions, Myocardial Infarction (5.4) 05/2018\nAbacavir tablets, a nucleoside analogue human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)\nBefore initiating abacavir, screen for the HLA-B*5701 allele. (2.1)\nAdults: 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily. (2.2)\nPediatric Patients Aged 3 Months and Older: Administered either once or twice daily. Dose should be calculated on body weight (kg) and should not exceed 600 mg daily. (2.3)\nPatients with Hepatic Impairment: Mild hepatic impairment – 200 mg twice daily. (2.4)\nTablets: 300 mg scored (3)\nPresence of HLA-B*5701 allele. (4)\nPrior hypersensitivity reaction to abacavir. (4)\nModerate or severe hepatic impairment. (4)\nLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.(5.2)\nImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.3)\nThe most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. (6.1)\nThe most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 5%) in pediatric HIV-1 clinical trials were fever and/or chills, nausea and vomiting, skin rashes, and ear/nose/throat infections. (6.2)\nTo report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\nMethadone: An increased methadone dose may be required in a small number of patients. (7.1)\nLactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. (8.2)\n2.1 Screening for HLA-B*5701 Allele prior to Starting Abacavir Tablets 2.2 Recommended Dosage for Adult Patients 2.3 Recommended Dosage for Pediatric Patients 2.4 Recommended Dosage for Patients with Hepatic Impairment\n5.1 Hypersensitivity Reactions 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis 5.3 Immune Reconstitution Syndrome 5.4 Myocardial Infarction\n6.1 Clinical Trials Experience in Adult Subjects 6.2 Clinical Trials Experience in Pediatric Subjects 6.3 Postmarketing Experience\n7.1 Methadone\n8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Impaired Hepatic Function\n12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology\n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology\n14.1 Adult Trials 14.2 Pediatric Trials\n• Sections or subsections omitted from the full prescribing information are not listed.\nAbacavir tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.\n2.1 Screening for HLA-B*5701 Allele prior to Starting Abacavir Tablets\nScreen for the HLA-B*5701 allele prior to initiating therapy with abacavir tablets [see Boxed Warning, Warnings and Precautions (5.1)].\n2.2 Recommended Dosage for Adult Patients\nThe recommended dosage of abacavir tablets for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.\n2.3 Recommended Dosage for Pediatric Patients\nAbacavir tablets are available as scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing abacavir tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow abacavir tablets, the oral solution formulation should be prescribed. The recommended oral dosage of abacavir tablets for HIV-1-infected pediatric patients is presented in Table 1.\nTwice-Daily Dosing Regimen\nOnce-Daily\nDosing Regimena\n(300 mg)\n½ tablet\n>20 to <25\n1½ tablets\n≥25\n2 tablets\n2.4 Recommended Dosage for Patients with Hepatic Impairment\nThe recommended dose of abacavir tablets in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily. To enable dose reduction, abacavir oral solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, abacavir tablets are contraindicated in these patients.\nAbacavir tablets, containing abacavir sulfate equivalent to 300 mg abacavir, are yellow colored, biconvex, capsule shaped, coated tablet, debossed with 'D' and '88' on either side of the score line on one side and plain with a score line on other side.\nAbacavir tablets are contraindicated in patients:\nwho have the HLA-B*5701 allele [see Warnings and Precautions (5.1)].\nwith prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1)].\nwith moderate or severe hepatic impairment [see Use in Specific Populations (8.6)].\nSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.\nDue to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:\nAll patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment.\nAbacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.\nBefore starting abacavir, review medical history for prior exposure to any abacavir-containing product. NEVER restart abacavir or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.\nTo reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).\nIf a hypersensitivity reaction cannot be ruled out, do not restart abacavir or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours.\nIf a hypersensitivity reaction is ruled out, patients may restart abacavir. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir or any other abacavir-containing product is recommended only if medical care can be readily accessed.\nA Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.\n5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis\nLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with abacavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.\n5.3 Immune Reconstitution Syndrome\nImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.\nAutoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.\n5.4 Myocardial Infarction\nSeveral prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled, clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.\nAs a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).\nThe following adverse reactions are discussed in other sections of the labeling:\nSerious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].\nLactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2)].\nImmune reconstitution syndrome [see Warnings and Precautions (5.3)].\nMyocardial infarction [see Warnings and Precautions (5.4)].\n6.1 Clinical Trials Experience in Adult Subjects\nBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\nSerious and Fatal Abacavir-Associated Hypersensitivity Reactions\nIn clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.\nOther signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).\nAdditional Adverse Reactions with Use of Abacavir\nTherapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.\nTable 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024a) through 48 Weeks of Treatment\na This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.\nb Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.\nLamivudine plus Efavirenz\nZidovudine plus\nDreams/sleep disorders\nDrug hypersensitivity\n<1%b\nHeadaches/migraine\nFatigue/malaise\nAbdominal pain/gastritis/gastrointestinal signs and symptoms\nTreatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.\nTable 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment\nIndinavir plus\nMalaise and fatigue\nHypersensitivity reaction\nFever and/or chills\nEar/nose/throat infections\nViral respiratory infections\nRenal signs/symptoms\nPain (non-site-specific)\nFive subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.\nAbacavir Once Daily versus Abacavir Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving abacavir once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving abacavir twice daily. However, subjects receiving abacavir 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received abacavir 300 mg twice daily. Five percent (5%) of subjects receiving abacavir 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving abacavir 300 mg twice daily. Two percent (2%) of subjects receiving abacavir 600 mg once daily had severe diarrhea while none of the subjects receiving abacavir 300 mg twice daily had this event.\nLaboratory Abnormalities: Laboratory abnormalities (Grades 3 to 4) in therapy-naive adults during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.\nTable 4. Laboratory Abnormalities (Grades 3 to 4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment\nULN = Upper limit of normal.\nn = Number of subjects assessed.\nLaboratory Abnormalities\nLamivudine plus\nEfavirenz\nElevated CPK (>4 X ULN)\nElevated ALT (>5 X ULN)\nElevated AST (>5 X ULN)\nHypertriglyceridemia (>750 mg/dL)\nHyperamylasemia (>2 X ULN)\nNeutropenia (ANC <750/mm3)\nAnemia (Hgb ≤6.9 gm/dL)\nThrombocytopenia (Platelets <50,000/mm3)\nLeukopenia (WBC ≤1,500/mm3)\nLaboratory abnormalities in CNA3005 are listed in Table 5.\nTable 5. Treatment-Emergent Laboratory Abnormalities (Grades 3 to 4) in CNA3005\nGrade 3/4 Laboratory Abnormalities\nALT (>5 x ULN)\nNeutropenia (<750/mm3)\n1 (<1%)\nHyperglycemia (>13.9 mmol/L)\nAnemia (Hgb ≤6.9 g/dL)\nThe frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.\n6.2 Clinical Trials Experience in Pediatric Subjects\nTherapy-Experienced Pediatric Subjects (Twice-Daily Dosing)\nTreatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m2 twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m2 twice daily from CNA3006 are listed in Table 6.\nTable 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment\nAbacavir plus Lamivudine plus Zidovudine\nLamivudine plus Zidovudine\nLaboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving abacavir (CNA3006) as compared with adult subjects (CNA30024).\nOther Adverse Events\nIn addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.\nPediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of abacavir was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.\nThe following adverse reactions have been identified during postmarketing use of abacavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures.\nBody as a Whole\nRedistribution/accumulation of body fat.\nMyocardial infarction.\nLactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)].\nSuspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.\nThere have also been reports of erythema multiforme with abacavir use [see Adverse Reactions (6.1)].\nThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy. Healthcare Providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.\nAvailable data from the APR show no difference in the overall risk of birth defects for abacavir compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks' gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.\nIn animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose (see Data).\nHuman Data: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens.\nAbacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)].\nAnimal Data: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.\nThe Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir is present in human milk. There is no information on the effects of abacavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving abacavir.\nThe safety and effectiveness of abacavir have been established in pediatric patients aged 3 months and older. Use of abacavir is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of abacavir in adults and pediatric subjects [see Dosage and Administration (2.3), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)].\nClinical trials of abacavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of abacavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.\n8.6 Patients with Impaired Hepatic Function\nA dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see Dosage and Administration (2.4)]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate or severe hepatic impairment; therefore, abacavir is contraindicated in these patients [see Contraindications (4), Clinical Pharmacology (12.3)].\nAbacavir sulfate is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1. The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula:\nAbacavir sulfate USP is a white to off-white solid and is soluble in water.\nAbacavir tablets USP are for oral administration. Each tablet contains abacavir sulfate USP equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, iron oxide yellow, polysorbate 80, titanium dioxide, and triacetin.\nIn vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.\nAbacavir is an antiretroviral agent [see Microbiology (12.4)].\nPharmacokinetics in Adults\nThe pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day.\nAbsorption: Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%. Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcghour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcghour per mL.\nEffect of Food: Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, abacavir tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of abacavir oral solution and abacavir tablets. Therefore, these products may be used interchangeably.\nDistribution: The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 h) to plasma abacavir AUC(0-6 h) ratio ranged from 27% to 33%.\nBinding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.\nElimination: In single-dose trials, the observed elimination half-life (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.8 ± 0.24 L per hour per kg (mean ± SD).\nMetabolism: In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide. The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.\nExcretion: Elimination of abacavir was quantified in a mass balance trial following administration of a 600 mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.\nPatients with Renal Impairment: The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.\nPatients with Hepatic Impairment: The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see Contraindications (4), Use in Specific Populations (8.6)].\nPregnant Women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.\nPediatric Patients: The pharmacokinetics of abacavir have been studied after either single or repeat doses of abacavir in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults. Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution.\nThe pharmacokinetics of abacavir dosed once daily in HIV-1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice-versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.\nGeriatric Patients: The pharmacokinetics of abacavir have not been studied in subjects older than 65 years.\nMale and Female Patients: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.\nRacial Groups: There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics.\nDrug Interaction Studies\nEffect of Abacavir on the Pharmacokinetics of Other Agents: In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways.\nBased on in vitro study results, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.\nEffect of Other Agents on the Pharmacokinetics of Abacavir: In vitro, abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.\nLamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.\nEthanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1-infected male subjects. Each subject received the following treatments on separate occasions: a single 600 mg dose of abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g per kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC∞ and a 26% increase in abacavir t1/2. Abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females.\nMethadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients [see Drug Interactions (7)]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.\n12.4 Microbiology\nAbacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.\nAntiviral Activity\nThe antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 microM) used in the treatment of chronic HCV infection had no effect on the anti–HIV-1 activity of abacavir in cell culture.\nHIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV-1 RT. M184V or I substitutions resulted in an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.\nThirty-nine percent (7 of 18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold mean decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5 of 17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).\nCross-Resistance\nCross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, and tenofovir in cell culture and in subjects. An increasing number of thymidine analogue mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.\nAbacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.\nMutagenicity\nAbacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.\nAbacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.\nAbacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.\n13.2 Animal Toxicology and/or Pharmacology\nMyocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.\n14.1 Adult Trials\na Subjects achieved and maintained confirmed HIV-1 RNA less than or equal to 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test 1 PCR).\nCNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either abacavir (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), white (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells per mm3, and median baseline plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.\nHIV-1 RNA\n≥10,000 to ≤100,000\n>100,000\nCNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm3 (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.6 to 6.99 log10 copies per mL).\na Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1).\nAbacavir 600 mg\nq.d. plus EPIVIR plus\nb.i.d. plus EPIVIR plus\n14.2 Pediatric Trials\nCNA3006 was a randomized, double-blind trial comparing abacavir 8 mg per kg twice daily plus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m2 twice daily versus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m2 twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), white (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log10 copies per mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks, the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies per mL was significantly higher in subjects receiving abacavir plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log10 copies per mL in the group receiving abacavir plus lamivudine plus zidovudine compared with -0.21 log10 copies per mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells per mm3 in the group receiving abacavir plus lamivudine plus zidovudine and 9 cells per mm3 in the group receiving lamivudine plus zidovudine.\nARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naive subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed compared with 71% of subjects in the once-daily cohort.\nTwice-Daily Dosing (n=333)\nHIV-1 RNA ≥80 copies/mLc\nAbacavir tablets USP, containing abacavir sulfate equivalent to 300 mg abacavir, are yellow colored, biconvex, capsule shaped, coated tablet, debossed with 'D' and '88' on either side of the score line on one side and plain with a score line on other side. They are packaged as follows:\nBottles of 60 NDC 65862-073-60\nStore at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].\nHypersensitivity Reactions\nInform patients:\nthat a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of abacavir, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir. The complete text of the Medication Guide is reprinted at the end of this document.\nto carry the Warning Card with them.\nhow to identify a hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].\nthat if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir.\nthat a hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir is not immediately discontinued.\nto not restart abacavir or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.\nthat if they have a hypersensitivity reaction, they should dispose of any unused abacavir to avoid restarting abacavir.\nthat a hypersensitivity reaction is usually reversible if it is detected promptly and abacavir is stopped right away.\nthat if they have interrupted abacavir for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.\nto not restart abacavir or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.\nLactic Acidosis/Hepatomegaly with Steatosis\nAdvise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking abacavir if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.2)].\nImmune Reconstitution Syndrome\nAdvise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when abacavir is started [see Warnings and Precautions (5.3)].\nPregnancy Registry\nAdvise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy [see Use in Specific Populations (8.1)].\nInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].\nInstruct patients that if they miss a dose of abacavir, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].\nAvailability of Medication Guide\nInstruct patients to read the Medication Guide before starting abacavir and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.\n279 Princeton-Hightstown Road\nAurobindo Pharma Limited\nHyderabad-500 038, India\nAbacavir Tablets USP\n(a bak' a vir)\nWhat is the most important information I should know about abacavir tablets?\nAbacavir tablets can cause serious side effects, including:\nSerious allergic reactions (hypersensitivity reaction) that can cause death have happened with abacavir tablets and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.\nIf you get a symptom from 2 or more of the following groups while taking abacavir tablets, call your healthcare provider right away to find out if you should stop taking abacavir tablets.\nIf you stop abacavir tablets because of an allergic reaction, never take abacavir or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or TRIZIVIR) again.\nIf you have an allergic reaction, dispose of any unused abacavir tablets. Ask your pharmacist how to properly dispose of medicines.\nIf you take abacavir tablets or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death.\nIf you stop abacavir tablets for any other reason, even for a few days, and you are not allergic to abacavir tablets, talk with your healthcare provider before taking them again. Taking abacavir tablets again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to them before.\nIf your healthcare provider tells you that you can take abacavir tablets again, start taking them when you are around medical help or people who can call a healthcare provider if you need one.\nWhat are abacavir tablets?\nAbacavir tablets are a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).\nThe safety and effectiveness of abacavir tablets has not been established in children under 3 months of age.\nWhen used with other antiretroviral medicines to treat HIV-1 infection, abacavir tablets may help:\nreduce the amount of HIV-1 in your blood. This is called \"viral load\".\nincrease the number of CD4+ (T) cells in your blood, that help fight off other infections.\nAbacavir tablets do not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV- 1 infection and decrease HIV-related illnesses.\nWho should not take abacavir tablets?\nDo not take abacavir tablet if you:\nhave a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir tablets.\nare allergic to abacavir or any of the ingredients in abacavir tablets. See the end of this Medication Guide for a complete list of ingredients in abacavir tablets.\nWhat should I tell my healthcare provider before taking abacavir tablets?\nBefore you take abacavir tablets, tell your healthcare provider if you:\nhave been tested and know whether or not you have a particular gene variation called HLA-B*5701.\nhave or have had liver problems, including hepatitis B or C virus infection.\nhave heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.\ndrink alcohol or take medicines that contain alcohol.\nare pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.\nPregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.\nare breastfeeding or plan to breastfeed. Do not breastfeed if you take abacavir tablets.\nYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.\nSome medicines interact with abacavir tablets. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with abacavir tablets. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take abacavir tablets with other medicines.\nany other medicine to treat HIV-1\nHow should I take abacavir tablets?\nTake abacavir tablets exactly as your healthcare provider tells you.\nDo not change your dose or stop taking abacavir tablets without talking with your healthcare provider. If you miss a dose of abacavir tablets, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.\nStay under the care of a healthcare provider while taking abacavir tablets.\nAbacavir tablets may be taken with or without food.\nFor children aged 3 months and older, your healthcare provider will prescribe a dose of abacavir tablets based on your child's body weight.\nTell your healthcare provider if you or your child has trouble swallowing tablets. Abacavir comes as a tablet or as a liquid (oral solution).\nDo not run out of abacavir tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run out, get more from your healthcare provider or pharmacy.\nIf you take too much abacavir tablets, call your healthcare provider or go to the nearest hospital emergency room right away.\nWhat are the possible side effects of abacavir tablets?\nAbacavir tablets can cause serious side effects including:\nSee \"What is the most important information I should know about abacavir tablets?\"\nBuild-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take abacavir tablets. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:\nfeel very weak or tired\nunusual (not normal) muscle pain\nstomach pain with nausea and vomiting\nfeel cold, especially in your arms and legs\nfeel dizzy or light-headed\nhave a fast or irregular heartbeat\nSerious liver problems can happen in people who take abacavir tablets. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take abacavir tablets. Call your healthcare provider right away if you have any of the following signs of liver problems:\nyour skin or the white part of your eyes turns yellow (jaundice)\ndark or \"tea-colored\" urine\nlight-colored stools (bowel movements)\nloss of appetite for several days or longer\npain, aching, or tenderness on the right side of your stomach area\nYou may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).\nChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking abacavir tablets.\nHeart attack (myocardial infarction). Some HIV-1 medicines including abacavir tablets may increase your risk of heart attack.\nThe most common side effects of abacavir tablets in adults include:\ngenerally not feeling well\nbad dreams or sleep problems\nThe most common side effects of abacavir tablets in children include:\near, nose, or throat infections\nThese are not all the possible side effects of abacavir tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\nHow should I store abacavir tablets?\nStore abacavir tablets at room temperature, between 20° to 25°C (68° to 77°F).\nKeep abacavir tablets and all medicines out of the reach of children.\nGeneral information for safe and effective use of abacavir tablets\nMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use abacavir tablets for a condition for which it was not prescribed. Do not give abacavir tablets to other people, even if they have the same symptoms that you have. It may harm them.\nIf you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about abacavir tablets that is written for health professionals.\nFor more information call Aurobindo Pharma USA, Inc. at 1-866-850-2876.\nWhat are the ingredients in abacavir tablets?\nActive ingredient: abacavir\nInactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, iron oxide yellow, polysorbate 80, titanium dioxide, and triacetin.\nThe brands listed are trademarks of their respective owners and are not trademarks of the Aurobindo Pharma Limited. The markers of these brands are not affiliated with and do not endorse the Aurobindo Pharma Limited or its products.\n(Front of Card)\nWARNING CARD\nPatients taking abacavir tablets may have a serious allergic reaction (hypersensitivity reaction) that can cause death. If you get a symptom from 2 or more of the following groups while taking abacavir tablets, call your healthcare provider right away to find out if you should stop taking this medicine.\nNausea, vomiting, diarrhea, or abdominal (stomach area) pain\nShortness of breath, cough, or sore throat\nAlways carry this Warning Card with you to help recognize symptoms of this allergic reaction.\n(Back of Card)\nIf you must stop treatment with abacavir tablets because you have had an allergic reaction to abacavir, NEVER take abacavir tablets or another abacavir-containing medicine (EPZICOM®, TRIUMEQ ®, or TRIZIVIR®) again. If you have an allergic reaction, dispose of any unused abacavir tablets. Ask your pharmacist how to properly dispose of medicines. If you take abacavir tablets or another abacavir-containing medicine again after you have had an allergic reaction, WITHIN HOURS you may get life-threatening symptoms that may include very low blood pressure or death.\nPlease read the Medication Guide for additional information on abacavir tablets.\nEPZICOM, TRIUMEQ, and TRIZIVIR are registered trademarks of the ViiV Healthcare group of companies.\nPACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 300 mg (60 Tablet Bottle)\nNotice to Authorized Dispenser: Each time ABACAVIR\nTABLETS USP are dispensed, give the patient an attached\nMedication Guide and Warning Card from the carton.\nAUROBINDO 60 Tablets\nABACAVIR\nabacavir tablet, film coated\nABACAVIR SULFATE (UNII: J220T4J9Q2) (ABACAVIR - UNII:WR2TIP26VS) ABACAVIR 300 mg\nColor YELLOW Score 2 pieces\nShape CAPSULE (Biconvex) Size 18mm\nFlavor Imprint Code D;88\nLabeler - Aurobindo Pharma Limited (650082092)\nAurobindo Pharma Limited 918917642 ANALYSIS(65862-073) , MANUFACTURE(65862-073)\nAurobindo Pharma Limited 918917626 API MANUFACTURE(65862-073)"

"Rett syndrome: symptoms\nFever: in children\nAnti-aging creams: what really works! : Interview of an expert in cosmetology\nABACAVIR / LAMIVUDINE MYLAN PHARMA 600 mg / 300 mg\nGeneric drug from Kivexa\nactive ingredients: Abacavir + Lamivudine\nCoated tablet\nABACAVIR / LAMIVUDINE MYLAN PHARMA is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents and children weighing at least 25 kg (see Warnings and Precautions for Use section). and pharmacodynamic properties ).\nBefore beginning treatment with abacavir, HLA-B * 5701 should be screened for any HIV-infected patient, regardless of their race (see Warnings and Precautions section). ). Abacavir should not be used in patients with the HLA-B * 5701 allele.\nDosage ABACAVIR / LAMIVUDINE MYLAN PHARMA 600 mg / 300 mg film-coated tablet box of 30\nHypersensitivity to the active substances or to any of the excipients listed under Composition . See Warnings and Precautions and Adverse Reactions sections.\nAdverse effects Abacavir / lamivudine Mylan Phar\nSummary of the security profile\nAdverse reactions reported with abacavir / lamivudine are consistent with known safety profiles for abacavir and lamivudine when administered separately. For most of these adverse effects, the causality study could not formally determine the respective responsibilities of the active substances, the many concurrent treatments, and the HIV infection.\nMost of the effects listed in the following table occur frequently (nausea, vomiting, diarrhea, fever, lethargy, rash) in patients with abacavir hypersensitivity reactions. Therefore, in patients with any of these symptoms, the presence of a hypersensitivity reaction should be carefully investigated (see Warnings and Precautions ). Cases of erythema multiforme, Stevens-Johnson syndrome or Lyell syndrome, for which the hypothesis of a hypersensitivity reaction to abacavir could not be ruled out, have been very rarely reported. In these cases, medicines containing abacavir must be permanently discontinued.\nSummary table of adverse effects\nAdverse reactions considered to be related to abacavir or lamivudine are listed below by organ class and absolute frequency. The frequencies are defined according to the following categories: very frequent (> 1/10), frequent (1/100), uncommon (1/1000), rare (1/10 000) and very rare (<1/10 000) .\nBody class\nUncommon : neutropenia and anemia (both sometimes severe), thrombocytopenia\nVery rare: erythroblastopenia\nCommon: hypersensitivity reaction\nMetabolism and nutrition disorders\nFrequent: anorexia\nVery rare : lactic acidosis\nCommon: headache\nCommon : headache, insomnia\nVery rare: cases of peripheral neuropathy (or paresthesia) have been reported\nCommon: cough, nasal symptomatology\nFrequent : nausea, vomiting, diarrhea\nRare : pancreatitis reported but causal relationship to abacavir treatment is uncertain\nCommon: nausea, vomiting, abdominal pain or cramps, diarrhea\nRare : elevation of serum amylase. Cases of pancreatitis have been reported\nUncommon: transient elevation of liver enzymes (ASAT, ALAT)\nRare: hepatitis\nCommon: rash (no systemic symptoms)\nVery rare: erythema multiforme, Stevens-Johnson syndrome and Lyell's syndrome\nCommon: rash, alopecia\nRare : angioedema\nMusculoskeletal and systemic disorders\nCommon: arthralgia, muscle disorders\nRare: rhabdomyolysis\nFrequent: fever, lethargy, fatigue\nFrequent: tiredness, malaise, fever\nDescription of some adverse effects\nHypersensitivity to abacavir\nThe signs and symptoms associated with a hypersensitivity reaction to abacavir are listed below.\nThese have been identified during clinical trials or post-marketing follow-up. Adverse reactions reported in at least 10% of patients with a hypersensitivity reaction appear in bold.\nIn almost all patients with a hypersensitivity reaction, the syndrome has fever and / or rash (usually maculopapular or urticarial), however some patients have had a reaction without fever or rash.\nOther symptoms suggestive of hypersensitivity include gastrointestinal, respiratory or general symptoms such as lethargy and malaise.\nRash (usually maculopapular or urticarial)\nNausea, vomiting, diarrhea, abdominal pain, mouth ulcers\nDyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure\nVarious effects\nFever, lethargy, malaise, edema, lymphadenopathy, low blood pressure, conjunctivitis, anaphylaxis\nNervous system disorders / Psychiatric disorders\nHeadache, paresthesia\nlymphopenia\nHepatic dysfunction, hepatitis, liver failure\nMyalgia, rarely rhabdomyolysis, arthralgia, elevation of creatine phosphokinase\nRenal and urinary disorders\nElevation of creatinine, renal insufficiency\nSymptoms related to this hypersensitivity reaction worsen with continued treatment and may be life-threatening; in rare cases they have been fatal.\nResumption of abacavir therapy after a hypersensitivity reaction results in a rapid reappearance of symptoms within a few hours. This recurrence is usually more severe than the initial episode and can lead to life-threatening hypotension and lead to death. In rare cases, similar reactions have also occurred in patients who have restarted abacavir therapy, despite having experienced only one of the symptoms suggestive of a hypersensitivity reaction (see above). prior to stopping treatment with abacavir; very rarely reactions have also been observed in patients for whom treatment was reintroduced when they did not previously show any symptoms of hypersensitivity (that is, patients previously considered to be abacavir-tolerant).\nMetabolic parameters\nIncreased body weight, blood lipid and glucose levels may occur during antiretroviral therapy (see Warnings and Precautions section ).\nImmune restoration syndrome\nIn HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur. Cases of autoimmune disorders (such as Graves' disease) have also been reported in a context of immune restoration; however, the reported onset time varies more, and these events may occur several months after initiation of treatment (see Warnings and Precautions ).\nCases of osteonecrosis have been reported, particularly in patients with known risk factors, advanced HIV-related disease, or combination therapy with long-term antiretrovirals. Their frequency of occurrence is not known (see section Warnings and Precautions ).\nPediatric population\nThe safety data supporting the once-daily dosing regimen in children are from the ARROW study (COL105677) in which 669 pediatric patients (aged 12 months to 17 years) infected with HIV-1 received abacavir and lamivudine in one or two daily doses (see section 5.1 Pharmacodynamic properties ). In this population, 104 pediatric patients infected with HIV-1 and weighing at least 25 kg received abacavir and lamivudine as a tablet once daily. No new safety concerns have been identified in pediatric patients receiving the recommended dosage, either once or twice daily, compared to adult patients.\nThe reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr.\nHorny foot: Symptoms\nSpotting: other diseases involved\nDental caries: the causes\nThe andrologist: male infertility\nThe relationship with the brothers and sisters\nOrthorexia: treatments\nCushing's disease\nLosing thighs: sports\nAnemia: Symptoms\nCook while you get your fill of vitamins !\nFracture of the basin: sources and notes\nPsychoth Choose What Therapy\nNis Lengthen The P"

"What Does it Mean When a CBD Product Says it Has 0.3% THC?\nThe Significance of 0.3 Percent THC\nHow THC Content Is Measured\nDo All CBD Products Have 0.3% THC?\nAccording to federal law, cannabidiol (CBD) products like CBD oil may only be classified as such if they contain 0.3% or less tetrahydrocannabinol (THC), the main psychoactive compound in cannabis. In addition, CBD products must be hemp-derived rather than originating from the marijuana plant.\nLearn more about how the magic number 0.3% came to be, how THC content is measured and understand how much THC different types of CBD products contain.\nThe Agriculture Improvement Act of 2018 states that a product is not considered a controlled substance under federal law if it contains less than 0.3% THC. This is significant because cannabis is still considered a Schedule I controlled substance under federal law.\nFurthermore, the 2018 Farm Bill allows the Food and Drug Administration (FDA) to retain regulatory authority over cannabis-derived products. Therefore, CBD products must be derived from the hemp plant and not the cannabis plant in order to be considered legal. A CBD product derived from the marijuana plant is illegal regardless of how much THC it contains.\nInterestingly, the origin of the THC limit of 0.3% has nothing to do with whether or not a CBD product can make a user intoxicated. Canadian scientist Dr. Ernest Small compiled a study in 1976 that defined the 0.3% figure as a distinguishing measure between high-THC and low-THC cannabis. Dr. Small's work somehow became lost in translation over the years, with the federal government using the 0.3% measure as a way to differentiate hemp from marijuana.\nTHC content is measured through a variety of methods. One common method is the High-Performance Liquid Chromatography (HPLC) technique, which measures chemical compounds in a liquid solution. Currently, the HPLC is the most widely used method to measure THC content and the content of other cannabinoids, but the technique is not foolproof.\nAccuracy Concerns\nDue to a lack of standardization of measuring methods, there are accuracy concerns in calculating the amount of THC present in a product. Different laboratories use different procedures, and states have their own varying testing requirements.\nBut these accuracy issues may become a thing of the past, as the National Institute of Standards and Technology (NIST) works to help labs achieve uniform accuracy. As part of the Cannabis Quality Assurance program, NIST will strive to make laboratory testing and measuring results more consistent.\nAs NIST research chemist Brent Wilson explains, \"When you walk into a store or dispensary and see a label that says 10% CBD, you want to know that you can trust that number.\"\nMore importantly, from a legal standpoint, accurate measuring of THC will ensure that a substance does not exceed the 0.3% federal limit and can legitimately be classified as a CBD product.\nCBD products contain 0.3% THC or less, so not all products have exactly 0.3% concentration of the cannabinoid. There are three types of CBD products:\nFull-spectrum CBD products\nBroad-spectrum CBD products\nCBD isolate products\nFull-spectrum CBD products contain the highest amount of THC (up to 0.3%), while broad-spectrum CBD may contain only trace amounts of THC that are so small they would be difficult to measure. Finally, CBD isolate products contain no THC at all, nor do they contain other cannabinoids or terpenes that may be therapeutic.\nCBD isolate is the product of choice for people who only want to consume CBD, while broad-spectrum and full-spectrum products are useful for people who want to experience a complete range of therapeutic compounds from the cannabis plant. Integrating a variety of cannabinoids and terpenes (as well as flavonoids) activates the entourage effect, which maximizes the effectiveness of each compound as they work together.\nCBD products must contain 0.3% THC or less in accordance with federal law. This low concentration of THC is unlikely to cause psychoactive effects in CBD users. However, there are accuracy concerns in measuring THC, and products stripped of t other cannabinoids and terpenes may lose valuable therapeutic potential.\nIs 0.3% THC enough to get me high?\nMost people will not feel high from consuming a CBD product with 0.3% THC. However, since CBD can have mildly psychoactive effects, you may feel your mood shift. For example, a CBD tincture could make you feel uplifted or relaxed depending on your reaction to the cannabinoid.\nWhat percentage of THC is considered low?\nCannabis products containing less than 10% THC concentration are generally considered low. However, low THC is different for each individual. An inexperienced cannabis user might find 8% THC potent, while an experienced cannabis user might feel that 8% has minimal effect.\nExplore CBD and cannabis products legally with a medical marijuana card. Connect with the qualified healthcare team at Leafwell and start your MMJ card application online in minutes.\nDo Magic Mushrooms Produce the Same Effects as THC?\nWhat Are THC Crystals and What Are They Used For?\nWhat Are THC Pills?\nTHC and psilocybin (magic mushrooms) can be used for both recreation and health, but are they similar? Learn more about these two psychedelic substances.\nTHC crystals offer an unadulterated method of consuming THC, free from other cannabinoids or terpenes.\nDiscreet, long-lasting, and precisely dosed, THC pills offer a promising consumption option for medical marijuana patients."

"AOAC Approves LC-DAD Method for Cannabinoids Detection and Analysis in Hemp\nShareShareShareShareShare\nThe Association of Official Agricultural Chemists International (AOAC International) recently recognized a liquid chromatography-diode array detection (LC-DAD) method to analyze cannabinoids in hemp plants. Originally, the LC-DAD method had been approved as an Official Method of Analysis 2018.11 (1) for use in testing for cannabinoids in cannabis plants, oils, and concentrates (2).\nScott Coates, Program Lead for AOAC's Cannabis Analytical Science Program (CASP), stated, \"Until now, no globally recognized method for validating the potency of hemp was available to laboratories\" (2).\nWith its new validation, the LC-DAD method grants laboratories the ability to assess tetrahydrocannabinol (THC) in hemp on a dry-weight basis. This basis is explained further under the United States Department of Agriculture's Interim Final Rule in the 2018 Agriculture Improvement Act, also called the Farm Bill, which governs over the production of hemp (3). The program's major requirement is that hemp is tested for THC levels.\nThe federal government defines plant materials containing no more than 0.3% THC as hemp, often rebuked by critics demanding that the THC level should be increased. With 0.3% THC or lower, these materials can be processed to be used in cannabidiol (CBD) consumer products. At the federal level, marijuana is classified as a Schedule 1 controlled substance. Although this has not been reconsidered, states across the country have begun decriminalizing the consumption and cultivation of low-THC form (hemp) and high-THC form (marijuana).\nAs stated in the AOAC's press release (2), the Official Method of Analysis 2018.11 is an LC-DAD technique with optional mass spectrometric detection of Δ9-tetrahydrocannabinol (Δ9-THC) and tetrahydrocannabinolic acid (THCA) individually, so their concentrations can be reported either individually or as total THC. \"Official Method of Analysis 2018.11 is applicable to concentrates, oils, and all plant materials of Cannabis sp., including hemp,\" the release stated (2).\nThe method was modified to also include a sample dry weight determination procedure. \"The performance of this method has been demonstrated thoroughly, and laboratories in the hemp industry can confidently implement this straightforward method for determination of total THC on a dry-weight basis,\" said Rebecca Phillips, chair of the AOAC Expert Review Panel and a Research Chemist at the U.S. National Institute of Standards and Technology (NIST) (2).\nAfter a stringent review and validation process, the method was judged against requirements from the Standard of Method Performance Requirement (SMPR) Quantitation of Cannabinoids in Plant Materials od Hemp (Low THC Varieties Cannabis sp.) (4). This standard is ascribed in the U.S. Department of Agriculture Hemp Program's Interim Final Rule and was engineered by AOAC's Cannabis Analytical Science Program (CASP) in 2019. SMPR is the preferred standard laboratories use to select a method to analyze THC levels.\nShare160Tweet100SendShare28Pin36\nCBD.how hosted a \"Customer Appreciation Day \"at Herbsnleaf in Costa Mesa, California\nAn Expert's Guide to Keeping a Cannabis Journal\nWhat is the Difference Between Delta-9, THC, Delta-8, CBD and Weed?\nFDA declines to regulate CBD; calls on Congress for fix\nWhy does cannabis keep some people skinny? Experts explain how weed and metabolism are connected\nAurora Cannabis to Host Second Quarter Fiscal Year 2023 Investor Conference Call\nComo Conservar La Marihuana Por Mucho Tiempo\nSoft Secrets \"Perfect Grow\" What Makes a Great Seed?\nThis is an online news portal that aims to share latest news about \"News, Culture, Science, Health, Shop\" and much more stuff like that. Feel free to get in touch with us!\n© 2020 matans3.sg-host.com - All rights reserved!"

"Patent application title: METHODS FOR CANNABINOID QUANTIFICATION\nAssignees: Compassionate Analytic Inc.\nIPC8 Class: AG01N3394FI\nUSPC Class: 436 93\nClass name: Chemistry: analytical and immunological testing heterocyclic carbon compound (i.e., o, s, n, se, te, as only ring hetero atom) hetero-o (e.g., ascorbic acid, etc.)\nA method for quantification of the concentration of one or more cannabinoid compounds in a liquid sample is provided. The method involves contacting the liquid sample with at least one cannabinoid-sensitive visualization reagent, allowing the at least one cannabinoid-sensitive visualization reagent to develop for a defined amount of time; and comparing the resulting color change of the at least one cannabinoid-sensitive visualization reagent to a calibrated quantification reference chart.\n1. A method for quantification of the concentration of one or more cannabinoid compounds in a liquid sample, the method comprising: a) contacting the liquid sample with at least one cannabinoid-sensitive visualization reagent; b) allowing the at least one cannabinoid-sensitive visualization reagent to develop for a defined amount of time; and c) comparing the resulting color change of the at least one cannabinoid-sensitive visualization reagent to a calibrated quantification reference chart.\n2. The method of claim 1, wherein the at least one cannabinoid-sensitive visualization reagent is present in a liquid form.\n3. The method of claim 1, wherein the at least one cannabinoid-sensitive visualization reagent is present in a solid form.\n4. The method of claim 1 or 2, wherein the liquid sample is contacted separately with the at least one cannabinoid-sensitive visualization reagent.\n5. The method of claim 3, wherein the at least one cannabinoid-sensitive visualization reagent is impregnated in a test strip.\n6. The method of claim 5, wherein the test strip comprises a porous matrix uniformly impregnated with the at least one cannabinoid-sensitive visualization reagent.\n7. The method of any one of claims 1-6, wherein the at least one cannabinoid-sensitive visualization reagent reacts with THC, CBD, or CBN.\n8. The method of claim 7, wherein the cannabinoid is THC.\n9. The method of claim 7, wherein the cannabinoid is CBD.\n10. The method of claim 8, wherein the at least one cannabinoid-sensitive visualization reagent is one or more diazonium salts, a Duquenois reagent, a Ghamrawy reagent, or a modified Ghamrawy reagent.\n11. The method of claim 10, wherein the one or more diazonium salts are: Fast Blue B, Fast Blue BB, Fast Red B, Fast Red GG, Fast Orange GR, Fast Corinth V, Fast Garnet GC, Fast Red AV, or Fast Bordeaux GP.\n12. The method of claim 9, wherein the at least one cannabinoid-sensitive visualization reagent is a strong base.\n13. The method of claim 13, wherein the strong base is potassium hydroxide or sodium hydroxide.\n14. The method of claim 7-13, wherein the at least one cannabinoid-sensitive visualization reagent is impregnated in a test strip.\n15. The method of claim 14, wherein the test strip comprises a porous matrix uniformly impregnated with the at least one cannabinoid-sensitive visualization reagent.\n16. A method for quantification of one or more cannabinoid compounds in a solid test sample, the method comprising: 1) contacting the solid test sample with an extraction solvent, wherein one or more cannabinoids are extracted from the solid sample into an extraction solvent resulting in a cannabinoid-containing liquid extraction solution; 2) contacting the cannabinoid-containing liquid extraction solution with one or more cannabinoid-sensitive visualization reagents; and 3) comparing the intensity of the resulting color change of the one or more cannabinoid-sensitive visualization reagents to a calibrated quantification reference chart.\n17. An apparatus comprising a test strip impregnated with at least one cannabinoid-sensitive visualization reagent.\n18. The apparatus of claim 17 wherein the at least one cannabinoid-sensitive visualization reagent is one or more diazonium salts, a Duquenois reagent, a Ghamrawy reagent, a modified Ghamrawy reagent, and potassium hydroxide.\n19. A kit for quantification of the concentration of one or more cannabinoid compounds in a sample, the kit comprising: 1) at least one cannabinoid sensitive visualization reagent; and 2) a calibrated quantification reference chart.\n20. The kit of claims 19 wherein the at least one cannabinoid-sensitive visualization reagent is present in a liquid form or a solid form.\n21. The kit of claim 19 or 20, wherein the at least one cannabinoid-sensitive visualization reagent is pre-measured as a dry reagent in one or more reaction containers.\n22. The kit of any one of claims 19-21, wherein the at least one cannabinoid-sensitive visualization reagent is impregnated into a test strip.\n[0001] This application claims priority from U.S. Provisional Patent Application Ser. No. 61/771,263 filed on Mar. 1, 2013, entitled \"Cannabidiol Quantification\"; U.S. Provisional Patent Application Ser. No. 61/827,128 filed on May 24, 2013 entitled \"Cannabinoid Quantification, In Solution\"; and U.S. Provisional Patent Application Ser. No. 61/884,409 filed on Sep. 30, 2013 entitled \"Cannabinoid Quantification\", all of which are expressly incorporated by reference herein to the extent permitted by law.\n[0002] The present invention relates to compositions and methods for accurate quantification of cannabinoid compounds in a sample.\n[0003] The legal production, sale and use of cannabis for medical purposes is becoming more prevalent in many countries, including the United States and Canada. It is important for medical cannabis growers, dispensaries and end-users to know the concentration of certain cannabinoids, particularly delta-9-tetrahydrocannabinol (THC) in specific plant samples--such information can be important for strain development, for optimizing production/growing cycles, for complying with jurisdiction-specific legal requirements, and for other quality control purposes. Quantification of cannabinoids in a sample generally requires a laboratory test, for instance using gas chromatography, which can be expensive and generally requires time to send the sample to an appropriate lab and wait for the results. Home-based tests, such as Alpha-Cat, have been developed using thin-layer chromatography, however this test is still quite complex for the average untrained user, and the quantification resolution of the test is limited.\n[0004] Reagents are known in the art that react chemically with CBD, under specific reaction conditions, to create a color change. Mechoulam (Tetrahedron 24(16): 5615-5624, 1968) teaches that CBD, when contacted with 5% ethanolic potassium hydroxide (KOH) is converted to quinone, which has a purple color.\n[0005] U.S. Pat. No. 4,771,005, issued to Spiro, teaches methods for positive/negative cannabinoid detection in human sample using a diazonium salt, for instance Fast Blue BB.\n[0006] WO/1989/009395 (published in the name of Fraser and Johnson) teaches a test paper for positive/negative cannabinoid detection using diazonium salt, for instance Fast Blue BB.\n[0007] U.S. Pat. No. 8,124,420, issued in the name of Amisar, teaches a test paper and kit for detection and/or identification of a range of drugs of abuse, which may include cannabinoids, and the test paper may include a diazonium salt, for instance Fast Corinth V.\n[0008] Fischedick et al. (2009 Phytochem Anal 20:421-6.) teaches a method for quantifying cannabinoids in a sample using high performance thin layer chromatography (HPTLC).\n[0009] In one aspect of the invention, a method for quantification of the concentration of one or more cannabinoid compounds in a liquid sample is provided. The method involves contacting the liquid sample with at least one cannabinoid-sensitive visualization reagent; allowing the at least one cannabinoid-sensitive visualization reagent to develop for a defined amount of time; and comparing the resulting color change of the at least one cannabinoid-sensitive visualization reagent to a calibrated quantification reference chart. The at least one cannabinoid-sensitive visualization reagent may be present in a liquid form. The at least one cannabinoid-sensitive visualization reagent may be present in a solid form. The liquid sample may be contacted separately with the at least one cannabinoid-sensitive visualization reagent. The at least one cannabinoid-sensitive visualization reagent may be impregnated in a test strip. The test strip may include a porous matrix uniformly impregnated with the at least one cannabinoid-sensitive visualization reagent. The at least one cannabinoid-sensitive visualization reagent reacts with cannabinoids, which can include THC, CBD, or CBN. Optionally, the cannabinoid may be solely THC, CBD or another cannabinoid. The at least one cannabinoid-sensitive visualization reagent may include one or more diazonium salts, a Duquenois reagent, a Ghamrawy reagent, or a modified Ghamrawy reagent. The one or more diazonium salts may include Fast Blue B, Fast Blue BB, Fast Red B, Fast Red GG, Fast Orange GR, Fast Corinth V, Fast Garnet GC, Fast Red AV, or Fast Bordeaux GP. Optionally, the at least one cannabinoid-sensitive visualization reagent may be a strong base, which may be potassium hydroxide or sodium hydroxide. Further, the at least one cannabinoid-sensitive visualization reagent may be impregnated in a test strip. Further still, the test strip may include a porous matrix uniformly impregnated with the at least one cannabinoid-sensitive visualization reagent.\n[0010] In another aspect of the invention, a method for quantification of one or more cannabinoid compounds in a solid test sample is provided. The method involves contacting the solid test sample with an extraction solvent, wherein one or more cannabinoids are extracted from the solid sample into an extraction solvent resulting in a cannabinoid-containing liquid extraction solution; contacting the cannabinoid-containing liquid extraction solution with one or more cannabinoid-sensitive visualization reagents; and comparing the intensity of the resulting color change of the one or more cannabinoid-sensitive visualization reagents to a calibrated quantification reference chart.\n[0011] In another aspect of the invention, an apparatus which includes a test strip impregnated with at least one cannabinoid-sensitive visualization reagent is disclosed. Optionally the at least one cannabinoid-sensitive visualization reagent may be one or more diazonium salts, a Duquenois reagent, a Ghamrawy reagent, a modified Ghamrawy reagent, and potassium hydroxide.\n[0012] In another aspect of the invention, a kit for quantification of the concentration of one or more cannabinoid compounds in a sample is disclosed. The kit includes at least one cannabinoid sensitive visualization reagent, and a calibrated quantification reference chart. Optionally, the at least one cannabinoid-sensitive visualization reagent is present in a liquid form or a solid form. Further and optionally, the at least one cannabinoid-sensitive visualization reagent is pre-measured as a dry reagent in one or more reaction containers. Further still, the at least one cannabinoid-sensitive visualization reagent is impregnated into a test strip.\n[0013] Aspects of the present invention are based, in part, on the finding that certain cannabinoid-sensitive visualization reagents may be used to quantify the cannabinoid concentration in a sample. Herein, it has been demonstrated that the use of one or more cannabinoid-sensitive visualization reagents which cause an absorbance shift (color change) in a solution upon contact with cannabinoids including THC and/or CBD, may be utilized to quantify the concentration of such cannabinoids in a given sample. Quantification is achieved by contacting the one or more cannabinoid-sensitive visualization reagents with a liquid cannabinoid-containing sample, or alternatively with a liquid extraction from a solid cannabinoid-containing sample, and comparing the resulting absorbance shift to that caused by samples with known cannabinoid concentrations. Herein, examples have been provided of such assays to determine the concentration of THC, CBD, and/or other cannabinoids in a solid plant test sample, or a liquid test sample. Examples have been provided of a calibrated quantification reference chart, useful in said assay, calibrated to determine the cannabinoid concentration in a solid plant test sample, and suitable for solid plant test samples having cannabinoid concentration ideally between 0-25%, but potentially higher. In some embodiments, the calibrated quantification reference chart has been optimized for this cannabinoid concentration range by extracting cannabinoids from series of solid samples having known cannabinoid concentrations ranging from 0% to 25%, using a consistent and uniform extraction solvent composition, volume, and extraction time for all of the samples, and contacting the resulting cannabinoid-containing extraction liquid with a defined amount of one or more cannabinoid-sensitive visualization reagents. The resulting absorbance shift, or color change, caused by each of the samples of known cannabinoid concentration provides a calibrated quantification reference chart for use in the experimental assay for the test sample--by extracting the cannabinoids from the unknown test sample using the exact same extraction solvent composition, volume, and extraction time; contacting the resulting cannabinoid-containing extraction liquid with the same amount/concentration of the one or more cannabinoid-sensitive visualization reagents; and comparing the resulting absorbance shift(s), or color change(s), with the calibrated quantification reference chart, one may thus determine the cannabinoid concentration in the unknown solid test sample. In the examples provided herein, the extraction solvent composition, volume, and extraction time have been optimized to ensure that the absorbance shift caused by contacting the resulting cannabinoid-containing extraction solution with the one or more cannabinoid-sensitive visualization reagents is in the optimized range of the visualization reagent, such that the absorbance, or color change intensity, is proportional to the cannabinoid concentration in the test sample. In certain aspects of the invention, the cannabinoid that may be quantified is one or more of THC, CBD and/or CBN, and the cannabinoid-sensitive visualization reagent one or more of: i) diazonium salt, for instance Fast Blue B, Fast Blue BB, Fast Blue RR, Fast Corinth V, Fast Garnet, Fast Bordeaux, and the like; ii) a Duquenois reagent; and iii) a Ghamrawy reagent or modified Ghamrawy reagent. In certain aspects of the invention, the cannabinoid that may be quantified is CBD, and the cannabinoid-sensitive visualization reagent is a strong base for instance potassium hydroxide or sodium hydroxide, wherein the medium in which the strong base contacts the CBD is methanol, ethanol, propanol, or another lower alcohol solvent.\n[0014] Examples have been provided of a variety of visualization reaction compositions and methods suitable for the present invention. In certain aspects of the invention, the visualization reaction may occur in a liquid solution, wherein the one or cannabinoids of the liquid test sample, or extracted from the solid test sample, are contacted with the one or more cannabinoid-sensitive visualization reagents in solution, for instance using a solvent composition that is permissive for the visualization reaction. In certain aspects, the cannabinoids of the test sample are separately contacted with each of the one or more cannabinoid-sensitive visualization reagents in separate reaction vessel. In other aspects of the invention, the visualization reaction may be accomplished using a test paper, wherein the test paper is impregnated with a cannabinoid-sensitive visualization reagent. In certain aspects, the test paper may be a test strip comprising one or more test pads, wherein each test pad is impregnated with a different cannabinoid-sensitive visualization reagent. In this regard, one of unique features of the present invention is based in part on the finding that certain cannabinoid-sensitive visualization reagents have different, and potentially overlapping, quantification ranges and/or sensitivities. Thus, in certain aspects of the present invention, the use of more than one cannabinoid-sensitive visualization reagent may allow for an extended range and accuracy of quantification. Another feature is that certain cannabinoid sensitive visualization reagents may be impregnated on a test strip and included in a kit in such a way that the activity of the visualization reagent is retained when the strip is eventually used by the end-user.\n[0015] Two sets of identical figures are being submitted herewith: a first set rendered in black and white, and a second set is rendered in colour.\n[0016] FIG. 1 depicts a calibrated quantification reference chart for THC samples having an ideal range of 5-20%. The quantification reference chart was generated using Fast Blue BB. The chart shows a light yellow colour at the left side, changing to a darker yellow/orange on the right side.\n[0017] FIG. 2 depicts an extended range calibrated quantification reference chart. The chart includes overlapping ranges for 2 different cannabinoid-sensitive visualization reagents, to allow for quantification from 0% to over 25% THC in a solid sample.\n[0018] FIG. 3 depicts a calibrated quantification reference chart for CBD samples having ideal range 0-15%. Moving from left to right, the figure shows the color changing from very light purple at the lower end of the scale to a much darker purple at the higher end of the scale.\n[0019] FIG. 4 depicts a calibrated reference chart for Fast BB impregnated test strips. The chart shows that, moving from left to right, the color change of the strip goes from a very light orange/red at the low end of the scale to a much darker red at the higher end of the scale.\n[0020] FIG. 5 depicts representative test papers prepared using 30% KOH (left), 10% KOH (middle), and 1% KOH (right).\n[0021] FIG. 6 depicts a CBD Calibrated Reference Chart. Moving from left to right on the chart, the color change shown on the chart goes from a very light violet/purple for the lower CBD % to a much darker purple for higher CBD %.\n[0022] FIG. 7 depicts a THC Calibrated Reference Chart using modified Ghamrawy reagent impregnated test papers. Moving from left to right on the chart, the color change shown on the chart goes from a very light violet/purple for the lower THC % to a much darker purple for higher THC %.\n[0023] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention. As employed throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings.\n[0024] The term `sample` means a complex substance that may be tested or analyzed for the presence of certain compounds. A `sample` may be a liquid sample or a solid sample. A liquid sample may comprise a bodily fluid such as urine or blood. A liquid sample may comprise a solvent extract of a solid sample, wherein various compounds from the solid sample are extracted into the liquid solvent using methods known in the art. A solid sample may include plant material, for instance cannabis plant material.\n[0025] The term `cannabis` means a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. The term `cannabis` may also refer to plant material derived or extracted from the cannabis plant, for instance the leaves, stem, seeds, flowering bodies, or other portions of the plant.\n[0026] The term `cannabinoid` or `cannabinoids` means a class of chemical compounds which include the phytocannabinoids (oxygen-containing C21 aromatic hydrocarbon compounds found in the cannabis plant), and chemical compounds which mimic the actions of phytocannabinoids or have a similar structure (e.g., endocannabinoids, found in the nervous and immune systems of animals and that activate cannabinoid receptors). Phytocannabinoids are known to occur in significant quantities in the cannabis plant, and may include, but are not limited to tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and cannabigerol (CBG).\n[0027] The term `THC` means tetrahydrocannabinol and may include different isoforms and variants, such as delta-9-Tetrahydrocannabinol (Δ9-THC) and delta-8-tetrahydrocannabinol (Δ8-THC). The inventors herein disclose methods and an apparatus for quantification of THC and/or other cannabinoids from a sample, for instance from a solid cannabis sample.\n[0028] The term `CBD` means cannabidiol, a cannabinoid often found in cannabis, and having a CAS registry number 13956-29-1. Cannabidiol is known to have many beneficial medicinal qualities.\n[0029] The term `extraction` means to transfer compounds from a sample into another medium, for instance into a liquid solvent. The solvent may be chosen such that certain desired compounds are soluble in the solvent, and thus when the sample is contacted with the solvent, the desired compounds are transferred to the solvent. Extraction of solid samples may be aided or enhanced by grinding, macerating or otherwise pulverizing the sample material. Extraction is aided by shaking, vortexing or otherwise mixing the solvent with the sample. Uniform extraction yields may be achieved by using defined extraction methods, including duration of extraction, solvent composition, and the like. In certain embodiments, a solid sample may be heated prior to extraction--this may serve to chemically convert certain compounds that are not soluble in the extraction solvent into compounds that are soluble in the extraction solvent. Furthermore, the converted compounds may be more reactive with visualization reagents. In certain embodiments of the invention, solid cannabis samples are heated prior to extraction in order to decarboxylate the acid form of THC, CBD, etc. into non-acid forms which are more readily extracted and more readily react with the visualization reagents of the present invention. Ideally, the heat conversion is carried out a temperature that is below the volatilization temperature of the cannabinoids, but above the decarboxylation temperature. In this way, any THC-A and CBD-A in the solid sample, may be converted to THC and CBD prior to extraction, and the subsequent visualization reactions of the invention will give a more accurate quantification of total THC and/or total CBD in the sample.\n[0030] A `visualization reagent` means a reagent or compound that changes color upon contact with a particular analyte or class of analytes, or alternatively causes the analyte to change color upon contact with the visualization reagent, or alternatively causes a color change in a reaction medium containing a particular analyte or class of analytes. The change in color will result in a change in the spectral absorbance of the reaction medium, detection of which may be visible to the naked eye, or may be more accurately quantified using a device such as a colorimeter, spectrometer, spectrophotometer, or the like. Visualization reagents may alternatively be referred to as colorimetric reagents. There are numerous types of visualization reagents described in the art. Certain visualization reagents may be suitable for quantification of analytes, while others may not. Suitable visualization reagents may cause a color change that is proportional to the concentration of the analyte, over a specific analyte concentration range--sometimes referred to as the `linear range` or `optimal range` of the visualization reagent. The optimal range of the visualization reagent for the specific analyte must be wide enough to provide quantification information across a sufficient range to be a useful visualization reagent. A visualization reaction may require contacting the visualization reagent with the analyte in reaction conditions suitable to cause the appropriate chemical reaction. For instance, a suitable solvent may be used to facilitate the visualization reaction. The suitable solvent of the present invention may be an alcohol such as methanol, ethanol, propanol and the like.\n[0031] A `diazonium salt`, or `diazonium compound`, is a compound belonging to a group of organic compounds sharing a common functional group R--N2+X-- where R can be any organic residue such alkyl or aryl and X is an inorganic or organic anion such as a halogen. Diazonium salts, especially those where R is an aryl group, are important intermediates in the organic synthesis of azo dyes. Diazonium salts are often used as visualization reagents by conversion of the diazonium salt into an azo dye, such conversion causing a change in absorbance. Examples of diazonium salts may include, but are not limited to, Fast Blue B (3,3'-dimethoxybenzidine (o-dianisidine)), Fast Blue BB (4-Benzoylamino-2,5-diethoxyaniline), Fast Red B (2-Methoxy-4-nitroaniline), Fast Red GG (4-Nitroaniline), Fast Orange GR (2-Nitroaniline), Fast Corinth V (2-methoxy-5-methyl-4-(4-methyl-2-nitrophenyl)-azobenzene-diazonium), Fast Garnet GC (4-(m-Tolylazo)-3-methylaniline), Fast Red AV, and Fast Bordeaux GP.\n[0032] A `Duquenois reagent` is a reagent used in a Duquenois-Levine test for detecting cannabis (see: P. Duquenois and H. N. Moustapha, J. Egypt. Med. Ass., 1938, 21, 224.) A Duquenois reagent may comprise a mixture of vanillin and acetaldehyde, along with hydrochloric acid. In certain embodiments, the hydrochloric acid may be substituted for another acid. In certain embodiments, the strong acid may be present as a dry form, for instance p-toluenesulfonic acid, and may be impregnated in a test paper/strip.\n[0033] A `Ghamrawy reagent` refers to a combination of compounds that may be used for detection of THC and CBD. A Ghamrawy reagent is further described in: Kovar, Karl-Artur and Martina Laudszun. (Chemistry and Reaction Mechanisms of Rapid Tests for Drugs of Abuse and Precursors Chemicals, United Nations Scientific and Technical Notes v.89-51669, Germany. February 1989. The Ghamrawy reagent consists of p-dimethylaminobenzaldehyde (p-DMAB) along with concentrated sulfuric or hydrochloric acid. In certain embodiments, the Ghamrawy reagent may be modified--the inventors have identified other strong acids that may be useful for catalyzing the color reaction with p-DMAB. For instance, p-toluenesulfonic acid that may be used instead of hydrochloric acid or sulfuric acid. This acid is advantageous for use in test strips, by virtue of the fact that p-toluenesulfonic acid may be present as a solid, whereas hydrochloric and sulfuric acid generally are not. Furthermore p-toluenesulfonic acid is non-corrosive and thus will not degrade the test strip. This surprising finding has enabled the use of test papers/strips impregnated with the modified Ghamrawy reagent for quantification of THC and/or CBD. Thus, a `modified Ghamrawy reagent` comprises p-DMAB and a strong acid, for instance p-toluenesulfonic acid. Other strong acids that may be present as a solid may also be used in a modified Ghamrawy reagent.\n[0034] The term `KOH` means `potassium hydroxide`. Potassium hydroxide may have the CAS registry number 1310-58-3. The term `NaOH` means `sodium hydroxide`. Sodium hydroxide may have the CAS registry number 1310-73-2.\n[0035] The term `cannabinoid-sensitive visualization reagent` refers to a reagent such as a visualization reagent that undergoes a change in properties, such as spectral absorbance, upon contact with a cannabinoid. In the context of the present invention, the change in chemical properties may occur due to a change in either reactant in the visualization reaction, or even a change in the reaction medium itself. Alternatively, the change in chemical properties may occur due to the formation of a new compound, such as a reaction by-product. A cannabinoid-sensitive visualization reagent may be a diazonium salt. Certain diazonium salts are known to cause a change of color in the presence of cannabinoids such as THC, CBD and/or CBN--such diazonium salts include, but are not limited to, Fast Blue B, Fast Blue BB, Fast Corinth V, and Fast Garnet GC. A cannabinoid-sensitive visualization reagent may be a Duquenois reagent. A cannabinoid-sensitive visualization reagent may be a Ghamrawy reagent or a modified Ghamrawy reagent. A cannabinoid-sensitive visualization reagent may be potassium hydroxide or sodium hydroxide.\n[0036] The term `permissive` or `permissive solvent` refers to solvents that have a composition that allow the desired chemical reaction to occur. For instance, certain chemical reactions may proceed much more readily in an alcohol than in water. In such case, the alcohol would be a permissive solvent and would be the desired solvent for the reaction. In various embodiments, the use of permissive solvents is important for the utility of the invention.\n[0037] The term `calibrated quantification reference chart` means a chart, graph, or other visual representation showing the specific absorbance shift or color change of one or more specific visualization reagents caused by a specific analyte across a range of specific concentration, under specific conditions, such that comparison of an analyte at an unknown concentration, using the same one or more specific visualization reagents under the same specific conditions, to the calibrated quantification reference chart will allow one to determine the concentration of that analyte in the unknown test sample. The specific absorbance shift or color change may be determined for instance using a test paper, test strip, a colorimeter, a spectrometer, or by visual inspection. The present invention utilizes a calibrated quantification reference chart to determine the concentration of cannabinoids in a sample. In certain embodiments of the invention, a calibrated quantification reference chart may be used or created for determining the cannabinoid concentration in an unknown solid sample by extracting cannabinoids from series of solid samples having known cannabinoid concentrations, using a uniform extraction solvent composition, volume, and extraction time for all of the samples, and contacting the resulting cannabinoid-containing extraction liquid with a defined amount of one or more cannabinoid-sensitive visualization reagents. The resulting absorbance shift(s), or color change(s), caused by each of the samples of known cannabinoid concentration provides a calibrated quantification reference chart for use in the experimental assay for the unknown test sample. By then extracting the cannabinoids from the unknown test sample using the exact same extraction solvent composition, volume, and extraction time; contacting the resulting cannabinoid-containing extraction liquid with the same amount/concentration of one or more cannabinoid-sensitive visualization reagents; and comparing the resulting absorbance shift(s), or color change(s), with the calibrated quantification reference chart, one may thus determine the cannabinoid concentration in the unknown solid sample.\n[0038] The term `porous matrix` refers to a solid material, ie. a matrix, that is permeated with pores or small holes to allow absorbance of a fluid into the matrix. A porous matrix may be a type of paper or filter, such as blotting paper. Examples of a porous matrix include Whatman paper, CF1, CF2, CF3, cellulose paper, and the like.\n[0039] The term `test paper` refers to a porous matrix which is impregnated with a diagnostic reagent, for instance a cannabinoid-sensitive visualization reagent such as a diazonium salt, Duquenois reagent, Ghamrawy reagent, or modified Ghamrawy reagent. Impregnation of the porous matrix with the reagent may be accomplished in several different ways. The reagent to be impregnated into the porous matrix to form the test paper may first be dissolved in a suitable solvent, and the porous matrix then contacted with or submersed in the resulting solution containing the dissolved reagent. For instance, the solvent may be an alcohol such as methanol, ethanol or propanol. Preferably, the solvent may be a ketone such as acetone or methyl ethyl ketone--these solvent may prevent degradation of the dye and reduce background coloration on the test strips. Evaporation of the solvent will result in a dry test strip impregnated with the reagent. Suitable solvents should thus be chosen such that the reagent is miscible in the solvent, and such that the solvent is volatile enough to effectively evaporate away from the porous matrix. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, isopropanol, petroleum ether, methyl ethyl ketone, acetone, dimethylchloride, hexane. In certain embodiments, the visualization reagent may be heated after impregnation of the test paper, or during the drying of the test paper. Such heating may activate the visualization reagent. In certain embodiments the test paper may be subsequently sealed into an air tight package, for instance by vacuum sealing. This may preserve the activation or activity of the visualization reagent. A test paper may be contacted with a test compound, for instance a cannabinoid, in a suitable solvent, and the reaction of the test compound with the diagnostic reagent may cause the test paper to change color. In various embodiments of the invention, the color change of the test paper may be proportional to the concentration of one or more cannabinoids in the solution, and may thus be used to quantify the cannabinoid concentration.\n[0040] The term `test strip` refers to a strip of material to which is attached one or more test papers. A test strip may be elongated to allow for ease of contacting with the test solution, for instance by dipping into a test tube or the like. The test strip may include i) a backing material, which may be absorbent or non-absorbent, and is preferentially but not necessarily inert; ii) one or more test papers comprising one or more cannabinoid-sensitive visualization reagents; and iii) an adhesive to attach the one or more test papers to the backing material.\nQuantification of Cannabinoid Concentration in Liquid or Solid Samples Using One or More Cannabinoid-Sensitive Visualization Reagents\n[0041] Herein, the inventors describe methods for determination of the cannabinoid concentration in liquid or solid samples using one or more cannabinoid-sensitive visualization reagents. The inventors have surprisingly determined that certain cannabinoid-sensitive visualization reagents can be utilized in conjunction with a calibrated reference chart to determine the actual concentration of cannabinoids in a sample, rather than merely detecting the presence or absence of cannabinoids, and are thus suitable for cannabinoid quantification. In certain embodiments of the invention, such one or more cannabinoid-sensitive visualization reagents are first contacted with a cannabinoid-containing liquid sample, or with a liquid extraction of a cannabinoid-containing solid sample, under conditions which cause a color change or absorbance shift of the one or more visualization reagents, wherein such color change or absorbance shift is proportional to the cannabinoid concentration. The color change or absorbance shift of the visualization reagent is then compared to a calibrated quantification reference chart, wherein the calibrated quantification reference chart is created by testing a series of liquid or solid sample of known cannabinoid concentration under the exact same test conditions as the sample of unknown concentration--ideally the calibrated quantification reference chart would show the color change or absorbance shift at a number of known cannabinoid concentrations. In such a way, one may compare the color change or absorbance shift of the sample of unknown cannabinoid concentration to the calibrated quantification reference chart to determine the cannabinoid concentration in the unknown sample. Determination of the color change or absorbance shift may be accomplished by numerous means, for instance using a colorimeter or spectrophotometer, or by visual inspection. In certain embodiments, the one or more cannabinoid-sensitive visualization reagents is a diazonium salt, such as Fast Blue B, Fast Blue BB, Fast Corinth V, Fast Garnet GC, and the like, which are useful for quantification of THC, CBD and/or CBN. In other embodiments, the cannabinoid-sensitive visualization reagent is a strong base, for instance potassium hydroxide or sodium hydroxide, useful for quantification of CBD. In other embodiments, the one or more cannabinoid-sensitive visualization reagents is a Duquenois reagent, a Ghamrawy reagent, or a modified Ghamrawy reagent.\n[0042] In one embodiment of the invention, there is provided a method for quantification of the concentration of one or more cannabinoid compounds from a liquid test sample, the method involves: 1) contacting the cannabinoid-containing liquid sample with a defined amount of one or more cannabinoid-sensitive visualization reagents; 2) allowing the resulting visualization reaction(s) to develop for a defined amount of time; and 3) comparing the intensity of the resulting color change, or absorbance shift, of the one or more cannabinoid-sensitive visualization reagents to a calibrated quantification reference chart, wherein such comparison allows determination of the cannabinoid concentration in the test sample. The calibrated quantification reference chart may be produced, for instance, by contacting a series of calibrated liquid samples having pre-determined cannabinoid concentrations with the same amount/composition of one or more cannabinoid-sensitive visualization reagents under the exact same conditions as to be used for the unknown test sample, including using the same one or more cannabinoid-visualization reagents and the same color development time as to be used for the test sample. In certain embodiments wherein two or more cannabinoid-sensitive visualization reagents are used, each visualization reagent may be separately contacted with the cannabinoid(s) of the test sample. In certain embodiments, the method may be useful for the quantification of cannabinoids THC, CBD and/or CBN in a liquid sample. The one or more cannabinoid-sensitive visualization reagents may be a diazonium salt. The one or more cannabinoid-sensitive visualization reagents may be chosen from the following: Fast Blue B, Fast Blue BB, Fast Blue RR, Fast Corinth V, Fast Garnet, Fast Bordeaux. The diazonium salt(s) and the cannabinoids may be contacted in permissive solvent. The one or more cannabinoid-sensitive visualization reagents may be a Duquenois reagent, a Ghamrawy reagent, and/or a modified Ghamrawy reagent. In other embodiments, the method may be useful for the quantification of CBD in a liquid sample. The cannabinoid-sensitive visualization reagent may be a strong base, for instance potassium hydroxide, sodium hydroxide. The strong base, for instance potassium hydroxide, and/or cannabinoid(s) may be contacted in a permissive solvent such as a lower alcohol, for instance methanol, ethanol, propanol, and the like.\n[0043] In another embodiment of the invention, there is provided a method for quantification of one or more cannabinoid compounds in a solid test sample, the method involves: 1) contacting a defined amount of solid test sample with a defined volume of an extraction solvent for a defined amount of time, wherein one or more cannabinoids are extracted from the solid sample into an extraction solvent resulting in a cannabinoid-containing liquid extraction solution; 2) contacting the resulting cannabinoid-containing liquid extraction solution with defined amount of one or more cannabinoid-sensitive visualization reagent; 3) allowing the resulting visualization reaction(s) to develop for a defined amount of time; and 4) comparing the intensity of the resulting color change, or absorbance shift, of the one or more cannabinoid-sensitive visualization reagents to a calibrated quantification reference chart, wherein such comparison allows determination of the cannabinoid concentration in the solid test sample. The calibrated quantification reference chart may be produced by performing the same assay method on a series of solid samples having known cannabinoid concentrations and recording the resulting absorbance changes. For instance, the calibrated quantification reference chart may be produced by contacting a series of solid samples having pre-determined cannabinoid concentrations with the same defined amount of the same defined extraction solvent composition, and then contacting a defined amount of resulting cannabinoid-containing extraction solution with one or more cannabinoid-sensitive visualization reagents under the exact same conditions as to be used for each test sample, including using the same one or more cannabinoid-visualization reagent compositions and concentrations, and the same color development time as to be used for the test sample. In certain embodiments wherein two or more cannabinoid-sensitive visualization reagents are used, each visualization reagent is separately contacted with the cannabinoid(s) of the test sample. In certain embodiments, the method may be useful for quantification of the concentration cannabinoids THC, CBD and/or CBN in a solid test sample. The one or more cannabinoid-sensitive visualization reagent may be a diazonium salt. The cannabinoid-sensitive visualization reagent may be chosen from the following: Fast Blue B, Fast Blue BB, Fast Blue RR, Fast Corinth V, Fast Garnet, Fast Bordeaux. The diazonium salt(s) and the cannabinoids may be contacted in permissive solvent. The cannabinoid-sensitive visualization reagent may be a Duquenois reagent, a Ghamrawy reagent, or a modified Ghamrawy reagent. In certain embodiments, the method may be useful for the quantification of CBD in a solid test sample. The cannabinoid-sensitive visualization reagent may be a strong base, for instance potassium hydroxide, sodium hydroxide. The strong base, for instance potassium hydroxide, and/or cannabinoid(s) may be contacted in a permissive solvent such as a lower alcohol, for instance methanol, ethanol, propanol, isopropanol, etc.\n[0044] Extended Range Of Quantification\n[0045] Herein, cannabinoid quantification assays are described which have an extended range of quantification. The cannabinoid quantification assays described in various embodiments of the invention all have a lower and upper limit of quantification, below and above which quantification is relatively ineffective. Below the lower limit of quantification, the cannabinoid concentration is too low to cause a significant absorbance shift, or color change, from the cannabinoid-sensitive visualization reagent. Above the upper limit of quantification, the absorbance shift, or color change, may become saturated such that no further color change may be detected, even with an increased concentration of the test analyte. Optimal quantification results are thus achieved between the lower and upper limits of quantification, and the greater the distance between these two values, the more useful the assay may be--suitable visualization reagents must be tested and selected in order to obtain a useful quantification assay. Since cannabinoids may exist at wide range different concentrations in a particular sample, it would be desirable to develop assays with extended ranges. In order to accomplish this, the present inventors take advantage of the fact that different visualization reagents, such as cannabinoid-sensitive visualization reagents, often have different sensitivity to, and/or optimal ranges for, the test compound in question, for instance cannabinoids. These different visualization reagents may have different lower and upper limits of quantification, and thus different effective quantification ranges. In fact, certain visualization reagents may have overlapping quantification ranges, which may be useful for developing an extended range assay method using multiple visualization reagents.\n[0046] In certain embodiments of the invention, there is provided an extended range cannabinoid quantification assay method involving the use of two or more cannabinoid-sensitive visualization reagents, useful for quantification of cannabinoids in a liquid or solid test sample. The extended range cannabinoid quantification assay method may have certain advantages over assay methods using a single visualization reagent. The assay method may be carried out using the same steps as described in other aspects of the invention that use a single visualization reagent (described herein), except that two or more visualization reactions are carried out in parallel, for instance in separate tubes or on separate test papers, and the absorbance shift, or color change, of each of the visualization reactions is compared to a calibrated reference chart, wherein the calibrated reference chart shows the calibrated quantification values for each of the two or more cannabinoid-sensitive visualization reagents used in the assay. In certain embodiments of the invention, the assay method may be useful for quantification of cannabinoid concentrations across an extended range. In certain embodiments of the invention, the two or more cannabinoid-sensitive visualization reagents have differing cannabinoid sensitivity and or optimal quantification ranges. In certain embodiments of the invention, the optimal quantification ranges of each of the one or more visualization reagents are overlapping. The overlapping ranges allows for the quantification of cannabinoids in a sample across a wider range, which may improve the utility of the assay. For instance, and by way of non-limiting example, user may have a number of solid samples with expected THC %'s between 0 and 25%; the use of first single visualization reagent may allow optimal quantification of THC between 0-10% in the solid sample. The use of a second visualization reagent with an optimal quantification range of 10-25% would extend the overall optimal range of the assay to 0-25%. The use of additional cannabinoid-sensitive visualization reagents having even different quantification ranges may be used to further extend the quantification range of the assay method. It should be noted that the use of more than one visualization reagent can also improve the accuracy of quantification of cannabinoids in the overlapping region of the optimal quantification ranges of the visualization reagents, due to multiple readouts from the two or more visualization reagents. In certain embodiments of the invention, the two or more cannabinoid-sensitive visualization reagents may be diazonium salts and/or Duquenois-Levine reagent and/or Ghamrawy reagent and/or modified Ghamrawy reagent. In certain embodiments of the invention, the diazonium salts may be selected from: Fast Blue B, Fast Blue BB, Fast Blue RR, Fast Corinth V, Fast Garnet, Fast Bordeaux, or other cannabinoid-sensitive diazonium salts.\n[0047] Visualization\n[0048] In certain embodiments of the invention, methods are described for contacting cannabinoids from a test sample with one or more cannabinoid-sensitive visualization reagents, which results in an absorbance shift, or color change, suitable for quantification of the cannabinoids in the test sample. As exemplified in various working examples provided herein, the invention provides different compositions and methods useful for carrying out the visualization reaction. In certain embodiments, the visualization reaction may be carried out in a liquid solution, for instance in a reaction vessel such as a test tube, microtube, sample container, etc. A liquid solution of the cannabinoid-sensitive visualization reagent may be added to a liquid cannabinoid-containing solution, according to the methods of the present invention, and the color reaction may thus occur in solution. In certain embodiments of the invention, the cannabinoid-sensitive visualization reagent solution may be prepared fresh at the time of use.\n[0049] An aspect of the present invention is to provide simple assays for cannabinoid quantification, and thus there are herein provided additional methods for reducing the number of required steps to complete the disclosed assays. These simplified assays are thus easier to use, have reduced handling which can increase accuracy, and are more cost effective. In certain cases, the simplification of the assays makes them more suitable for developing a test kit, as the modified steps may increase the shelf life of the reagents in the test kit. For instance, it is known that diazonium salt dyes such as Fast Blue B, Fast Blue BB, Fast Corinth V, etc. are inherently unstable in solution, particularly in aqueous solutions, and that this property has hindered the development of usable cannabinoid tests with this reagent, even for screening purposes. Thus, in certain embodiments of the invention, the diazonium salt visualization reagent may be provided in its dry powder form, and in certain aspects may be pre-measured in a defined amount in the reaction tube, or in a separate pouch to be added to the reaction tube. Other visualization reagents may similarly be provided in dry form. The user may then carry out the first steps of the quantification assay method in a first tube, thus extracting the cannabinoids from a solid sample in a defined amount of extraction solvent composition and volume, and then transfer a defined amount of the resulting cannabinoid-containing extraction liquid into a second tube containing a dry, pre-measured visualization reagent, and then mixing to dissolve the visualization reagent in the cannabinoid-containing extraction liquid, and comparing the resulting absorbance shift to a calibrated quantification reference chart. In the case of more than one visualization reagent, each may be provided in separate tubes. In certain embodiments of the invention, the diazonium salt may be stabilized as a salt of BF3, picric acid, sodium perchlorate, or other salts known in the art to stabilize such diazonium compounds, for instance as described in U.S. Pat. No. 4,771,005 and U.S. Pat. No. 8,124,420. In certain embodiments of the invention, the dry reagent may also include a solid diluent, preferable an inert solid diluent. The solid diluent may be useful for accurate measurement purposes, and may also serve as a dessicant and/or light protectant to aid in the stability of the dry reagent. In certain embodiments, the solid diluent may be soluble in the extraction solution to be used in the visualization reaction.\n[0050] In another aspect of the invention, there is provided a simplified assay for quantification of CBD in a sample. Potassium hydroxide and sodium hydroxide are cannabinoid-sensitive visualization reagents that are specific for CBD. In general, to obtain an absorbance shift, the potassium hydroxide must be contacted with CBD in an ethanolic medium. The inventors have disclosed herein that an absorbance shift may also occur with potassium hydroxide in a methanolic medium, or other lower alcoholic media. Thus, in order to reduce the number of steps for the CBD quantification assays of the present invention, it would be desirable to extract the CBD from the sample using an extraction solvent such as methanol, ethanol, propanol, or other lower alcohols. In this way, the subsequent visualization reaction may be easily accomplished, by adding, for instance, solid potassium hydroxide in a pre-measured amount, or by adding a small amount of a concentrated potassium hydroxide solution, without a requirement to change the reaction medium, since the extracted CBD will be in a suitable solvent that is permissive for the visualization reaction with potassium hydroxide. This simplified assay may be particularly suitable for development of a test kit, since the visualization reagent, for instance potassium hydroxide or sodium hydroxide, may be provided in a non-alcoholic stock solution, such as an aqueous solution, that is more suitable for shipping and storage. Similarly, the visualization reagent, potassium hydroxide or sodium hydroxide may be provided in a concentrated form, in either alcoholic or non-alcoholic solution, thus allowing the addition of a very small amount, such as a drop or a few drops, without requiring the CBD containing extraction solution to be exchanged to a lower alcohol to allow the visualization reaction.\n[0051] Test Papers And Strips\n[0052] Certain embodiments of the invention are based, in part, on the surprising finding that test papers impregnated with certain cannabinoid-sensitive visualization reagents may be used to quantify the cannabinoid concentration in a sample. The inventor has provided examples of such test papers suitable for quantifying cannabinoids such as THC, CBD and/or CBN in a sample. Certain test papers are particularly useful for quantifying CBD in a test sample. Certain test papers are particularly useful for quantifying THC in a test sample. In these embodiments, the previously described methods for quantifying cannabinoids using cannabinoid-sensitive visualization reagents is accomplished by carrying out the visualization reaction on the test paper or test strip, rather than in solution in a reaction vessel.\n[0053] CBD Test Papers and Strips\n[0054] In certain embodiments, the cannabinoid-sensitive visualization reagent, for instance KOH or NaOH, is specific for CBD, and is present on the test paper in a sufficient amount to cause a colorimetric reaction on the test paper when the test strip is contacted with CBD in a permissive solvent. The permissive solvent may be an alcohol such as ethanol, methanol, or isopropanol. The inventors disclose that test strips impregnated with a CBD-specific cannabinoid-sensitive visualization reagent such as KOH, which undergoes an absorbance shift (changes color) upon contact with CBD in an appropriate solvent, may be utilized to quantify the concentration of such CBD in a given sample. Quantification is achieved by contacting the said test strip with a liquid CBD-containing sample (in a permissive solvent), or alternatively with a liquid extraction from a solid CBD-containing sample (in a permissive solvent), and comparing the resulting absorbance shift to that caused by samples with known CBD concentrations. The inventors have provided an example of such an assay to determine the concentration of CBD in a solid plant sample. The inventors have provided an example of a quantification reference chart, useful in said assay, calibrated to determine the CBD concentration in a solid plant sample, and suitable for solid plant samples having CBD concentration between 0-15%, and possibly higher. The calibrated reference chart has been optimized for this CBD concentration range by extracting cannabinoids from a series of solid samples having known CBD concentrations ranging from 0% to 15%, using a uniform extraction solvent composition, volume, and extraction time for all of the samples, and contacting the resulting CBD-containing extraction liquid with test strips impregnated with KOH. The resulting absorbance shift, or color change, caused by each of the samples of known CBD concentration provides a reference chart for use in the experimental assay for the unknown sample--by extracting the CBD from the unknown sample using the exact same extraction solvent composition, volume, and extraction time; contacting the resulting CBD-containing extraction liquid with the test papers impregnated with KOH; and comparing the resulting absorbance shift, or color change, with the calibrated quantification reference chart, one may thus determine the CBD concentration in the unknown solid sample. In an Example provided herein, the extraction solvent composition, volume, and extraction time have been optimized to ensure that the absorbance shift caused by contacting the resulting CBD-containing extraction solution with test papers impregnated with KOH is in the linear range of the visualization reagent, such that the absorbance, or color change intensity, is proportional to the CBD concentration. An important feature of the quantification method using the KOH-impregnated test papers is that the solvent used to extract or otherwise dissolve the CBD is of an appropriate composition to allow the visualization reaction to occur on the test paper. In an Example detailed herein, for instance, the KOH is dried onto the paper, and the CBD-containing test samples are dissolved in methanol or propanol, thus when the liquid test sample is contacted with the test strip, the methanol or propanol solvent creates an appropriate environment for the visualization reaction to occur between the KOH and CBD. In these various embodiments, the test papers may be affixed to a solid support, for instance to form a test strip, colorimetric strip, dipstick, and the like. As used herein, the terms `test paper` and `test strip` may be used interchangeably.\n[0055] In one aspect of the invention, there is provided an apparatus including a test strip wherein the test strip comprises a porous matrix uniformly impregnated with a CBD-specific cannabinoid sensitive visualization reagent. The CBD-specific cannabinoid-sensitive visualization reagent may be a strong base. The CBD-specific cannabinoid-sensitive visualization reagent may be KOH or NaOH. In certain embodiments, the CBD-specific cannabinoid-sensitive visualization reagent is present on the test strip in sufficient amount to cause a colorimetric chemical reaction when contacted with CBD and a permissive solvent. The permissive solvent may be an alcohol. The permissive solvent may be ethanol, methanol, or propanol. In some embodiments, the CBD-specific cannabinoid-sensitive visualization reagent is present in the test paper in sufficient amount to allow quantification of CBD in a CBD containing sample.\n[0056] In another aspect of the invention, there is provided a method for quantification of the concentration of CBD in a liquid sample, the method involves: 1) contacting the liquid sample with a test strip comprising a porous matrix uniformly impregnated with a CBD-specific cannabinoid-sensitive visualization reagent, wherein the liquid sample comprises a solvent of an appropriate composition to allow a colorimetric reaction between the CBD and the CBD-specific cannabinoid-sensitive visualization reagent; 2) removing the test strip from the liquid sample and allowing it to develop for a defined amount of time; and 3) comparing the intensity of the resulting color change, or absorbance shift, of the test strip to a calibrated quantification reference chart, such that comparison of the color intensity change or absorbance shift of the test sample to calibrated quantification reference chart allows determination of the CBD concentration in the test sample. The calibrated quantification reference chart may be produced, for instance, by contacting a series of calibrated samples having pre-determined CBD concentrations with a series of test strips under the exact same conditions as to be used for the test sample, including using the same CBD-specific cannabinoid-sensitive visualization reagent, the same liquid solvent, and the same color development time as to be used for the test sample. The CBD-specific cannabinoid-sensitive visualization reagent may be a strong base. The CBD-specific cannabinoid-sensitive visualization reagent may be a KOH. The permissive liquid solvent may be an alcohol. The appropriate liquid solvent may be methanol, ethanol, or isopropanol.\n[0057] In another aspect of the invention, there is provided a method for quantification of CBD in a solid sample, the method involves: 1) contacting a defined amount of solid sample with a defined volume of an extraction solvent for a defined amount of time, wherein CBD is extracted from the solid sample into the extraction solvent resulting in a CBD-containing liquid extraction solution, and wherein the extraction solvent has a composition suitable to allow the reaction of the extracted CBD with a CBD-specific cannabinoid-sensitive visualization reagent; 2) contacting the resulting liquid extraction solution with a test strip comprising a porous matrix uniformly impregnated with a CBD-specific cannabinoid-sensitive visualization reagent; 3) removing the test strip from the liquid extraction solution and allowing it to develop for a defined amount of time; and 4) comparing the intensity of the resulting color change, or absorbance shift, of the test strip to a calibrated quantification reference chart, such that comparison of the color intensity change or absorbance shift of the test sample to a calibrated quantification reference chart allows determination of the CBD concentration in the test sample. The calibrated quantification reference chart may be created by performing the identical method as used on the unknown solid sample on a series of solid samples of known CBD concentration, and recording the resultant color change, or absorbance shift, caused by the known CBD concentrations. The CBD-sensitive visualization reagent may be a strong base. The CBD-specific cannabinoid-sensitive visualization reagent may be a KOH. The extraction solvent may be an alcohol. The extraction solvent may be methanol, ethanol, or isopropanol.\n[0058] The inventors further disclose that test papers or strips impregnated with a strong base such as KOH rapidly lose effectiveness towards CBD when exposed for only a short time to ambient air. This means that such strips may only be effective when freshly prepared, which is a significant limitation for the applicability in field tests or in kits. The inventors have successfully extended the shelf life of such test strips by vacuum sealing to remove any air and/or moisture from contacting the strips, allowing their use days, weeks, or months after preparation. In certain embodiments, there is provided a CBD-sensitive test paper and/or strip comprising a porous matrix uniformly impregnated with a CBD-sensitive visualization reagent, wherein the test paper and/or strip is provided in a sealed container or package. The sealed container or package may include a dessicant.\n[0059] THC Test Papers and Strips\n[0060] The inventors also provide examples of compositions and methods for quantifying cannabinoids THC, CBD and/or CBN in a test sample, using test strips comprising a porous matrix impregnated with cannabinoid-sensitive visualization reagents. In certain embodiments of the invention, the test strip comprises multiple test papers wherein each test paper is impregnated with a different cannabinoid-sensitive visualization reagent.\n[0061] In other aspects of the invention, the one or more cannabinoid-sensitive visualization reagents is a diazonium salt. In other embodiments, one of the cannabinoid-sensitive visualization reagents is a Ghamrawy reagent or a modified Ghamrawy reagent. The inventors have developed a method for manufacturing test papers with a modified Ghamrawy reagent. Such reagents have been described as requiring hydrochloric acid or sulfuric acid to be effective. As these acids are generally only present in liquid form, these reagents have previously only been suitable for liquid based reactions. The inventors have identified strong acids that may also exist as a solid, for instance p-toluenesulfonic acid. Thus, in certain embodiments, the modified Ghamrawy reagent comprises p-DMAB and p-toluenesulfonic acid. In certain embodiments, the test paper is manufactured by dissolving the modified Ghamrawy reagents in a solvent such as methanol--either together or separately--and then contacting the test paper with the reagent and allowing to dry. The test strip may be heated during the drying process, which the inventors have shown to improve the effectiveness of the test papers. In other embodiments, the test strips may comprise a Duquenois reagent.\n[0062] In other aspects of the invention, there is thus provided an apparatus which includes a test strip, wherein the test strip comprises a porous matrix uniformly impregnated with one or more cannabinoid-sensitive visualization reagents. In certain embodiments, the one or more cannabinoid-sensitive visualization reagents are present on the test strip in sufficient amount to cause a colorimetric chemical reaction when contacted with cannabinoids and an appropriate solvent. In some embodiments, the cannabinoid-sensitive visualization reagents are present in sufficient amount to allow quantification of THC and/or CBD and/or CBN in a cannabinoid containing sample. In certain embodiments, the one or more visualization reagents are present in different discrete regions of the test strip, for instance on separate test papers that are affixed to the test strip. In certain embodiments, the cannabinoid-sensitive visualization reagents are diazonium salts such as Fast Blue B, Fast Blue BB, Fast Garnet, and/or Fast Corinth V. In certain embodiments, the cannabinoid-sensitive visualization reagent may also be a Duquenois reagent. In certain embodiments, the cannabinoid-sensitive visualization reagent may be a Ghamrawy reagent or a modified Ghamrawy reagent. In certain embodiments, the test strip further comprises an inert support.\n[0063] In another aspect of the invention, there is provided a method for quantification of the concentration of one or more cannabinoid compounds in a liquid sample, the method involves: 1) contacting the liquid sample with a test strip comprising a porous matrix uniformly impregnated with one or more cannabinoid-sensitive visualization reagents; 2) removing the test strip from the liquid sample and allowing it to develop for a defined amount of time; and 3) comparing the intensity of the resulting color change, or absorbance shift, of the one or more cannabinoid-sensitive visualization reagents to a calibrated quantification reference chart, such that comparison of the color intensity change or absorbance shift of the test sample to the calibrated quantification reference chart allows determination of the cannabinoid concentration in the test sample. The calibrated quantification reference chart may be produced, for instance, by contacting a series of calibrated samples having pre-determined cannabinoid concentrations with a series of test strips under the exact same conditions as to be used for the test sample, including using the same one or more cannabinoid-visualization reagents and the same color development time as to be used for the test sample. In certain embodiments, the test strip comprises one or more test papers, each individually impregnated with different cannabinoid-sensitive visualization reagents. The cannabinoid-sensitive visualization reagent may be a diazonium salt. The cannabinoid-sensitive visualization reagent may be chosen from the following: Fast Blue B, Fast Blue BB, Fast Garnet and Fast Corinth V. The cannabinoid-sensitive visualization reagent may be a Duquenois reagent. The cannabinoid compound to be quantified may be THC. In certain embodiments, the cannabinoid-sensitive visualization reagent may be a Ghamrawy reagent or a modified Ghamrawy reagent.\n[0064] In another aspect of the invention, there is provided a method for quantification of one or more cannabinoid compounds in a solid sample, the method involves: 1) contacting a defined amount of solid sample with a defined volume of an extraction solvent for a defined amount of time, wherein cannabinoids are extracted from the solid sample into the extraction solvent resulting in a cannabinoid-containing liquid extraction solution; 2) contacting the resulting liquid extraction solution with a test strip comprising a porous matrix uniformly impregnated with one or more cannabinoid-sensitive visualization reagents; 3) removing the test strip from the liquid extraction solution and allowing it to develop for a defined amount of time; and 4) comparing the intensity of the resulting color change, or absorbance shift, of the cannabinoid-sensitive visualization reagent to a calibrated quantification reference chart, such that comparison of the color intensity change or absorbance shift of the test sample to a calibrated quantification reference chart allows determination of the cannabinoid concentration in the test sample. The calibrated quantification reference chart may be created by performing the identical method as used on the unknown solid sample on a series of solid samples of known cannabinoid concentration, and recording the resultant color change, or absorbance shift, caused by the known cannabinoid concentrations. In certain embodiments, the test strip comprises one or more test papers, each individually impregnated with different cannabinoid-sensitive visualization reagents. The cannabinoid-sensitive visualization reagent may be a diazonium salt. The cannabinoid-sensitive visualization reagent may be chosen from the following: Fast Blue B, Fast Blue BB, Fast Garnet and Fast Corinth V. The cannabinoid compound to be quantified may be THC. The cannabinoid-sensitive visualization reagent may be a Duquenois reagent. The cannabinoid compound to be quantified may be THC. In certain embodiments, the cannabinoid-sensitive visualization reagent may be a Ghamrawy reagent or a modified Ghamrawy reagent\n[0065] Kits\n[0066] In another aspect of the invention, there is provided a kit for quantification of the concentration of one or more cannabinoid compounds in a sample, the kit comprising: 1) optionally, a solvent for extraction of cannabinoid compounds from a solid sample; 2) one or more cannabinoid-sensitive visualization reagent; and 3) a calibrated quantification reference chart. In a further embodiment, the calibrated quantification reference chart may be replaced by an instruction or set of instructions guiding or directing to a calibrated quantification reference chart, for instance via web link, URL, email address, or other means. In certain embodiments, the extraction solvent has a composition that is permissive for a visualization reaction with the cannabinoid-sensitive visualization reagents. In certain embodiments, the kit is useful for the quantification of THC in a test sample, and the one or more cannabinoid-sensitive visualization reagents is chosen from: a diazonium salt, for instance Fast Blue B, Fast Blue BB, Fast Corinth V, and Fast Garnet GC; a Duquenois reagent; a Ghamrawy reagent; and/or a modified Ghamrawy reagent. In certain embodiments of the invention the kit is useful for the quantification of CBD in a test sample, and the cannabinoid-sensitive visualization reagent is a strong base, for instance potassium hydroxide or sodium hydroxide. In certain embodiments, the cannabinoid-sensitive visualization reagent is provided in a pre-measured amount suitable for single test reactions. In certain embodiments, the pre-measured cannabinoid-sensitive visualization reagent is provided in dry form. The pre-measured cannabinoid-sensitive visualization reagent may be provided in a ready to use reaction vessel, for instance a test tube, plastic tube, eppendorf tube, and the like, or in a separate pouch or container. In certain embodiments, the dry reagent may further include a solid diluent. In certain embodiments, the extraction solvent may have a composition that is: 1) suitable for dissolving the dry pre-measured cannabinoid-sensitive visualization reagent; and 2) permissive for a visualization reaction between the cannabinoid and the cannabinoid-sensitive visualization reagent.\n[0067] In another aspect of the invention, there is provided a kit for extended range quantification of the concentration of one or more cannabinoid compounds in a sample, the kit includes: 1) optionally, a solvent for extraction of cannabinoid compounds from the sample; 2) two or more cannabinoid-sensitive visualization reagents; and 3) a calibrated quantification reference chart, wherein the calibrated quantification reference chart comprises calibrated quantification reference for each of the two or more cannabinoid-sensitive visualization reagents. In a further embodiment, the calibrated quantification reference chart may be replaced by an instruction or set of instructions guiding or directing to a calibrated quantification reference chart, for instance via web link, URL, email address, or other means. In certain embodiments, the extraction solvent has a composition that is permissive for a visualization reaction with the two or more cannabinoid-sensitive visualization reagents. In certain embodiments, the kit is useful for the quantification of THC in a test sample, and the cannabinoid-sensitive visualization reagents are chosen from: a diazonium salt, for instance Fast Blue B, Fast Blue BB, Fast Corinth V, and Fast Garnet GC; a Duquenois reagent; a Ghamrawy reagent; and/or a modified Ghamrawy reagent. In certain embodiments, the cannabinoid-sensitive visualization reagent is provided in a pre-measured amount suitable for a single test reaction. In certain embodiments, the pre-measured cannabinoid-sensitive visualization reagent is provided in dry form. The dry reagent may further include a solid diluent The pre-measured cannabinoid-sensitive visualization reagent may be provided in a ready to use reaction vessel, for instance a test tube, plastic tube, eppendorf tube, and the like, or may be provided in a separate pouch or container. In certain embodiments, the extraction solvent may have a composition that is 1) suitable for dissolving the dry pre-measured cannabinoid-sensitive visualization reagent; and 2) permissive for a visualization reaction between the cannabinoid and the cannabinoid-sensitive visualization reagent.\n[0068] The following examples are provided for illustrative purposes, and are not intended to be limiting.\nExample 1--Quantification of THC Content of an Unknown Solid Cannabis Sample Using the Compositions and Methods of the Invention--Visualization in Solution\n[0069] A. Preparation of Cannabinoid-Sensitive Visualization Reagents\n[0070] Fast Blue BB diazonium salt was dissolved in methanol to a final concentration of 0.1%.\n[0071] B. Production of Calibrated Quantification Reference Chart\n[0072] Solid cannabis samples with known THC concentration were used to create the calibrated quantification reference chart. These cannabis samples were known to have negligible concentrations of other cannabinoids that might also react with the cannabinoid-sensitive visualization reagent, such as CBD or CBN. For each sample, the following protocol was followed to extract the THC into a liquid THC containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325° F. for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbled, and a 0.1 g portion was placed into a plastic tube. Exactly 5.0 mL of methanol or isopropanol was placed into the plastic tube. The tube with the 0.1 g solid sample and 5.0 mL of methanol or isopropanol was shaken vigorously for 30 seconds. A 1.0 mL aliquot of the resulting THC containing extraction solution was transferred to an eppendorf tube. One drop (˜20 uL) of cannabinoid-sensitive visualization reagent from step A was added, and the reaction was allowed to develop for exactly 10 minutes. This procedure was completed in parallel with a number of solid cannabis samples having different known THC concentrations. After the colour development step, all the resulting color reactions were used to create the calibrated quantification reference chart shown in FIG. 1. The colors from each tube are then easily transferred to a suitable medium, for instance onto a reference card and the like, for ease of comparison at any future point. More specifically, as shown in FIG. 1, the calibrated quantification reference chart for THC samples is disclosed having an ideal range of 5-20%. The quantification reference chart was generated using Fast Blue BB. The chart shows a light yellow colour at the left side, changing to a darker yellow/orange on the right side.\n[0073] C. Determination of THC Concentration in Unknown Solid Cannabis Sample\n[0074] A solid cannabis sample with unknown THC concentration (and known to have low concentration of other cannabinoids that might react with the cannabinoid-sensitive visualization reagent, such as CBD or cannabinol) was prepared using the exact same methodology as the samples in Step B. The resulting THC-containing extraction liquid was contacted with cannabinoid-sensitive visualization reagent from Step A and color development for 10 minutes, exactly as in Step B. The resulting color change was then compared to the calibrated quantification reference chart from Step B to determine the THC concentration in the unknown sample.\nExample 2--Quantification of THC Content of an Unknown Solid Cannabis Sample Using an Extended Range Calibrated Quantification Reference Chart-Visualization in Solution\n[0075] A. Preparation of Two Cannabinoid-Sensitive Visualization Reagents\n[0076] Fast Blue BB salt was dissolved in methanol to a final concentration of 0.1%. Fast Corinth V was dissolved in methanol to a final concentration of 0.1%\n[0078] Solid cannabis samples with known THC concentration were used to create the calibrated quantification reference chart. These cannabis samples were known to have negligible concentrations of other cannabinoids that might also react with the cannabinoid-sensitive visualization reagent, such as CBD or cannabinol. For each sample, the following protocol was followed to extract the THC into a liquid THC containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325 degrees Celsius for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbed, and a 0.1 g portion was placed into a plastic container. Exactly 5.0 mL of methanol or isopropanol was placed into the plastic container. The container with the 0.1 g solid sample and 5.0 mL of methanol or isopropanol was shaken vigorously for 10 seconds. A 1.0 mL aliquot of the resulting THC containing extraction solution was transferred to a first eppendorf tube, and a 1.0 mL aliquot of the resulting THC containing extraction solution was transferred to a second eppendorf tube. One drop (˜20 uL) of Fast Blue BB cannabinoid-sensitive visualization reagent from step A was added to the first eppendorf tube, and one drop (˜20 uL) of Fast Corinth V cannabinoid-sensitive visualization reagent from step A was added to the second eppendorf tube, and the reaction in each tube was allowed to develop for exactly 10 minutes. This procedure was completed in parallel with a number of solid cannabis samples having different known THC concentrations. After the colour development step, all the resulting color changes for Fast Blue BB, and the resulting color changes for Fast Corinth V were used to create the extended range calibrated quantification reference chart (FIG. 2). More specifically, as shown in FIG. 2, an extended range calibrated quantification reference chart is detailed therein. The chart includes overlapping ranges for 2 different cannabinoid-sensitive visualization reagents, to allow for quantification from 0% to over 25% THC in a solid sample. The top row of colors is generated using Fast Corinth V. The bottom row of colors is generated using Fast Blue BB. The top row, moving from left to right, shows the color change starting as light orange at the bottom of the range and getting progressively more red at the top of the range. The ideal quantification range for the top row is 0-14%. The bottom row, moving from left to right, shows the color change starting at light yellow at the bottom of the range, and moving to darker orange at the top of the range. The ideal quantification range is 11-25%. The overlapping ideal ranges provides good quantification between 0-25% THC.\n[0080] A solid cannabis sample with unknown THC concentration (and known to have low concentration of other cannabinoids that might react with the cannabinoid-sensitive visualization reagent, such as CBD or cannabinol) was prepared using the exact same methodology as the samples in Step B. The resulting THC-containing extraction liquid was contacted with cannabinoid-sensitive visualization reagent from Step A and colour development for 10 minutes, exactly as in Step B. The resulting colour change was then compared to the extended range calibrated quantification reference chart from Step B to determine the THC concentration in the unknown sample.\nExample 3--Quantification of CBD Content of an Unknown Solid Cannabis Sample Using the Compositions and Methods of the Invention-Visualization in Solution\n[0081] A. Preparation of Cannabinoid-Sensitive Visualization Reagent\n[0082] Potassium hydroxide was dissolved in water to a final concentration of 20%.\n[0084] Solid cannabis samples with known CBD concentration were used to create the calibrated quantification reference chart. For each sample, the following protocol was followed to extract the CBD into a liquid CBD containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325 degrees Celsius for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbed, and a 0.1 g portion was placed into a plastic container. Exactly 3.0 mL of methanol or isopropanol was placed into the plastic container. The container with the 0.1 g solid sample and 3.0 mL of methanol or isopropanol was shaken vigorously for 10 seconds. A 1.0 mL aliquot of the resulting THC containing extraction solution was transferred to an eppendorf tube. Two drops (˜40 uL) of cannabinoid-sensitive visualization reagent potassium hydroxide from step A was added, and the reaction was allowed to develop for exactly 10 minutes. This procedure was completed in parallel with a number of solid cannabis samples having different known CBD concentrations. After the colour development step, all the resulting reactions were lined up in order of increasing THC concentration and the colors used to create the calibrated quantification reference chart (FIG. 3). The colors from each tube are then easily transferred to a suitable medium, for instance onto a reference card and the like, for ease of comparison at any future point. More specifically, as shown in FIG. 3, a calibrated quantification reference chart for CBD samples is depicted demonstrating an ideal range of 0-15%. Moving from left to right, the figure shows the color changing from very light purple at the lower end of the scale to a much darker purple at the higher end of the scale.\n[0086] A solid cannabis sample with unknown CBD concentration was prepared using the exact same methodology as the samples in Step B. The resulting CBD-containing extraction liquid was contacted with cannabinoid-sensitive visualization reagent from Step A and colour development for 10 minutes, exactly as in Step B. The resulting colour change was then compared to the extended range calibrated quantification reference chart from Step B to determine the CBD concentration in the unknown sample.\nExample 4--Quantification of THC Content of an Unknown Solid Cannabis Sample Using the Compositions and Methods of the Invention\n[0087] A. Preparation of Test Strips Impregnated with Fast Blue BB\n[0088] Fast Blue BB salt was dissolved in methanol to a final concentration of 1%. Strips of Whatman paper (CF2) were submersed in the 1% Fast Blue BB methanol solution, removed, and allowed to dry.\n[0090] Solid cannabis samples with known THC concentration were used to create the calibrated quantification reference chart. For each sample, the following protocol was followed to extract the THC into a liquid THC containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325 degrees Celsius for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbed, and a 0.1 g portion was placed into a plastic container. Exactly 15 mL of methanol or isopropanol was placed into the plastic container. The container with the 0.1 g solid sample and 15 mL of methanol or isopropanol was shaken vigorously for 10 seconds. A 1.5 mL aliquot of the resulting THC containing extraction solution was transferred to an eppendorf tube. An unused Fast Blue impregnated test strip from Part A was dipped briefly into the THC containing extraction solution, and excess liquid was shaken off the test strip. The test strip was allowed to air dry and the colour was allowed to develop for exactly 10 minutes from the point where the strip first touched the THC containing extraction solution. This procedure was completed in parallel with a number of solid cannabis samples having different known THC concentrations. After the colour development step, all the resulting test strips were lined up in order of increasing THC concentration, and a picture taken to create the calibrated quantification reference chart--see FIG. 4. More specifically, as shown in FIG. 4, a calibrated reference chart for Fast BB impregnated test strips is depicted. The chart shows that, moving from left to right, the color change of the strip goes from a very light orange/red at the low end of the scale to a much darker red at the higher end of the scale.\n[0092] A solid cannabis sample with unknown THC concentration was prepared using the exact same methodology as the samples in Step B. The resulting THC-containing extraction liquid was tested by dipping a Fast Blue BB impregnated test strip from Step A briefly into the THC containing extraction liquid, removing excess liquid, and allowing air drying and colour development for 10 minutes, exactly as in Step B. The resulting colour change was then compared to the calibrated quantification reference chart from Step B to determine the THC concentration in the unknown sample.\nExample 5--Quantification of CBD Content of an Unknown Solid Cannabis Sample Using the Compositions and Methods of the Invention\n[0093] A. Preparation of Test Strips Impregnated with KOH\n[0094] KOH was dissolved in methanol to a final concentration between 1-30% methanol (1%, 10%, 30%). Strips of Whatman paper (CF1) were submersed in the KOH solution, removed, and allowed to dry. Dried test strips were dipped in a methanol extract of a CBD containing Cannabis sample. The Cannabis sample contained 15% CBD and the extract was prepared by i) macerating the sample and heating at 325 degrees Fahrenheit for 5 minutes to convert CBD-A to CBD; ii) adding 0.1 g of the heated sample to 1.0 mL of methanol; and iii) shaking vigorously for 20 seconds. After the test strips were dipped in the CBD liquid extract, they were allowed to develop for 5 minutes. FIG. 5 shows that impregnation of the test strips using 1% or 10% KOH in methanol did not result in a significant color change in the subsequent reaction with the CBD liquid extract, however using 30% did allow for a significant colorimetric reaction to occur. More specifically, as shown in FIG. 5, representative test papers are depicted having been prepared using 30% KOH (left), 10% KOH (middle), and 1% KOH (right).\n[0096] Solid cannabis samples with known CBD concentration were used to create the calibrated quantification reference chart. For each sample, the following protocol was followed to extract the CBD into a liquid CBD containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325 degrees Fahrenheit for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbled, and a 0.1 g portion was placed into a plastic container. Exactly 1.0 mL of methanol or isopropanol was placed into the plastic container. The container with the 0.1 g solid sample and 1.0 mL of methanol or isopropanol was shaken vigorously for 20 seconds. An aliquot of the resulting CBD containing extraction solution was transferred to an eppendorf tube. A KOH impregnated test strip was prepared as in Part A, except that the impregnation of the test strips was performed with KOH dissolved in methanol at a concentration of 20% w/v. An unused KOH impregnated test strip was dipped briefly into the CBD containing extraction solution, and excess liquid was shaken off the test strip. The test strip was allowed to air dry and the color was allowed to develop for exactly 5 minutes from the point where the strip first touched the CBD containing extraction solution. This procedure was completed in parallel with a number of solid cannabis samples having different known CBD concentrations. After the color development step, all the resulting test strips were lined up in order of increasing CBD concentration, and a picture taken to create the calibrated quantification reference chart--see FIG. 6. It can be seen that the color intensity increases in direct correlation with the increasing CBD concentration in the sample. More specifically, as shown in FIG. 6, a CBD Calibrated Reference Chart is depicted. Moving from left to right on the chart therein, the color change shown on the chart goes from a very light violet/purple for the lower CBD % to a much darker purple for higher CBD %.\n[0097] C. Determination of CBD Concentration in Unknown Solid Cannabis Sample\n[0098] A solid cannabis sample with unknown CBD concentration was prepared using the exact same methodology as the samples in Step B. The resulting CBD-containing extraction liquid was tested by dipping a KOH impregnated test strip from Step A briefly into the CBD containing extraction liquid, removing excess liquid, and allowing air drying and color development for 5 minutes, exactly as in Step B. The resulting color change was then compared to the calibrated quantification reference chart from Step B to determine the CBD concentration in the unknown sample.\n[0099] A. Preparation of Test Papers Impregnated with Modified Ghamrawy Reagent\n[0100] A 10% solution of p-dimethylaminobenzaldehyde (p-DMAB) in methanol was prepared in a tube. In a separate tube, a 5 M solution of p-toluenesulfonic acid in methanol was prepared. Squares of CF4 paper (GE Healthcare) were immersed in the p-DMAB solution and allowed to dry, and then quickly dipped in the p-toluenesulfonic acid solution. The strips were then placed in an oven at 200 degrees Fahrenheit for 2 minutes until the strips were completely dry.\n[0101] B. Preparation of Calibrated Reference Chart\n[0102] Solid cannabis samples with known THC concentration were used to create the calibrated quantification reference chart. For each sample, the following protocol was followed to extract the THC into a liquid THC containing solution. The solid sample was macerated into small pieces, and a portion was wrapped in aluminum foil. This was heated at 325 degrees Celsius for exactly 5 minutes. The resulting solid sample was removed from the foil, crumbed, and a 0.1 g portion was placed into a plastic container. Exactly 15 mL of methanol or isopropanol was placed into the plastic container. The container with the 0.1 g solid sample and 15 mL of methanol or isopropanol was shaken vigorously for 10 seconds. A 1.5 mL aliquot of the resulting THC containing extraction solution was transferred to an eppendorf tube. An unused modified Ghamrawy reagent impregnated test strip from Part A was dipped briefly into the THC containing extraction solution, and excess liquid was shaken off the test strip. The test strip was allowed to air dry and the colour was allowed to develop for exactly 10 minutes from the point where the strip first touched the THC containing extraction solution. This procedure was completed in parallel with a number of solid cannabis samples having different known THC concentrations. After the colour development step, all the resulting test strips were lined up in order of increasing THC concentration, and a picture taken to create the calibrated quantification reference chart--see FIG. 7. More specifically, as shown in FIG. 7, a THC Calibrated Reference Chart using modified Ghamrawy reagent impregnated test papers is depicted. Moving from left to right on the chart therein, the color change shown on the chart goes from a very light violet/purple for the lower THC % to a much darker purple for higher THC %.\n[0103] C. Quantification of THC Concentration in a Test Sample of Unknown Concentration\n[0104] A solid cannabis sample with unknown THC concentration (and known to have low concentration of other cannabinoids that might react with the cannabinoid-sensitive visualization reagent, such as CBD) was prepared using the exact same methodology as the samples in Step B. The resulting THC-containing extraction liquid was contacted with cannabinoid-sensitive visualization reagent from Step A and colour development for 10 minutes, exactly as in Step B. The resulting colour change was then compared to the calibrated quantification reference chart from Step B to determine the THC concentration in the unknown sample.\n[0105] While specific embodiments of the invention have been described and illustrated, such embodiments should be considered illustrative of the invention only and not as limiting the invention as construed in accordance with the accompanying claims. Other features and advantages of the invention will be apparent from the following description of the drawings and the invention, and from the claims.\nPatent applications in class Hetero-O (e.g., ascorbic acid, etc.)\nPatent applications in all subclasses Hetero-O (e.g., ascorbic acid, etc.)\n2016-01-07 System and method for performing droplet inflation\n2016-05-12 Rapid quantitative element testing\n2016-05-26 Method and apparatus for inspecting a gas sample\n2016-03-24 A dual gas sensor structure and measurement method\n2016-01-14 Method for fractionating dioxins\n2015-12-24 Vapochromic coordination polymers for use in analyte detection\n2015-05-21 Sampling system and process for sampling\nTop Inventors for class \"Chemistry: analytical and immunological testing\"\n1 Andreas Bergmann\n2 Richard E. Reitz\n3 Joachim Struck\n4 Georg Hess\n5 Tetsuo Nagano"

"A complete Cannabis chromosome assembly and adaptive admixture for elevated cannabidiol (CBD) content\nChristopher J. Grassa, Jonathan P. Wenger, Clemon Dabney, Shane G. Poplawski, S. Timothy Motley, Todd P. Michael, C.J. Schwartz, George D. Weiblen\ndoi: https://doi.org/10.1101/458083\nChristopher J. Grassa\n1Sunrise Genetics, Inc., Ft. Collins, CO, USA.\n2Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.\n3Economic Herbarium of Oakes Ames, Harvard University, Cambridge, MA, USA.\nFor correspondence: cj_grassa@fas.harvard.edu tmichael@jcvi.org gweiblen@umn.edu\nJonathan P. Wenger\n4Department of Plant and Microbial Biology, University of Minnesota, Saint Paul, MN, USA.\nClemon Dabney\nShane G. Poplawski\n5Department of Informatics, J. Craig Venter Institute, San Diego, CA, USA.\nS. Timothy Motley\nTodd P. Michael\nC.J. Schwartz\nGeorge D. Weiblen\nCannabis has been cultivated for millennia with distinct cultivars providing either fiber and grain or tetrahydrocannabinol. Recent demand for cannabidiol rather than tetrahydrocannabinol has favored the breeding of admixed cultivars with extremely high cannabidiol content. Despite several draft Cannabis genomes, the genomic structure of cannabinoid synthase loci has remained elusive. A genetic map derived from a tetrahydrocannabinol/cannabidiol segregating population and a complete chromosome assembly from a high-cannabidiol cultivar together resolve the linkage of cannabidiolic and tetrahydrocannabinolic acid synthase gene clusters which are associated with transposable elements. High-cannabidiol cultivars appear to have been generated by integrating hemp-type cannabidiolic acid synthase gene clusters into a background of marijuana-type cannabis. Quantitative trait locus mapping suggests that overall drug potency, however, is associated with other genomic regions needing additional study.\nResources available online at: http://cannabisgenome.org\nSummary A complete chromosome assembly and an ultra-high-density linkage map together identify the genetic mechanism responsible for the ratio of tetrahydrocannabinol (THC) to cannabidiol (CBD) in Cannabis cultivars, allowing paradigms for the evolution and inheritance of drug potency to be evaluated.\nTHCA (delta-9-tetrahydrocannabinolic acid) and CBDA (cannabidiolic acid) are chemicals uniquely produced by Cannabis plants. When decarboxylated to THC and CBD, these molecules bind to endocannabinoid receptors in the nervous systems of vertebrates and elicit a broad range of neurological effects in humans (1). Cannabinoid receptor types CB1 and CB2 preferentially bind THC and CBD, respectively, with CB1 being among the most abundant post-synaptic neuron receptor in the human brain whereas CB2 is more prevalent in the peripheral nervous system (2-7). Archeological and forensic evidence suggests that the psychoactivity of THC played a role in early domestication (8-9) and in selective breeding to increase marijuana potency during the late 20th century (2). Current explanations for the evolution of cannabinoid content focus on the duplication and divergence of cannabinoid synthase gene loci (11-13).\nDomesticated Cannabis is divided into two major classes of cultivars: hemp and marijuana. Hemp, cultivated as a source of fiber, oil, and confectionary seed, produces modest amounts of CBDA and minimal THCA. Marijuana produces mostly THCA and much greater overall quantities of cannabinoids than hemp. Recent interest in CBD has led to the emergence of a new class of cultivars similar to marijuana. Like marijuana, these cultivars are generally short, highly branched plants with massive female inflorescences containing a high density of glandular trichomes and elevated cannabinoid content. Unlike marijuana, the predominant cannabinoid produced by these cultivars is CBDA. A principal component analysis of single nucleotide polymorphisms (SNPs) segregating in a diverse sample of Cannabis genotypes indicates that the THCA/CBDA ratio is associated with a major axis of population genetic differentiation (Fig. 1a). Hemp and marijuana cultivars are separated in the first principal component while the second component describes a continuum between naturalized populations and domestic cultivars. Estimated genetic divergence between population pairs (Fstmarijuana-naturalized = 0.128, Fsthemp-naturalized = 0.147, and Fstmarijuana-hemp = 0.229) reflect a history of independent breeding trajectories with little gene flow between domesticated populations selected for divergent traits. However, economic incentives and regulatory policies that favored potent marijuana and non-intoxicating hemp in the past have shifted recently and plant breeders responded with targeted introgression.\nFig. 1. Marijuana and hemp are distinct populations of domesticated Cannabis.\nPopulation genetic structure of Cannabis inferred from 2,051 SNPs and 367 accessions delineates hemp, marijuana, and naturalized populations. The domesticated populations are both more closely related to naturalized populations than to each other. This reflects independent breeding trajectories with little gene flow between domesticated populations selected for divergent traits. Individuals were filtered to exclude relatives closer than the 5th degree. SNPs were filtered to reduce linkage disequilibrium and remove sites failing a chi-squared test for Hardy-Weinberg Equilibrium. (A) Principal components analysis (PCA) of the genotype matrix, integrating new data (plotted as squares) with previous population surveys (plotted as circles, triangles, or diamonds to indicate data source). Clusters were determined from k-means and are named according to a simple classification of hemp cultivars (yellow), marijuana cultivars (blue), and naturalized individuals (10). PC1 divides hemp and marijuana populations. PC2 describes the domestication continuum. The position of focal individuals with whole genomes sequenced in this study are indicated with arrows. Carmen is an industrial fiber hemp cultivar. Skunk#1 is an intoxicating marijuana cultivar. CBDRx has a predominantly marijuana-like genome, but is non-intoxicating. (B) Individuals are modeled with admixed genomes of idealized donor populations rather than being discreetly categorized. ADMIXTURE plot indicting ancestry contributions at k=3. Colors are consistent with populations defined for k-means classification on the PCA. Individuals are ordered left to right according to their position along the first principal component with their estimated ancestry proportions indicated by proportion of color contributing to the vertical segment. Focal individuals are indicated with arrows. The Skunk#1 genome ancestry is estimated to be 78% marijuana and 22% naturalized. The Carmen genome ancestry is estimated to be 94% hemp and 6% marijuana. The CBDRx genome is estimated to be 89% marijuana and 11% hemp.\nThe enzymes THCA and CBDA synthase (hereafter THCAS and CBDAS) compete for a common precursor (cannabigerolic acid or CBGA) and have been implicated in alternative explanations for the THCA/CBDA ratio. Some researchers focus on the role of sequence variation among THCAS gene copies (3), (4), while others (5) argue that the presence of a nonfunctional CBDAS allele in the homozygous state alters the cannabinoid ratio in favor of THCA. The public release of six Cannabis genomes, two of which were sequenced with long read technology, points to significant copy number variation among synthase genes across cultivars and yet their genomic structure has remained elusive (Table S1). The complexity of the Cannabis genome has also frustrated attempts to assemble complete chromosomes from thousands of contigs (Table S1), hindering the study of associations between cannabinoid synthase genes and drug potency.\nIn order to resolve the chromosomes of Cannabis and understand associations between cannabinoid synthase loci and cannabinoid content, we sequenced 100 whole genomes using a mixture of short and long read technologies. We sequenced near-isogenic marijuana (Skunk#1) and hemp (Carmen), an F1 hybrid, and 96 recombinant F2 individuals to construct an ultra-high-density genetic map and identify quantitative trait loci (QTL). We also used the genetic map to resolve the 10 Cannabis chromosomes (Fig. 2c) of the F1 and a high-CBDA cultivar (CBDRx) that were sequenced with long reads. Both genomes have higher contig contiguity than currently available Cannabis genomes (Table S1). These assemblies enabled us to completely resolve the cannabinoid synthase genes to three linked regions between 25-33 Mbp on CBDRx chromosome 9 (Fig. 2). The three regions are located on large contigs and contain 13 synthase gene copies. All but a single copy (located at 30Mbp) were found in two clusters of tandem arrays, consisting of seven (at 25 Mbp) and five copies each (at 29 Mbp). Each region has a single complete synthase coding sequence (Fig. 3d,e), with the two arrays having additional copies that are either incomplete or containing stop codons. All of the cannabinoid synthase loci are located in a highly repetitive pericentromeric region with suppressed recombination, and are linked in genetic and physical space (Fig. 2). The genomic context of these genes suggests distinct mechanisms by which copy number might evolve and differ among cultivars.\nFig. 2. Genes responsible for chemotype on chromosome 9 are under selection in marijuana populations and have been targets for introgression by breeders.\nThe locations of three cannabinoid synthase gene clusters are indicated by vertical lines transecting panels. Note that physical and genetic map coordinates are right-to-left. (A) Genes (pink lines) and percent repeat content (grey bars) in 1Mbp windows across the chromosome, (B) Manhattan plot of the population branch statistic (PBS), which is an Fst-based three-population test with extreme values suggesting lineage-specific evolutionary processes. The values for the marijuana branch are displayed here in grey dots across chromosome 9 with a histogram of the genome-wide distribution on the right. The 99.995th percentile of the distribution is indicated with a dashed red line and values at SNPs within 100kbp of a cannabinoid synthase gene are indicated with red dots. We observe extreme values near CBDAS (but not THCAS), which is consistent with selection for nonfunctional CBDAS alleles in marijuana. (C) Painted ancestry of chromosome 9 in CBDRx with genomic segments derived from hemp in yellow and genomic segments derived from marijuana in blue. This analysis suggests a functional CBDAS allele from hemp was introgressed into a marijuana genome background to render the cultivar nonintoxicating. Ancestry blocks of CBDRx were called with AncestryHMM at SNPs separated by at least 0.3 cM and having high marijuana-hemp Fst. The genome-wide ancestry proportions of CBDRx were 89% marijuana and 11%. (D) The genetic map was anchored to the physical map using 211,106 markers segregating in an F2 mapping population. Lines connecting the genetic and physical maps indicate the positions of markers in physical and genetic space here. Physically consecutive markers with the same cM position have been consolidated to grey triangles. Grey triangles with the greatest area indicate regions of the genome with the least recombination. (E) A red arrow marks the position in the genetic map of the only QTL associated with the THC/CBD chemotype. This trait is perfectly correlated with the physical position of CBDAS and colocated with a genomic segment introgressed from hemp in the CBDRx genome. The total length of the genetic map is 818.6 cM, with a mean distance of 0.66 cM between observed crossovers.\nThe resolution of the three cannabinoid synthase regions with long read sequencing and correction-free assembly also provides insight into why the THCAS and CBDAS gene regions did not assemble previously (4) (Table S1). Each region is riddled with highly abundant transposable element sequences (Fig. 3e) and the two synthase clusters are comprised of 31-45 kb tandem repeats nested between Long Terminal Repeat (LTR) retrotransposons (Fig. 3a-c). The LTR (LTR08) associated with the CBDAS copies at 29 Mbp is predominantly restricted to this locus in the genome, and only small fragments of similar sequence were found on other chromosomes. In contrast, the LTR (LTR01) associated with THCAS repeats at 26 Mbp is found in high abundance over the entire genome and flanks the 29 Mbp cluster, suggesting that it may have played a role in the movement of the CBDAS cluster (Fig. 3). The fact that the LTR08 is specific to the CBDAS cassette in the genome further suggests it could be of distinct origin relative to the THCAS cassette.\nFig. 3. Cannabinoid synthase genes are located in tandemly repeated cassettes.\nGenes (blue) are clustered among long terminal repeats (LTR) colored as follows: LTR ends (10) LTR body (grey), unclassified LTR (orange), LTR01 remnants (purple), and an unclassified LTR fragment (green). The synthase gene cluster at 26Mbp includes seven copies of a cassette (A) ranging 38-84 kb in length and flanked by a pair of LTR01. Synthase genes at 29 Mbp are located in a different cassette (B) ranging 28-57 kb in length and having a single LTR08 upstream. (C) The entire 29 Mbp synthase gene cluster is flanked by LTR01 and the third cassette is interrupted by an LTR01 remnant. (D) CBDRx cannabinoid synthase gene tree rooted with closely related berberine bridge enzyme (BBE-like) sequences from rose (Rosa), hops (Humulus) and CBDRx. CBDRx sequences >97% similar are collapsed at the tips of the tree. (E) Functionally annotated maps of the cannabinoid synthase gene clusters in CBDRx. Genes in each of the three regions identified in Fig 2 are located in highly repetitive regions that include terminal repeat retrotransposons in miniature (TRIM), large retrotransposon derivatives (LARD), Gypsy, Copia and other unclassified long terminal repeats (LTR).\nCoverage analysis confirmed that we identified 100% of the synthase gene copies in the CBDrx assembly (Table S3). In contrast, we identified 43 of 45 gene copies in the F1 assembly. These were resolved to either Carmen (22 copies) or Skunk #1 (23 copies) haplotypes. Most copies in the F1 assembly were solitary on short contigs, while one contig had three cassettes and seven contigs had two cassettes. Contigs bearing multiple cassettes confirmed the synthase-LTR tandem repeat structure. According to small size they could be not completely assembled, as was observed in previous assemblies like the Purple Kush genome where only 16% (5/30) of synthase homologs were assembled, all on short contigs (Table S3). That each cannabinoid synthase homolog within a tandem array shares the same promoter sequence suggests that variation in copy number within a gene cluster might have arisen by illegitimate recombination. However, another attractive model based on the architecture of the synthase-LTR tandem repeats is that breeding has selected for the activation and movement of synthase-LTR cassettes (6).\nIt is known from other systems that increases in copy number of biosynthetic gene clusters can elevate secondary metabolite production (7). Variation among Cannabis cultivars in the multiplicity of cannabinoid synthase loci (Table S2) encourages speculation that gene copy number might play a role in determining overall cannabinoid content. However, none of the five separate QTL we identified for total cannabinoid content (potency), were associated with cannabinoid synthase gene clusters (Fig. 4). For example, the strongest QTL for potency, accounting for 17% of variation in cannabinoid quantity, was located on chromosome 3 rather than chromosome 9. This suggests that traits and/or gene regulatory elements not linked to the cannabinoid synthase gene clusters affect cannabinoid quantity to a greater extent than the synthases themselves.\nFig. 4. Composite genetic linkage and quantitative trait locus (QTL) map derived from a marijuana (Skunk#1) x hemp (Carmen) experimental cross.\nMap comprises ten linkage groups constructed from 211,106 markers segregating in 1,175 patterns from Illumina-based WGS of 96 F2 female plants integrated with 60 markers (48 AFLP, 11 microsatellite, 1 Sanger-sequence marker) scored across a subset of 62 F2 female plants (5). Segregation patterns represented as horizontal hash marks on linkage group bars. Quantitative trait loci (QTL) for ten phenotypes detected by composite interval mapping (P < 0.05; 1000 permutations) scored over 96 F2 plants indicated as vertical bar and whisker (1-LOD and 2-LOD intervals, respectively) plots to the right of corresponding linkage groups. Partial R2 for additive and dominance effects indicated above QTL plots. Genetic distance (centimorgans) scale bar to left of panel.\nThe CBDAS loci in particular appear to have been subject to recent selection in marijuana as evidenced by the population branch statistic (PBS) (8) (Fig. 2b) and dN/dS ratios (5). Contrary to the hypotheses of Onofri et al (3), these findings suggest that divergence at CBDAS loci rather than THCAS loci are primarily responsible for the THCA/CBDA ratio. We estimated genome-wide ancestry proportions of CBDRx to be 89% marijuana and 11% hemp. Most of the hemp-derived ancestry of CBDRx genome is found on only two chromosomes: 9 and 10. Notably, the genomic region associated with the QTL for log(THC/CBD), outlier branch lengths of the PBS genome scan for marijuana, as well as the identified CBDAS (but not THCAS), all lie within a shared segment with hemp ancestry. The CBDAS genes located at 29-31 Mbp are also nested in a region of CBDRx chromosome 9 with hemp ancestry whereas the THCAS tandem array is located in a region of marijuana ancestry. This pattern is consistent with the hypothesis that a predominantly CBDA cannabinoid profile is the result of introgression of hemp-like alleles into a marijuana genetic background to elevate CBDA production. That approximately 20% of chromosome 9 is hemp derived and tightly aligned with the QTL for the THCA/CBDA ratio provides further support for admixture combined with artificial selection resulting in new types of Cannabis, such as CBDRx, that present unprecedented combinations of phenotypic traits (9).\nHere we generate the first chromosome scale assembly of the highly complex Cannabis genome, which required ultra-long nanopore sequencing reads and correction-free assembly to resolve the LTR-nested structure of the THCA and CBDA synthase tandem repeats on chromosome 9, two of which are traced back to hemp introgressions explaining the origin of high-CBDA cultivars. The architecture of the synthase loci suggests potential mechanisms for copy number variation, and strategies to manipulate these loci to improve cultivars. However, QTL results suggest that there are additional loci controlling potency in need of further investigation. After decades of regulation as a controlled substance, economic trends, recent changes in law, and the chromosome assembly presented here can accelerate the study of a plant that has co-evolved with human culture since the origins of agriculture.\nData and materials availability\nThe Cannabis CBDRx and F1 genome and annotation are deposited at the European Nucleotide Archive under study PRJEB29284.\nCRBRx, a high-CBDA cultivar (15% CBDA and 0.3% THCA), was grown indoors in Colorado. Plants were grown in a compost enriched soil. CBDRx plants were grown indoors at 20-25C and 55-70% humidity under a mixture of fluorescent T-5 lamps and 1100W High Pressure Sodium Lamps manufactured by PL Lights. We made clonal cuttings approximately 10cm in height that included stems and leaves. These were immediately transferred to 42mm coconut coir plugs for rooting, then a coconut and perlite blend once roots were observed, where they remained for 40 days. Plants were then transferred to soil in 10cm pots for for 4 weeks of vegetative growth. Rooting and vegetative growth conditions included an 18:6 hour light:dark cycle and water as needed. Plants were transferred to 20L pots 10 weeks of flowering conditions using a 12:12 our light:dark cycle. Plants were fertilized with a micronutrient blend certified by the Organic Materials Review Institute plus biochar. Under flowering conditions, plants were watered every 7-9 days. A single plant (CBDRx:18:580) was chosen while in the vegetative phase and recently emerged leaves were collected for DNA purification.\nThe genetic background and cultivation of the mapping population over which the linkage and QTL mapping are reported has been previously described (5). In brief, parental marijuana (Skunk#1) and hemp (Carmen) lines were sibling crossed for five generations to increase homozygosity. A single fifth-generation Skunk#1 female was fertilized with pollen from a single fifth-generation Carmen male. From the resulting seed, a single genetically female F1 (CO9) plant was isolated and vegetatively cloned. Stamen development was induced in mature pistillate CO9 clones via treatment with colloidal silver, resulting in monoecious plants. CO9 clones were fertilized with pollen from CO9 clones to produce an F2 seed generation. Female F2 plants were grown from seed to flowering maturity for 12 weeks under conditions previously described (5). Mature flowers of the parents and F2 plants were collected at harvest and dried for subsequent DNA purification.\nA single male F1 (CO11) plant full-sibling to the F1 (CO9) from which the mapping population descended was grown from seed under vegetative light (16h light: 8hr dark) and high nitrogen nutrient conditions equivalent to the initial four weeks of growth used for the mapping population (5) except that LED lighting (Valoya R150-NS1; Valoya Oy, Helsinki, Finland) was used. Fresh recently emerged leaves were collected from this plant for high molecular weight DNA purification.\nCannabinoid analysis\nCannabinoid analysis by GC was as described in Weiblen et al., (5).\nAgronomic trait phenotyping\nF2 plants were grown for four weeks under vegetative conditions followed by eight weeks under flowering conditions (5). After twelve weeks of growth, plant height was measured from the base of the primary stem to shoot apex after which plants were harvested at the stem base and dried for three weeks at ambient conditions. Dried plant tissue fractions (stems, leaves, inflorescences) were weighed and percent mass of each fraction was calculated relative to total harvested mass.\nIllumina sequencing\nWe extracted DNA from 15-20 mg of dried flowers from each of Skunk#1, Carmen, and 96 F2 individuals using a microfuge-scale CTAB-buffer/organic extraction protocol (adapted from (11). Isolated DNAs were quantified using the PicoGreen dsDNA assay kit (ThermoFisher), size-evaluated by Agilent TapeStation gDNA (Agilent, Santa Clara CA) and used as input for TruSeq DNA PCR-Free (Illumina, San Diego CA). All 96 PCR-free libraries from the F2 set were pooled on an equimolar basis using PicoGreen concentrations. Likewise, a second pool was created from the Skun#1 and Carmen libraries. We used quantitative PCR (qPCR) to assess functionality, which was approximately 25%. Each library pool was adjusted according to the qPCR results prior to sequencing. Libraries were sequenced on an Illumina HiSeq 2500 SBS V4 in 2×125bp read high-output mode (Illumina, San Diego CA) at the University of Minnesota Genomics Center. Raw reads were gently trimmed of low-quality bases and synthetic sequence using Trimmomatic (12).\nFor all Illumina data we trimmed reads of adapter sequence with Trimmomatic (12), aligned them to the reference assembly with BWA MEM (13), sorted and compressed the alignments with Samtools (14), and marked duplicates with Picard tools (15).\nPacBio sequencing\nGenomic DNA of the F1 was obtained from fresh young leaf tissue using a modified CTAB/organic extraction protocol (adapted from (11) in which the extraction buffer was supplemented with antioxidants (0.5% sodium diethyldithiocarbamate, 10mM sodium metabisulfite), and a DNAse inhibitor (200mM L-lysine). Precipitated DNAs were collected using a glass hook, rinsed with ethanol, and resuspended in deionized water. Genomic DNA was quantified using the PicoGreen dsDNA assay kit (ThermoFisher), size-evaluated by Agilent TapeStation gDNA and pulsed-field gel electrophoresis (PFGE), diluted to 50 ng/uL, and sheared via 20 passes through a 26G blunt needle. Shears were evaluated using PFGE. Approximately 15 μg of sheared and concentrated DNA was used as input into library prep using the SMRTbell Template Prep Kit 1.0 using a protocol for >30kb libraries (101-181-000 Version 05). The resulting library was size-selected with a 20 kb high-pass protocol using the PippinHT, and an additional DNA Damage Repair was performed to generate the final library. Sequencing was performed via diffusion loading with Sequel Binding Kit 2.0 and a mixture of Sequel Sequencing Kits 2.0 and 2.1.\nNanopore sequencing\nLeaf material from the inbred CBDrx line was flash frozen in liquid nitrogen. 5 g of flash frozen leaf tissue was ground in liquid nitrogen and extracted with 20 mL CTAB/Carlson lysis buffer (100mM Tris-HCl, 2% CTAB, 1.4M NaCl, 20mM EDTA, pH 8.0) containing 20μg/mL proteinase K for 20 minutes at 55°C. The DNA was purified by addition of 0.5x volume chloroform, which was mixed by inversion and centrifuged for 30 min at 3000 RCF, and followed by a 1x volume 1:1 phenol: [24:1 chloroform:isoamyl alcohol] extraction. The DNA was further purified by ethanol precipitation (1/10 volume 3 M sodium acetate pH 5.3, 2.5 volumes 100% ethanol) for 30 minutes on ice. The resulting pellet was washed with freshly-prepared ice-cold 70% ethanol, dried, and resuspended in 350 μL 1x TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 8.0) with 5 μL RNase A (Qiagen, Hilden) at 37°C for 30 min, followed by incubation at 4°C overnight. The RNase A was removed by double extraction with 24:1 chloroform:isoamyl alcohol, centrifuging at 22,600xg for 20 minutes at 4°C each time. An ethanol precipitation was performed as before for 3 hours at 4°C. The pellet was washed as before and resuspended overnight in 350 μL 1x TE.\nGenomic DNA sample was further purified for Oxford Nanopore (ONT) sequencing with the Zymo Genomic DNA Clean and Concentrator-10 column (Zymo Research, Irvine, CA). The purified DNA was then prepared for sequencing following the protocol in the genomic sequencing kit SQK-LSK108 (ONT, Oxford, UK). Briefly, approximately 1 μg of purified DNA was repaired with NEBNext FFPE Repair Mix for 60 min at 20°C. The DNA was purified with 0.5X Ampure XP beads (Beckman Coulter). The repaired DNA was End Prepped with NEBNExt Ultra II End-repair/dA tail module including 1 μl of DNA CS (ONT, Oxford, UK) and purified with 0.5X Ampure XP beads. Adapter mix (ONT, Oxford, UK) was added to the purified DNA along with Blunt/TA Ligase Master Mix (NEB, Beverly, MA) and incubated at 20°C for 30 min followed by 10 min at 65°C. Ampure XP beads and ABB wash buffer (ONT, Oxford, UK) were used to purify the library molecules and they were recovered in Elution Buffer (ONT, Oxford, UK). Purified library was combined with RBF (ONT, Oxford, UK) and Library Loading Beads (ONT, Oxford, UK) and loaded onto a primed R9.4 Spot-On Flow cell. Sequencing was performed with a MinION Mk1B sequencer running for 48 hrs. Resulting FAST5 files were base-called using the ONT Albacore software using parameters for FLO-MIN106, and SQK-LSK108 library type.\nFull length cDNA sequencing with Oxford Nanopore\nFresh CBDrx leaf tissue was flash frozen in liquid nitrogen and ground to a fine powder using a mortar and pestle. RNA was extracted from the powder using the Qiagen Plant RNeasy Plant Mini Kit (Qiagen, Netherlands). RNA quality was assesed using a bioanalyzer. High quality RNA was used to generate full length cDNA using the cDNA-PCR Sequencing Kit (SQK-PCS108, Oxford Nanopore Technologies, Oxford, UK). Resulting libraries were sequenced on the Oxford Nanopore GridION sequencer (Oxford Nanopore Technologies, Oxford, UK) for 48 hrs.\nNanopore genome assembly\nA total of 27 Gb of Oxford Nanopore sequence was generated on the MinION ONT platform. The resulting raw reads in fastq format were aligned (overlap) with minimap and an assembly graph (layout) was generated with miniasm2 (16). The resulting graph was inspected using Bandage (17). A consensus sequence was generated by mapping reads to the assembly with minimap2, and then Racon (18) three times. Finally, the assembly was polished with pilon (19) three times using the Illumina paired-end 2×100 bp sequence; the Illumina reads were mapped to the consensus assembly using BWA (13). All assembly steps were carried out on a machine with 231 Gb RAM and 56 CPU.\nWe sequenced CBDRx to a 34x coverage using long read Oxford Nanopore Technology (ONT) and the F1 to a 5x circular consensus coverage using PacBio Single Molecule Real-Time (SMRT) long read sequencing for the purpose of comparing THCAS and CBDAS variation in our mapping population to CBDRx. Both genomes were assembled using a correction-less assembly pipeline that consisted of an overlap (minimap2), layout (miniasm2) consensus (racon), followed by a polishing step (pilon) using the 64x Illumina 2×100 bp paired end reads (20). The resulting CBDRx assembly was 746 Mbp in 1,986 contigs with an N50 length of 742 kb and the longest contig 4.5 Mbp, while the F1 assembly was 1,389 Mbp in 12,204 contigs with an N50 length of 172 kb and the longest contig 1.9 Mbp (Table S2). Both genomes have higher contig contiguity than the Cannabis genomes currently available (Table S1), and form the basis for a complete chromosome assembly.\nGenetic Linkage Map\nOur core mapping population is made up of F2s germinated from seed collected from the CO9 clones. A pseudo F1 dataset was constructed by concatenating all F2 reads followed by random subsampling to a target genomic coverage of 100x. The pseudo F1 and parental reads were independently error corrected using k-mer histograms with k=25 with AllpathsLG (21). A de Bruijn graph was constructed from the error corrected pseudo F1 reads using McCortex assembler at k=19 (22). This program is unique in that genome assembly and variant discovery are performed simultaneously - reads are assembled, but the paths through \"bubbles,\" i.e. regions of the graph that diverge and rejoin are retained as variants. The bubble read coverage distribution is used to classify bubbles as repeats, homologous alleles, or errors. Parental reads and F2 reads were threaded through the graph independently. F2s were genotyped at variant sites at which Carmen and Skunk#1 were fixed for alternate alleles. Genotypes were updated via imputation using a sliding-window hidden markov model using LB-Impute (23) leveraging variant coverage information and physical linkage within a window of width 10 variants.\nSegregation patterns of genotypes containing no missing data across the population that appeared at least ten times were selected for use as map markers. Markers exhibiting segregation distortion by Chi^2 test were low in number and are retained in the map (~10% of markers). Linkage groups and marker order were inferred using the ant colony optimization in AntMap (24) solution to the traveling salesman path. Recombinations were counted directly and divided by the number of gametes in the population (192) to infer genetic distance between adjacent markers and summed consecutively in linear order to give map position on a linkage group.\nLinkage mapping\nMarkers obtained from a high-density map made using Illumina data built using AntMap for 96 F2 individuals were used to produce a composite map built by adding markers from Weiblen (5) using JOINMAP 4.1 (Wageningen, the Netherlands). Linkage groups were assembled from independent log-of-odds scores (LOD) based on G-tests for independence of two-way contingency tables. Linkage groups with LOD > 3.0 and containing four or more markers were used to construct a linkage map using the Kosambi (25) function. The high-density composite linkage map comprises ten linkage groups, 1,235 total segregation patterns, a map distance of 818.6 cM and a mean intermarker distance of 0.66 cM.\nQTL analysis\nCannabinoid profiles and biomass traits of the same 96 F2 individuals were analyzed with respect to the composite linkage map using Windows QTL CARTOGRAPHER v.2.5_011 (26); WinQTLCart). Composite interval mapping was used to estimate LOD over a walk speed of 1.0 cM and significant associations between traits and linkage groups were identified using an experiment-wise (P = 0.05) LOD threshold estimated in WinQTLCart using 1000 permutations. Results were plotted with MAPCHART 2.32 (Wageningen, the Netherlands).\nPseudomolecule generation\nThe genome assembly was evaluated for library contaminants using Blobtools (27) and the NCBI non-redundant database. Contigs with good evidence as derived from outside viridiplantae were removed. We aligned the genetic map bubbles to the CBDRx contigs with BWA (13). Contigs were deemed chimeric if they mapped to different linkage groups or more than 10 centimorgans away from each other and broken at the longest repeat between genetically mapped regions. An initial set of rough pseudomolecules were constructed by assigning contigs to linkage groups, ordering contigs by mean centimorgan (28), and orienting by cM position on either end. The F2 population was genotyped again via alignment to the rough pseudomolecules followed by LB-Impute. Population segregation patterns from this second round of genotyping were used to further saturate the genetic map if they increased map density without increasing the map length (29). Contigs were partitioned by linkage group and scaffolded with the Hi-C library using three iterations of Salsa (30). Allmaps was used to generate the final contig order and orientation with the template genetic map positions, second round genetic map positions, and Salsa contig positions as input. The pseudomolecules were further polished with an additional ten iterations of Racon followed by an additional ten iterations of Pilon. After chromosome-wide scaffolding and gap filling, 841 contiguous sequences spanning 714,498,588 bp were anchored to nuclear pseudomolecules. We genotyped the genetic mapping population for a third time against the CBDRx reference and visually inspected the segregation patterns for misorderings. We found most contigs to be largely collinear in genetic and physical space. We observed zero recombinanants on a minority of contigs and were unable to resolve their relative order and orientation. This was the case for two of the three synthase-bearing contigs on chromosome 9. For these, we manually reordered the synthase-bearing contigs to be physically adjacent, as we could not find evidence supporting an alternative arrangement and such an arrangement is most parsimonious with study-wide results.\nRepeat and gene prediction and annotation\nFull length LTRs were predicted using LTRfinder using the standard settings and 1 mismatch (31). The resulting full length LTRs were used to mask the genome using repeat masker (32). Four full-length cDNA nanopore read libraries were aligned to the reference with minimap2 (33) before and after error correction by Canu (34) of colocated batches. 142 RNAseq libraries found on the Sequence Read Archive were aligned to the reference with GSnap (35) and assembled into transcripts with Stringtie (36). 4 high-coverage RNASeq libraries were assembled using Trinity (28) in both de-novo and reference-guided modes. Contaminate sequence was removed using Seqclean (15). The full-length cDNAs, Stringtie assembly, and Trinity transcripts were assembled into gene models with the Program to Assemble Spliced Alignments (37). Additional transcriptome assemblies from Humulus lupulus (38) and Cannabis were aligned to the reference with GMap. Genes were predicted ab initio using Augustus (39). Non redundant RefSeq proteins (40) for viridiplantae were clustered at 90% identity with CD-HIT (41). Representative sequences for each cluster were aligned to the reference genome using Diamond (42) —extra-sensitive. Pairwise hits were locally realigned with AAT (43) and Exonerate protein2genome. Repetitive sequence was identified using the set union of three programs: RepeatMasker, Tephra, and Red (44). EvidenceModeler was used to integrate all evidence for and against protein-coding genes. PASA was updated with these results.\nCBDRx chromosome assembly analysis\nThe CBDRx ONT-based contig assembly was further resolved into chromosomes using a genetic map derived from progeny of the F1. Using whole-genome-shotgun sequencing (WGS) we scored 96 F2 plants for 211,106 markers segregating in 1,235 high-confidence patterns resulting in ten linkage groups, which we then used to anchor the ONT-based contigs. The final chromosome-resolved assembly of CBDRx captured 90.8% of the gene space as predicted by Benchmarking Universal Single Copy Orthologs (BUSCO) (45). The CBDRx genes were predicted using a combination of ab initio and empirical data including full length cDNA sequenced using ONT long read sequencing, as described above. After masking 63% of the genome for repeats that were made up of 17,536 full length long terminal repeats (LTRs), 42,052 protein coding genes were predicted in the CBDrx assembly. We identified the 345-355 bp subtelomeric repeat that has been defined in Humulus lupulus (46), and the 224 bp centromeric repeat (47). That 17% of the reads mapped to the centromere repeat and 14% mapped to the subtelomeric repeat is consistent with their predicted size in the genome. These observations support the first complete Cannabis chromosome assembly and a framework for examining the genomic structure of the THCAS and CBDAS loci in association with quantitative traits.\nTHCAS/CBDAS and coverage analysis\nIn addition to the gene prediction and annotation, and CBDAS and THCAS genes (AB292682 and AB057805 respectively) were used to search the final assembly. The THCAS and CBDAS gene sequence was blasted against the final CBDrx assembly to confirm their locations. We identified four locations on the genome with close hits to synthases:, chr9:26 Mbp, ch9:29 Mbp, ch9 31 Mbp, and the more-distantly related homologs at chr6:15 Mbp. To check that all of the genes were captured in the assembly a coverage analysis was performed. The Illumina reads were mapped to a single copy gene GIGANTEA (GI), one ribosomal cassette (18S-5S-26S) and the four version of the synthase genes. The results confirmed the 14 synthase genes and suggested 500-600 rDNA arrays, which is consistent with other genomes this size (Table S3). Coverage analysis in Carmen, Skunk#1 and Purple Kush (4) revealed 22, 24 and 30 synthase genes respectively.\nIndividuals with sequenced WGS libraries were genotyped with BCFtools. Genome-wide ancestry proportions at k=3 were estimated using ADMIXTURE (48). Individuals identified as having >99% ancestry were assigned to respective marijuana and hemp populations. A subset of segregating sites were selected for assigning ancestry tracts along chromosomes using a method intended to maximize informativeness and minimize linkage disequilibrium. Sites were ranked by Wright's Fst (49). Genetic positions for all segregating sites were interpolated along a B-spline function fitted to the empirically observed positions in the mapping population with coefficients penalized to maintain monotonicity (50). For each chromosome, the site with the highest Fst value and lowest genetic position was the first selected. Decreasing by Fst through all segregating sites, additional sites were selected so long as they were at least 0.03 cM from any previously selected site. Ancestry tracts were assigned by AncestryHMM (51) assuming a single pulse from hemp to marijuana eight generations in the past.\nWe obtained previously published population data from the original authors and genotyped individuals against the CBDRx reference using our standard pipeline including sites with a quality score greater than 500. In order to understand neutral population structure, we used Plink and Plink2 to filter the genotype matrix to minimize structure originating from familial relatedness, artifactual patterns in occupancy, selection, and genetic linkage. We selected a single representative individual from groups with KING-robust kinship coefficient greater than 0.015625. We retained bi-allelic sites called in at least 80% of individuals, with a minor allele frequency greater than 1%, observed heterozygosity less than 60%. We removed sites failing an exact test for Hardy-Weinberg at p-value of 1e-20 with a mid-p adjustment (52). We eliminated individuals genotyped at less than 90% of sites. We thinned sites for linkage disequilibrium in sliding windows with a width of 50 SNPs, a slide of 5 SNPs, and a variance inflation factor threshold of 2. We used this plink-filtered genotype matrix for PCA and k-means clustering, as well as Admixture analysis at k=3. We used the Population Branch Statistic to scan the genome for sites undergoing population-specific processes. We assigned individuals to populations based on their k-means cluster membership and retained all sites with a quality score greater than 500 for this analysis. We calculated Fst (53) for the three population pairs using VCFtools. The PBS is three population test. For populations (a,b,c):\nPBS_a = ((T_ab + T_ac − T_bc) / 2)\nPBS_b = ((T_ab + T_bc − T_ac) / 2)\nPBS_c = ((T_ac + T_bc − T_ab) / 2)\nT_ab = −log(1 − Fst_ab)\nT_ac = −log(1 − Fst_ac)\nT_bc = −log(1 − Fst_bc)\nThis work was supported by the David and Lucile Packard Foundation, J. Craig Venter Institute (T.P.M), and Sunrise Genetics Inc.\nG.D.W. and C.J.G, and C.J.S. designed the study. G.D.W., J.P.W., and C.D. developed the mapping population and prepared materials for genomic analysis. T.P.M, S.G.P, and S.T.M sequenced the CBDRx genome and full length cDNA. C.J.G. and T.P.M assembled, annotated, and analyzed the genomes. C.J.G. integrated the maps and analyzed the populations. J.P.W and C.D. measured phenotypes and performed QTL analysis. C.J.G., C.D., J.P.W., C.J.S., T.P.M and G.D.W. wrote the manuscript.\nC.J.G. and C.J.S. are members of the Board of Directors for Sunrise Genetics, Inc. T.P.M. is a member of the Scientific Advisory Board for Sunrise Genetics, Inc.\nVeronica Tonnell contributed DNA isolation for the mapping population. We thank Matthew Gibbs and Jason Schwartz for support from Sunrise Genetics Inc. Timothy Gordon of Functional Remedies provided the high-CBDA plant. C.J.G. is grateful to Cristina M. Moya for insightful conversations on human-plant interactions as well as hosting his sabbatical at the Max Planck Institute of Evolutionary Anthropology.\nE. Russo, Beyond Cannabis: Plants and the Endocannabinoid System. Trends in Pharmacological Sciences 37, 594–605 (2016).\nMelis M.\nS. A. Laredo, Marrs, W.R., Parsons, L.H., Endocannabinoid Signaling in Reward and Addiction: From Homeostasis to Pathology. In: Melis M. (eds) Endocannabinoids and Lipid Mediators in Brain Functions. Springer, Cham, (2017).\nJ. Maroon, J. Bost, Review of the neurological benefits of phytocannabinoids. Surg Neurol Int 9, 91 (2018).\nR. G. Pertwee, The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153, 199–215 (2008).\nT. F. Freund, I. Katona, D. Piomelli, Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83, 1017–1066 (2003).\nM. D. Van Sickle et al., Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310, 329–332 (2005).\nP. H. Reggio, Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown. Current Medicinal Chemistry 17, 1468–1486 (2010).\nH. E. Jiang et al., Ancient Cannabis Burial Shroud in a Central Eurasian Cemetery. Economic Botany 70, 213–221 (2016).\nE. Small, Cannabis: A Complete Guide., (CRC Press, Boca Raton, Florida, 2016).\nM. A. ElSohly et al., Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980-1997. J Forensic Sci 45, 24–30 (2000).\nC. Onofri, E. P. M. de Meijer, G. Mandolino, Sequence heterogeneity of cannabidiolic-and tetrahydrocannabinolic acid-synthase in Cannabis sativa L. and its relationship with chemical phenotype. Phytochemistry 116, 57–68 (2015).\nH. van Bakel et al., The draft genome and transcriptome of Cannabis sativa. Genome Biol 12, R102 (2011).\nG. D. Weiblen et al., Gene duplication and divergence affecting drug content in Cannabis sativa. New Phytol 208, 1241–1250 (2015).\nE. B. Chuong, N. C. Elde, C. Feschotte, Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet 18, 71–86 (2017).\nN. Manderscheid et al., An influence of the copy number of biosynthetic gene clusters on the production level of antibiotics in a heterologous host. J Biotechnol 232, 110–117 (2016).\nX. Yi et al., Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329, 75–78 (2010).\nL. H. Rieseberg et al., Major ecological transitions in wild sunflowers facilitated by hybridization. Science 301, 1211–1216 (2003).\nReferences only cited in the Materials and Methods\nJ. D. Doyle, J., A rapid DNA isolation procedure for small quantities of fresh leaf tissue. Phytochemical Bulletin 19, 11–15 (1987).\nA. M. Bolger, M. Lohse, B. Usadel, Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).\nH. Li, R. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).\nH. Li et al., The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).\nBroad Institute, Picard Tools. Broad Institute, Github repository, (2016).\nH. Li, Minimap and miniasm: fast mapping and de novo assembly for noisy long sequences. Bioinformatics 32, 2103–2110 (2016).\nR. R. Wick, M. B. Schultz, J. Zobel, K. E. Holt, Bandage: interactive visualization of de novo genome assemblies. Bioinformatics 31, 3350–3352 (2015).\nR. Vaser, I. Sovic, N. Nagarajan, M. Sikic, Fast and accurate de novo genome assembly from long uncorrected reads. Genome Res 27, 737–746 (2017).\nB. J. Walker et al., Pilon: an integrated tool for comprehensive microbial variant detection and genome assembly improvement. PLoS One 9, e112963 (2014).\nT. P. Michael et al., High contiguity Arabidopsis thaliana genome assembly with a single nanopore flow cell. Nat Commun 9, 541 (2018).\nS. Gnerre et al., High-quality draft assemblies of mammalian genomes from massively parallel sequence data. Proc Natl Acad Sci U S A 108, 1513–1518 (2011).\nZ. Iqbal, M. Caccamo, I. Turner, P. Flicek, G. McVean, De novo assembly and genotyping of variants using colored de Bruijn graphs. Nature Genetics 44, 226–232 (2012).\nC. A. Fragoso, C. Heffelfinger, H. Zhao, S. L. Dellaporta, Imputing Genotypes in Biallelic Populations from Low-Coverage Sequence Data. Genetics 202, 487–495 (2016).\nH. Iwata, S. Ninomiya, AntMap: Constructing genetic linkage maps using an ant colony optimization algorithm. Breeding Science 56, 371–377 (2006).\nD. D. Kosambi, The Estimation of Map Distances from Recombination Values. Annals of Eugenics 12, 172–175 (1944).\nOpenUrlWeb of Science\nS. Wang, C. Basten, Z. Zeng, Windows QTL Cartographer 2.5. 2006.\nD. R. a. B. Laetsch, Mark L, BlobTools: Interrogation of genome assemblies. F1000Research 6, (2017).\nB. J. Haas et al., De novo transcript sequence reconstruction from RNA-seq using the Trinity platform for reference generation and analysis. Nature Protocols 8, 1494–1512 (2013).\nE. Dijkstra, A note on two problems in connexion with graphs. Numerische mathematik 1, 269–271 (1959).\nJ. Ghurye, M. Pop, S. Koren, D. Bickhart, C. Chin, Scaffolding of long read assemblies using long range contact information. BMC Genomics 18, 527 (2017).\nZ. Xu, H. Wang, LTR_FINDER: an efficient tool for the prediction of full-length LTR retrotransposons. Nucleic Acids Res 35, W265–268 (2007).\nN. Chen, Using RepeatMasker to identify repetitive elements in genomic sequences. Current protocols in bioinformatics 5, 4–10 (2004).\nH. Li, Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 34, 3094–3100 (2018).\nS. Koren et al., Canu: scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation. Genome Res 27, 722–736 (2017).\nT. D. Wu, J. Reeder, M. Lawrence, G. Becker, M. J. Brauer, GMAP and GSNAP for Genomic Sequence Alignment: Enhancements to Speed, Accuracy, and Functionality. Methods Mol Biol 1418, 283–334 (2016).\nM. Pertea et al., StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33, 290–295 (2015).\nB. J. Haas et al., Automated eukaryotic gene structure annotation using EVidenceModeler and the program to assemble spliced alignments. Genome Biology 9, (2008).\nS. T. Hill, R. Sudarsanam, J. Henning, D. Hendrix, HopBase: a unified resource for Humulus genomics. Database (Oxford) 2017, (2017).\nK. J. Hoff, M. Stanke, WebAUGUSTUS-a web service for training AUGUSTUS and predicting genes in eukaryotes. Nucleic Acids Research 41, W123–W128 (2013).\nK. D. Pruitt, T. Tatusova, D. R. Maglott, NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35, D61–65 (2007).\nL. Fu, B. Niu, Z. Zhu, S. Wu, W. Li, CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics 28, 3150–3152 (2012).\nB. Buchfink, C. Xie, D. Huson, Fast and sensitive protein alignment using DIAMOND. Nat. Methods 12, 59–60 (2014).\nX. Huang, M. D. Adams, H. Zhou, A. R. Kerlavage, A tool for analyzing and annotating genomic sequences. Genomics 46, 37–45 (1997).\nH. Z. Girgis, Red: an intelligent, rapid, accurate tool for detecting repeats denovo on the genomic scale. BMC Bioinformatics 16, 227 (2015).\nF. A. Simao, R. M. Waterhouse, P. Ioannidis, E. V. Kriventseva, E. M. Zdobnov, BUSCO: assessing genome assembly and annotation completeness with single-copy orthologs. Bioinformatics 31, 3210–3212 (2015).\nM. G. Divashuk, O. S. Alexandrov, O. V. Razumova, I. V. Kirov, G. I. Karlov, Molecular cytogenetic characterization of the dioecious Cannabis sativa with an XY chromosome sex determination system. PLoS One 9, e85118 (2014).\nD. P. Melters et al., Comparative analysis of tandem repeats from hundreds of species reveals unique insights into centromere evolution. Genome Biol 14, R10 (2013).\nD. H. Alexander, J. Novembre, K. Lange, Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19, 1655–1664 (2009).\nS. Wright, Genetical structure of populations. Nature 166, 247–249 (1950).\nN. Pya, S. N. Wood, Shape constrained additive models. Statistics and Computing 25, 543–559 (2015).\nR. Corbett-Detig, R. Nielsen, A Hidden Markov Model Approach for Simultaneously Estimating Local Ancestry and Admixture Time Using Next Generation Sequence Data in Samples of Arbitrary Ploidy. Plos Genetics 13, (2017).\nJ. Graffelman, V. Moreno, The mid p-value in exact tests for Hardy-Weinberg equilibrium. Stat Appl Genet Mol Biol 12, 433–448 (2013).\nB. S. Weir, C. C. Cockerham, Estimating F-Statistics for the Analysis of Population-Structure. 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"Общее недоразвитие речи ОНР\nЗадержка психоречевого развития (ЗПРР)\nАлалия\nДисграфия\nЛечение детей со сложными речевыми и психологическими нарушениями\nОпыт зарубежных врачей\nPsychotherapy and Couples Counseling\nKidney Stone Removal Report Review — Does Joe Barton's System Work?\nHow to Increase Your Pull Up Strength\nHow My Many Hats Fuel My Creativity\nQuantum Mind Power — Instead of Holosync?\nДомой Опыт зарубежных врачей Medical Properties Of Medical Marijuana\nMedical Properties Of Medical Marijuana\nThe chemical components of Medical Marijuana, referred to as cannabinoids, play a major role in the real of medicine known as CAM (Complementary and Alternative Medicine). Medical Marijuana, also know as Medical Cannabis, has been employed for a wide array of medicinal uses for many centuries for its pharmacological effects on the CNS (Central Nervous System) and the immune system. Its anticancer properties and its ability to help the body cope with the side-effects of cancer as well as the treatment process through the activation of specific receptors through the body were discarded quite recently.\nThe non-psychtropic and modifying cannabinoid that has a number of different medical properties called Cannabidiol enterprises 75% of the total cannabinoids content in a few rare strains of cannabis. This modifying cannabinoid called Cannabinol has low psychoactive properties. It is known to reduce the psychoactive effects of THC by degenerating it. Its anti-inflammatory, analgesic, antispasmodic, and antioxidant properties are well-known.\nThe cannabinoid, Cannabigerol that is found in Cannabis, particularly its medicinal marijuana and hemp varieties is the precursor form of other cannabinoids like THC and CBD. It is a bone stimulant with antibacterial and anti-proliferative properties.\nTetrahydrocannabivarin is found in cannabis along with THC. This psychoactive cannabinoid has numerous medical benefits in THC, which include reduced appetite and as the dosage gets larger, it is known to oppose the medicinal properties of THC. There are a number of THCV-based pharmaceuticals that are currently undergoing human trials to address the problems of obesity and Type II diabetes.\nAkin to Tetrahydrocannabivarin is the non-psychoactive cannabinoid, Cannabichromene that is commonly found in cannabis and it also known to have a few medical properties. It is renamed for its anti-inflammatory, anti-proliferative, antimicrobial, analgesic properties, also stimulates the growth of bones and constricts blood vessels.\nOne of the principal psychoactive cannabinoid compounds found in marijuana is Tetrahydrocannabinol or THC that occurs naturally as THC-A, its acidic form and is not absorbably read by the body in its naturally occurring state. When heated, THC-A undergoes decarboxylation to a readily absorbable from that has a number of different medical benefits.\nBoth Tetrahydrocannabinol and Cannabidiol have anxiolytic, antispasmodic, anti-proliferative anticancer, anti-inflammatory, neuro-protective, antimetic, and neuropathic analgesic properties. In addition, Cannabidiol is also a bone-stimulant and immunosuppressant with antibacterial, antipsychotic, antiepileptic, anti-ischemic, anti diabetic, anti psoriatic, and vasorelaxation properties while the antioxidant Tetrahydrocannabinol stimulates appetite, reduces the growth of new nerve tissue, also protects nerves from damage.\nMercy M. James\nПредыдущая статьяDry Penis — Major Causes, Symptoms and Best Treatment\nСледующая статьяAdvantages and Disadvantages of Room Sharing\nВ 2013 году открыт центр \"Надежда\" для детей дошкольников с нарушением речи и с задержкой психического развития.\nТел.: 8-927-26-76-047 г. Кинель ул. 50 лет октября, 100\n© Создание и продвижение сайта APISTUDIO"

"Digital Content for the Pharmaceutical Industry\nPre-Clinical Research\nClinical Trials & Studies\nCRO, CMO, CRAMS & CDMO\nFormulation & Ingredients\nRA & Compliance\nLaboratory Equipment & Services\nProcess Engineering & Equipment\nEngineering, Design & Construction\nCold Chain Storage, Distribution & Logistics\nAddress: Masarykovatrida 1595/54, 415 01 Teplice, Czech Republic\nWeb: https://www.cbdepot.eu/\nCBDepot s.r.o.\nCBDepot is a pioneering producer and B2B supplier of upmarket cannabinoid solutions.\nThis innovative company serves fast-growing markets in the food, cosmetics, pharmaceuticals and health products sectors with high-quality natural and synthesized cannabinoid ingredients.\nCannabis-derived products were initially used as natural fibers (hemp) but have subsequently been found useful across a range of other sectors, including composite plastics, construction, paper, food and nutraceuticals and medicines.\nCBDepot specializes in bulk supply of cannabinoid ingredient, hemp flavoring ingredients and cannabinoid active pharmaceutical ingredients.Its products ensure that content of tetrahydrocannabinol (THC), the main intoxicating element of cannabis, are below detectable levels. Instead, its products emphasize the two other main natural ingredients, cannabidiol (CBD) and cannabigerol (CBG).\nCBD has linked with a range of health indications with strongest scientific evidence for its effectiveness in treating childhood epilepsy syndromes, such as Dravet and Lennox-Gastaut (LGS) that resist antiseizure medications. CBD has also been indicated to address anxiety and sleeping difficulties, for reducing chronic pain.\nCBG is non-intoxicating and does not interact with the body's endocannabinoid system in any way that interrupts mental faculties. Instead, its endocannabinoid interactions have been linked with appetite stimulus and inhibition of GABA neurotransmission in the brain, affecting pain, inflammation, and possibly reducing anxiety. Some studies also suggest that CBG may inhibit the growth of some tumors, while others show it may have neuroprotective effects. A 2014 study found evidence that CBG might suppress the human immune response.\nCBDepotlisted products include:\nIsolated trans-Cannabidiol (CBD): Derived from Cannabis Sativa leaves and HACCP certified to purity of ≧98% and allergens-free as per (EU) 1169/2011. Used for cosmetics, e-liquids and foods, with EU Cosmetics Ingredient Database claims as antioxidant, antiseborrhoeic, skin conditioner and skin protectant.\nSynthesized trans-Cannabidiol: Similar applications to above but derived from chemical synthesis.\nIsolated Cannabigerol: ≧93% purity and Kosher Parve certified\ncGMP trans-Cannabidiol (Cannabidiolum): Cannabis sativa L. derived active substance for pharmaceutical use\nSynthesized Cannabichromene: Glass vial-packaged product intended for research and forensic applications\nBroad Spectrum Distillate 50% CBD Hemp Flavoring Preparation: THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) and conforming to EC/1334/2008, Art. 3.2(d)(i))\nBroad Spectrum Distillate 50% CBG Hemp Flavoring Preparation: THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) that emphasizes CBG content while conforming to EC/1334/2008, Art. 3.2(d)(i)).\n10% CBD Hemp Flavoring Oil:Liquid form THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) and conforming to EC/1334/2008, Art. 3.2(d)(i))\n10% CBG Hemp Flavoring Oil: Liquid form THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) that emphasizes CBG content while conforming to EC/1334/2008, Art. 3.2(d)(i)).\nPowdered 5% CBD Hemp Flavoring Preparation: Powdered form THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) and conforming to EC/1334/2008, Art. 3.2(d)(i))\nPowdered 5% CBG Hemp Flavoring Preparation:Powdered form THC-free Natural hemp flavoring made from edible parts of hemp plant (Cannabis sativa L) that emphasizes CBG content while conforming to EC/1334/2008, Art. 3.2(d)(i)).\n10% CBD E-Liquid: White labelPropylene Glycol USP (90%) with Cannabidiol (10%) : transparent colorless hygroscopic viscous liquid for electronic cigarettes and cosmetics.\n10% CBG E-Liquid Concentrate: White label Propylene Glycol USP (90%) with Cannabidiol (10%) : transparent colorless hygroscopic viscous liquid for electronic cigarettes and cosmetics that emphasizes CBG content.\nMost of these products can be provided in bulk and white label forms.\nCompany history and structure\nEstablished in 2014, CBDepot has become a leader in helping to establish legal and quality standards for cannabinoid ingredients and the formulation of cannabidiol derivatives. Since foundation it has operated under legal license granted by the government of the Czech Republic.\nThe company's initial mission was the supply of \"Legal and Quality CBD\" at a time when sourcing ethical and quality isolated CBD was a challenge. CBDepot's scientific knowledge is based on close links with the Czech Academy of Sciences.\nIn 2017, the company's emphasis evolved to \"Legal Natural Cannabinoids\" because the legality of extraction of cannabis was still an issue. A short time previously, it had added CBG isolate and Cannabis Sativa Fraction 50% CBD and 50% CBG for food and food supplement markets to its product portfolio.\nRecently, the company changes its strapline \"Upmarket Cannabinoid Solutions\", reflecting its new ability to offer cannabinoid ingredients and substances to various markets such as: cosmetic, food, food supplement, e-cig liquid and pharmaceutical and Europe-wide recognition as a strong, ethical and transparent supplier of cannabinoids.\nThe company's Chief Sales Officer, Boris Baňas is an ex-board member of the European Industrial Hemp Association (EIHA), where he successfully campaigned for the establishment of new Europe-wide standards.\nTo learn more about CBDepot's services and capabilities and how they can assist your business, please contact the supplier.\nSupplier's News Feed\nPharmaceutical-Networking.Com is the leading digital content management solution for the Pharmaceutical industry, helping you build conversations with those most important to you.\nPharmaceutical-Networking.Com will create and deliver informative and engaging content about your company, product and services and — using a variety of channels — deliver it to its unique network of decision makers and influential leaders within the pharmaceutical industry. In addition to traditional direct marketing methods, Pharmaceutical-Networking.Com fully embraces the latest communication delivery tools online, on mobile and on social media — providing a truly digital and integrated approach required in today's B2B marketplace to support the vital interaction between buyers and suppliers online.\nSaffron Networking Ltd is a digital content company which provides online digital content management services with a focus on specific international B2B markets with the objective of connecting buyers and suppliers together through compelling relevant online networking.\nPharmaceutical-Networking.Com is a product of Saffron Networking Ltd. Copyright 2014."

"Thermo Fisher Scientific UHPLC/MS Identifies Cannabinoids in Baked Goods with Minimal Sample Preparation\nSAN JOSE, Calif. (October 19, 2009) – Thermo Fisher Scientific Inc., the world leader in serving science, today announced a new method for identifying marijuana cannabinoids in baked goods that is faster, easier-to-use and requires less sample preparation. Using ultra high performance liquid chromatography with mass spectrometry detection (UHPLC/MS), the application tests baked goods samples obtained from a local state police forensic laboratory and is detailed in the application note \"Identification of Cannabinoids in Baked Goods by UHPLC/MS\" which is available to download via the \"Learn more about Accela\" link at www.thermo.com/accela.\nMarijuana is the most common illegal drug in the U.S. and Europe and U.S. law enforcement agencies seize two million pounds of cannabis in various forms each year. The evidence is first screened for marijuana using simple chemical tests, such as the Duqenois-Levine test and then gas chromatography-mass spectrometry (GC/MS) is used to positively identify cannabinoids. This conventional technique works well for leaf marijuana, hashish and residue collected from smoking paraphernalia. UHPLC/MS however is an alternate method for identifying marijuana cannabinoids in complex food matrices such as baked goods.\nIncorporating the Thermo Scientific Accela UHPLC system, the Thermo Scientific MSQ Plus Mass Detector, a single quadrupole mass spectrometer and Thermo Scientific Xcalibur software, the system detected marijuana cannabinoids, Δ9-tetrahydrocannabinol (THC), cannabinol and cannabidiol in the baked goods, a complex food matrix. The team delivered results with simpler sample preparation, no derivatization and less instrument clean-up time.\nThe team extracted and separated cannabinoids on a Thermo Scientific Hypersil GOLD PFP column, and it showed that the cannabinoid standards eluted with good resolution at 4.1 minutes (cannabidiol), 5.1 minutes (THC) and 5.4 minutes (cannabinol). The extracts from a brownie and a cookie eluted at 5.1 minutes, testing positive for THC, demonstrating how little sample preparation is required for this method. It is simpler, faster and requires less sample material than traditional GC/MS techniques. Preparation time of ten minutes and a total run time of eight minutes shows the efficiency of UHPLC/MS detection.\nThe Accela™ is a high speed chromatographic system that provides fast and efficient chromatographic separations over a range of flow rates and pressures. It features optimized system delay volumes for fast separations and flexible sample format. The innovative quaternary pump is capable of conventional and ultra-high pressures while the Thermo Scientific LightPipe technology provides maximum sensitivity and resolution.\nFor more information about the Thermo Scientific UHPLC/MS solutions or to obtain a copy of the application note, please call +1 866-463-6522, e-mail mailto:analyze@thermofisher.comor visit www.thermo.com/accela.\nThermo Scientific is part of Thermo Fisher Scientific, the world leader in serving science.\nThermo Fisher Scientific Inc. (NYSE: TMO) is the world leader in serving science, enabling our customers to make the world healthier, cleaner and safer. With 2008 revenues of $10.5 billion, we have approximately 34,000 employees and serve over 350,000 customers within pharmaceutical and biotech companies, hospitals and clinical diagnostic labs, universities, research institutions and government agencies, as well as environmental and industrial process control settings. Serving customers through two premier brands, Thermo Scientific and Fisher Scientific, we help solve analytical challenges from routine testing to complex research and discovery. The Thermo Scientific brand represents a complete range of high-end analytical instruments as well as laboratory equipment, software, services, consumables and reagents to enable integrated laboratory workflow solutions. Fisher Scientific provides a complete portfolio of laboratory equipment, chemicals, supplies and services used in healthcare, scientific research, safety and education. Together, we offer the most convenient purchasing options to customers and continuously advance our technologies to accelerate the pace of scientific discovery, enhance value for customers and fuel growth for shareholders and employees alike. Visit www.thermofisher.com\nThermo Fisher Scientific Accelerates Multi-residue Analysis of Pesticides in Rice\nThermo Fisher Scientific's Mass Spectrometry Technology Helps Children's Hospital Boston Isolate Biomarker for Acute Pediatric Appendicitis\nThermo Fisher Scientific's Exactive LC/MS Wins Best New Product Award at the 2009 Gulf Coast Conference\nThermo Fisher Scientific Showcases Latest Innovations to Improve Biopharmaceutical and Proteomics Workflows\nNew Sample Preparation System Improves Proteomics Research Productivity\nNew Sample Preparation Solution Simplifies Food Safety Testing\nThermo Fisher Scientific Collaborates with the University of Sheffield to Advance Oligonucleotide Characterization and Analytical Workflows\nThermo Fisher Scientific to Resell IonSense ID-CUBE Ion Source. ID-CUBE with Orbitrap LC-MS systems simplify food, environmental, pharmaceutical and forensic analyses\nThermo Fisher Scientific Launches Technical Library on LC-MS Solutions for Endocrine Drug Analysis in Clinical Research\nFDA Further Expands EUA for Thermo Fisher Scientific's COVID-19 Diagnostic Tests\nThermo Fisher Scientific Acquires Continuous Emission Monitoring Assets from EPTEK Technology\nVan Andel Research Institute Installs World-Class Microscopes to Enable Discovery of the Molecular Basis of Disease\nThermo Fisher Scientific Wins R&D 100 Award for Thermo Scientific Vanquish Flex UHPLC\nNew UHPLC Columns Offer Users Expanded Application Flexibility\nNew High Resolution Mass Spectral Database Offers Essential Tool for Unknown Compound Identification\nImproved Determination of Key Analytes in Fine Particulate Matter\nTroubleshooting Guide Improves Gas Chromatography Performance\nSimultaneous Determination of Lithium, Sodium, and Calcium in Lithium Carbonate\nEnhance Sample Preconcentration and Reduce Workflow"

"The identification of the major psychoactive constituent of Cannabis and marijuana, Delta(9)-tetrahydrocannabinol, opened the way first to the cloning of the G-protein-coupled cannabinoid CB(1) and CB(2) receptors, and then to the isolation and characterisation of their endogenous agonists, the endocannabinoids. Considerable progress has been made in the characterisation of pathways and enzymes for the biosynthesis and degradation of anandamide and 2-arachidonoylglycerol, the two best-known endocannabinoids, as well as of endocannabinoid-related molecules, such as the N-acylethanolamines, which, as in the case of N-palmitoylethanolamine and N-oleoylethanolamine, may interact with other receptor types. However, it is still not fully understood how other plant cannabinoids, of which cannabidiol is the most studied representative, exert their pharmacological effects. Together with these issues, this first review article on the endocannabinoids describes the synthetic pharmacological tools that have been designed so far to interact with the proteins of the 'endocannabinoid system' and that can potentially be used as templates for the development of new therapies.\nPetrosino, Stefania, et al. \"Endocannabinoid Chemical Biology: a Tool for the Development of Novel Therapies.\" Current Opinion in Chemical Biology, vol. 13, no. 3, 2009, pp. 309-20.\nPetrosino S, Ligresti A, Di Marzo V. Endocannabinoid chemical biology: a tool for the development of novel therapies. Curr Opin Chem Biol. 2009;13(3):309-20.\nPetrosino, S., Ligresti, A., & Di Marzo, V. (2009). Endocannabinoid chemical biology: a tool for the development of novel therapies. Current Opinion in Chemical Biology, 13(3), pp. 309-20. doi:10.1016/j.cbpa.2009.04.616.\nPetrosino S, Ligresti A, Di Marzo V. Endocannabinoid Chemical Biology: a Tool for the Development of Novel Therapies. Curr Opin Chem Biol. 2009;13(3):309-20. PubMed PMID: 19457702.\nFAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels.\nNeurobiology and systems physiology of the endocannabinoid system.\nRole of lipids and lipid signaling in the development of cannabinoid tolerance.\nCannabinoid receptor ligands as potential anticancer agents--high hopes for new therapies?\nThe role of endocannabinoids in pain modulation and the therapeutic potential of inhibiting their enzymatic degradation.\nCannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders."

"planta medica international open\nOfficial Organ of the Society for Medicinal Plant and Natural Product Research\nZu den Ausgaben VOR Heft 2/2016\nPlanta Medica Letters\nPlanta Medica\nDrug Research\nPharmacopsychiatry\nSynfacts\nSynlett\nCC BY-NC-ND 4.0 · Planta Medica International Open 2020; 07(02): e81-e87\nOriginal Papers\nQuantification of Cannabinoids in Cannabis Oil Using GC/MS: Method Development, Validation, and Application to Commercially Available Preparations in Argentina\nNicolás Fernández\n1 Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Cátedra de Toxicología y Química Legal, Laboratorio de asesoramiento toxicológico analítico (CENATOXA), Ciudad Autónoma de Buenos Aires (CABA), Buenos Aires, Argentina\nLaura Jorgelina Carreras\nRafael Antonio Larcher\nAdriana Silvia Ridolfi\nPatricia Noemí Quiroga\nPDF Download Permissions and Reprints\nReagents and standards\nCalibrators and internal standard\nTested material\nGas chromatography and mass spectrometry analysis\nValidation procedure\nCalibration curves and limits\nIntra- and inter-day precision\nThe medicinal use of cannabis oil is increasing all over the world. Few analytical methods for the quantification of cannabinoids have been validated using internationally accredited guidelines. This work describes the development and validation of a selective and sensitive gas chromatography-mass spectrometry method for the qualitative analysis of the main cannabinoids, namely cannabidiolic acid, tetrahydrocannabinolic acid, cannabigerol, and cannabichromene as well as quantitative determination of cannabidiol, Δ9-tetrahydrocannabinol, and cannabinol, present in cannabis oils. The method was fully validated according to Food and Drug Administration and International Conference on Harmonization guidelines. A linear range of 0.1–30 μg/mL was obtained for CBD and Δ9-THC and 0.034–11.7 μg/mL for CBN, presenting determination coefficients above 0.99. The lower limits of quantification ranged from 0.034 to 0.1 μg/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 3.9–13.8 and 4.7–14.1%, respectively. Extraction efficiency at lower limits of quantification was 95–103%. Verification of method validity was performed with authentic cannabis oil samples. To our knowledge, this is the first method available in Argentina, validated according to international guidelines, for quantification of CBD, Δ9-THC, and CBN in cannabis oil. The primary application of this method is to differentiate between cannabis oils with high or low content of Δ9-THC, CBD, or mixed Δ9-THC/CBD. This is of fundamental importance for the patient and so that the physicians can carry out a suitable therapy.\ncannabis oil - Cannabis sativa L. - Cannabaceae - cannabinoids - gas chromatography - mass spectrometry - Method Validation Natural Products Analysis\nCBC cannabichromene\nCBD cannabidiol\nCBDA cannabidiolic acid\nCBG cannabigerol\nCBN cannabinol\nFDA Food and Drug Administration\nGC-MS gas chromatography-mass spectrometry\nISTD internal standard\nICH International Conference on Harmonization\nLLOQ lower limits of quantification\nMSTFA N-methyl-N-trimethylsilyltrifluoroacetamide\nTHCA tetrahydrocannabinolic acid\nΔ9-THC trans-Δ9-tetrahydrocannabinol\nWADA World Anti-Doping Agency\nThe medicinal use of Cannabis sativa L. (Cannabaceae) products is increasing all over the world. The most common therapeutic indications of cannabis and cannabinoids are for the treatment of pediatric resistant epilepsy, chronic noncancer pain, multiple sclerosis, dyskinesias of Huntington's and Parkinson's diseases, and tics of Tourette syndrome [1].\nCannabis oil extracts are prepared from dried Cannabis sativa L. inflorescences and incorporated in common edible oils (e. g., olive or sunflower) or even obtained using these oils as extraction media.\nCannabinoids are terpene phenolic compounds typical of the cannabis plant. Δ9-THC is the most psychoactive constituent in cannabis. It has many diverse pharmacological effects with therapeutic value in the treatment of different medical conditions [2] [3] [4] [5].\nOther non-psychotropic cannabinoids, mainly CBD and CBN, are increasingly researched, showing partially distinctive effects [6] [7] [8] [9] [10] [11]. Thus, quantification of these cannabinoids is also important to understanding the pharmacological properties of cannabis oil. Δ9-THC and CBD are present in the plant as THCA and CBDA, respectively [12] [13]. Decarboxylation is temperature-dependent [14] [15], and preheating of cannabis samples has been recommended to potentiate the final cannabis oil extract [16] [17].\nMedical cannabis oils generally possess high levels of the therapeutic CBD and lower levels (generally less than 0.3%) of the psychotropic Δ9-THC. The FDA has issued warning letters to firms that market unapproved new drugs that allegedly contain CBD. As part of these actions, the FDA has determined the cannabinoid content of some cannabis oil products (not approved by the FDA), and many were found to contain levels of CBD that are very different from the label claim [18].\nIn Argentina, cannabis and its derivatives are schedule IV-controlled substances (prohibited use) [19], but new regulations have allowed production for medical purposes through licensed producers [20]. Production of commercial cannabis oil in Argentina must take place in a facility using good manufacturing practices, and products must be tested for the presence and content of Δ9-THC and CBD, using validated analytical methods.\nSeveral methods, based on GC [21] [22] [23] [24] or LC [24] [25] [26] have been published for the determination of Δ9-THC, CBD, and other cannabinoids in cannabis oil. GC, one of the most used techniques for the quantitative analysis of cannabinoids in plant materials, has been in use for a long time. The high temperature of the injection port transforms the acid cannabinoids into the neutral cannabinoids. Since the cannabis oils contain the acidic and neutral forms, a derivatization step is required to prevent the decarboxylation [27] [28], and trimethylsilyl derivatives have been shown to be suitable for analysis [28] [29]. Thereby, the value of total cannabinoids can be measured by determining the acid and neutral form separately. In contrast to GC, LC-based techniques allow the direct analysis of cannabinoid (neutral and acid) in the extracted sample.\nThe main goal of the present work is the development, optimization, and validation of a method with a simple derivatization coupled to GC-MS for the determination of Δ9-THC, CBD, and CBN in cannabis oil.\nThe GC-MS validated method, according to FDA [30] and ICH [31] guidelines, has proven to be very accurate, highly reproducible, and sensitive to determine the target cannabinoids, with only 10 μL of sample tested. In addition, the method was successfully applied to the quantitative analysis of 10 different cannabis oils. The application of this method to differentiate between cannabis oils with high or low content of Δ9-THC, CBD, or mixed Δ9-THC/CBD will provide physicians with essential information so that they can carry out a suitable therapy with patient's pathology.\nAn accurate and robust analytical method has been developed for the quantification of 3 cannabinoids relevant to the health and safety of cannabis oil users. This process was optimized for dilution solvent and sonication time. Dilution solvents had been selected according to the existing literature [23] [25] [32] [33] and to the physical-chemical properties of the studied analytes. The solvents evaluated were methanol, ethanol, diethyl ether, and petroleum ether. To evaluate the effect of different sonication times, the samples were sonicated at various times (5, 10, 20, and 30 min). These experiments were performed in triplicate using cannabis oil, and the relative peak areas obtained for each cannabinoid were compared to establish the best dilution solvent and sonication time. An initial prescreening (methanol and 5 min sonication time) of cannabinoids was made in full scan mode. Mass spectrometric identification criteria were according to the WADA [34] [35]. The cannabinoids identified were Δ9-THC, CBD, CBN, CBC, CBG, THCA, and CBDA.\nThe statistical analysis of these data indicated that dilution solvent was the most significant factor ([Fig. 1]). Regarding diethyl ether, the recoveries obtained for Δ9-THC, CBN, CBC, THCA, and CBDA were significantly greater when compared to using methanol: [F (1.4)=10.85, p<0.05], [F (1.4)=36.74, p<0.05], [F (1.4)=8.37, p<0.05] [F (1.4)=102.94, p<0.05], and [F (1.4)=107.49, p<0.05], respectively. Subsequently, the recoveries obtained with diethyl ether for Δ9-THC, CBN, CBC, THCA, and CBDA were significantly greater when compared to using ethanol: [F (1.4)=10.53, p<0.05], [F (1.4)=10.79, p<0.05], [F (1.4)=16.94, p<0.05] [F (1.4)=157.39, p<0.05], and [F (1.4)=184.72, p<0.05], respectively. These results were obtained using Fisher's test, which evaluates the intra- and inter-group study variance.\nFig. 1 Relative peak areas and SDs obtained for different dilution solvents for cannabidiol (CBD), cannabinol (CBN), Δ9-tetrahydrocannabinol (Δ9-THC), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabichromene (CBC) and cannabigerol (CBG).\nDiethyl ether and petroleum ether extractions resulted in similar recoveries, with no significant differences between them. Lower standard deviations and associated errors are observed with diethyl ether, which makes diethyl ether the most promising option ([Fig. 1]).\nAnother relevant parameter, also studied, was the sonication time (5–30 min) that might result in a greater recovery of the target analytes, as well as influence signal intensity. All studied times of extraction resulted in similar recoveries, with no significant differences between them. The sonication appears not to depend on the time of exposure to the solvent mixture. In order to make the process faster, 5 min was chosen.\nThe data were used to develop an optimized sample preparation protocol using 10 µL of cannabis oil with 10 mL of diethyl ether, with sonication for 5 min and vortexing for 30 sec (3 cycle sonication/vortexing).\nFull method validation was conducted according to the FDA and ICH guidelines using olive and cannabis oil as matrix. The selectivity of the method was evaluated by analyzing of blank samples. No interfering substances were detected at the selected retention times and m/z windows for all cannabinoids. Using the above-mentioned criteria for positivity, all the analytes (Δ9-THC, CBD, and CBN) were successfully and unequivocally identified in all the spiked samples at the LLOQ. Therefore, the method was considered selective for Δ9-THC, CBD, and CBN determination.\nThe calibration model was evaluated from a set of 9 calibration points. The homoscedasticity assumption was tested in a linear regression analysis. The residual plot clearly showed that error was not randomly distributed around the concentration axis. The F-test also revealed a significant difference between the variances. There was evidence that variances were significantly different, thus homoscedasticity was not met.\nWeighted least squares regressions had to be adopted in order to compensate for heteroscedasticity. Six weighting factors were evaluated for each compound (1/x0.5, 1/x, 1/x2, 1/y0.5, 1/y, 1/y2). The weighting factor that resulted in the lower sum of relative errors and, simultaneously, a mean R2 value of at least 0.99 was chosen. This factor was 1/x2 for all analytes. The method obtained linear relationships by means of these weighted least squares regressions. Calibrators' accuracy [mean relative error (bias) between the measured and spiked concentrations] was within a±15% interval for all concentrations. Calibration data are shown in [Table 1].\nTable 1 Linearity and lower limit of quantification (LLOQ) data\nLinearity data (n=6)\nLLOQ (n=10)\nLineal range (μg/mL)\nSlope (mean±SD)\ny-Intercept (mean±SD)\nR2 (range)\nNominal conc. (μg/mL)\nMean calculated conc.±SD (μg/mL)\nCVa (%)\nREb (%)\nRecovery±S.D. (%)\n∆9-THC-d3\n1/X2\n0.1 – 30\n103±2\n∆9-THC\n0.04 – 11.7\n-0.018±0.001\nMean values and standard deviations. a Coefficient of variation (%). b Relative error (%) =[(spiked concentration − nominal concentration/nominal concentration) × 100]. CBD cannabidiol, Δ9-THC Δ9-tetrahydrocannabinol, CBN cannabinol and ∆9-THC-d3 Δ9-tetrahydrocannabinol-d3.\nThe LLOQs of the compounds were 0.1 µg/mL for Δ9-THC, CBD; and 0.04 µg/mL for CBN ([Table 1]), and the upper limit of quantification ranged from 11.7 (CBD) to 30.0 (Δ9-THC, CBD) µg/mL with a minimum of 9 calibration points.\nThese limits were considered satisfactory, especially when compared to those obtained by other authors. Citti et al. [36] used 100 μL (10 times higher) of cannabis oil, and the reported LLOQs for Δ9-THC, CBD, and CBN were greater than that presented herein. Bettiol et al. [37] and Deida et al. [38] applied 40 μL (4 times higher) of cannabis oil and reported LLOQs of 1.0 μg/mL for Δ9-THC, CBD, and CBN. The mentioned papers report higher LLOQs than ours when analyses were carried out using a LC-DAD or LC-MS system. A GC-MS analytical method reported by Ciolino et al. [23] presented a LLOQs of 0.3 μg/mL for Δ9-THC, CBD, and CBN; however, this work, unlike ours, started from gravimetrically measured samples.\nBoth intra-day and inter-day precisions for the entire extraction and analysis process were determined by extracting 2 cannabis oils over the course of 5 days, and 5 times on a single day. These oils were chosen to obtain a broad representation of analyte profiles. Cannabis oil A contains a high concentration of CBD and a low concentration of Δ9-THC and CBN, while cannabis oil B contains a low concentration of CBD and a high concentration of Δ9-THC and CBN.\nIntra-day precision was evaluated by analyzing, on the same day, 5 replicates of the cannabis oils. The obtained% RSD were lower than 13.8% at all studied concentration levels. ([Table 2]). The evaluation of inter-day precision was made within a 5-day period. The obtained% RSD were lower than 14.1% for all cannabinoids at the tested concentrations. ([Table 2]).\nTable 2 Intra-day and inter-day precision data.\nIntra-day (n=5)\nInter-day (n=15)\nMeasured±SD (μg/mL)\nRSDa (%)\nMean values and standard deviations. a Relative standard deviation (%). CBD cannabidiol, Δ9-THC Δ9-tetrahydrocannabinol and CBN cannabinol.\nThe recovery was evaluated at LLOQ for Δ9-THC, CBD, and CBN. The recoveries for the compounds were between 95% and 103% ([Table 1]). According to our results, the method can be considered a powerful technique, revealing a fast and efficient extraction of the target analytes with a lower sample volume.\nAfter validation of this analytical method, in order to demonstrate the applicability, it was successfully applied to routine analysis of 10 cannabis oils.\nIn controlled/regulated production cannabis oils (cannabis oil #1 and #2), CBD was detected at levels consistent with the product labeling, and Δ9-THC levels were very low, as expected for products derived from hemp oil ([Table 3]). In addition, cannabis oil #1 and #2 showed high ratios of CBD to Δ9-THC and CBN ([Table 3]).\nTable 3 Cannabinoid content of tested authentic samples.\nDeclared CBD*(mg/mL)\nCBD (mg/mL)\nΔ9-THC (mg/mL)\nCBN (mg/mL)\nCBD / Δ9-THC ratio\nNot declared\n*CBD declared on labels. ND: Not detected. CBD cannabidiol, Δ9-THC Δ9-tetrahydrocannabinol and CBN cannabinol.\nUncontrolled/unregulated production cannabis oils had CBD, Δ9-THC, and CBN concentrations that differed notably. Our analysis revealed that 2 preparations (samples oils #3 and #7) exhibited high levels of Δ9-THC and low or undetectable concentration of CBD, while in another 3 (samples oil #6, #8, and #9), the CBD content was not detectable and Δ9-THC ranged from 1.3 to 4.3 mg/mL ([Table 3]).\nCBD appears not to have adverse consequences at high doses; however, Δ9-THC concentrations observed in cannabis oils (especially oil # 3, # 4, # 7, # 8) could be enough to produce intoxication, especially among children [39].\nInterestingly, the web site from the CBD oil #4 producer reports a CBD/Δ9-THC ratio of 1:1, while we found a CBD/Δ9-THC ratio of 0.25:1.\nFinally, in the cannabis oil #10, CBD, Δ9-THC, and CBN were not detected, which would indicate that it was falsely sold as cannabis oil.\nCBN was quantifiable in most samples (except oil #5, #8, and # 10). CBN is formed by Δ9-THC oxidation during plant aging or inappropriate storage conditions [40]. Therefore, its determination may assist in the evaluation of the quality of cannabis oils.\nTaken together, the results highlighted the extreme variability of the uncontrolled/unregulated production of cannabis oils, and these results are in agreement with those obtained from products available on the United States and Italy markets [41] [42]. Bonn-Miller et al. [41] reported that 26% of tested products contained less CBD than declared on the label, while Pavlovich et al. [42] reported 9 out of 14 tested samples had concentrations that differed notably from the declared amount.\nIn conclusion, a GC-MS method was developed, optimized, validated, and applied for the simultaneous detection and quantification of CBD, Δ9-THC, and CBN in cannabis oil. The analyses were carried out using small sample volumes (10 μL of cannabis oil), and the method was successfully applied to real samples derived from Argentina's market.\nThe issues of variability of cannabinoid content in preparations and inaccurate label claims in the global market justify the need to have a method like the one that has been developed and validated to provide concentration data for each preparation.\nTo our knowledge, this is the first method available in Argentina validated according to international guidelines for quantification of CBD, Δ9-THC, and CBN in cannabis oil.\nIn addition, CBD and Δ9-THC concentration data in medicinal cannabis oil are crucial for physicians to be able to properly adapt the prescribed dose to the available preparation.\nFurther studies are needed to evaluate the impact of different cannabis oils on cannabinoids pharmacokinetics and clinical outcomes.\nAnalytical standards: Δ9-THC (purity 99.4%), CBD (purity 99.8%), CBN (purity 99.5%), and ISTD: Δ9-tetrahydrocannabinol-d3 (Δ9-THC -d3, purity 98.8%) were purchased from Cerilliant (Round Rock, TX, USA) as 1.0 and 0.1 mg/mL in methanol solutions.\nMethanol, ethanol, diethyl ether, petroleum ether, and ethyl acetate were provided from Merck Chemistry (Buenos Aires, Argentina); all chemicals were analytical ACS or chromatography grade. MSTFA was acquired from Thermo Fisher Scientific.\nA working solution (A) was prepared by proper dilution of stock solutions (1 mg/mL) with methanol to the final concentrations of 10.0 μg/mL for Δ9-THC and CBD. Additionally, working solutions of 400 and 4.0 μg/mL for CBN were prepared. As ISTD (Δ9-THC -d3) stock solutions of 0.1 mg/mL was used. All primary and working solutions were stored at −20°C into amber glass vials.\nWorking calibrators (0.1, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, 20.0, and 30.0 μg/mL Δ9-THC and CBD; and 0.04, 0.80, 1.50, 2.40, 3.20, 3.90, 5.90, 7.80, and 11.70 μg/mL CBN) were made daily by adding of each standard to 1.0 mL (final volume) of ethanol. For the 0.1 μg / mL Δ9-THC and CBD and 0.04 μg / mL CBN points, working solution (A) and 4.0 μg / mL CBN were used, respectively. For the rest of the points, stock solutions and a working solution of 400 μg / mL CBN, were used.\nThe cannabis oil extracts used in this study were obtained from subjects who attended the Analytical Toxicology Advisory Laboratory (CENATOXA) with a request for quantification of Δ9-THC and CBD.\nEight samples were obtained from uncontrolled/unregulated production cannabis oil (n =8) and 2 samples from controlled/regulated production cannabis oil (n =2).\nThe samples were analyzed using an HP 6890 N gas chromatograph, combined with an HP 5973 quadrupole mass spectrometer and an HP 6890 Series injector (all from Hewlett-Packard). Data were acquired and analyzed using Agilent Enhanced ChemStation G1701DA software (Agilent Technologies). The separation of the analytes was achieved using a capillary column (30 m ×0.25 mm I.D., 0.25 μm film thickness) with 5% phenylmethylsiloxane (HP-5 MS), supplied by J & W Scientific. Carrier gas (helium) was set at a constant flow rate of 1.0 mL/min. The volume of injection was 2 μL on split mode (split ratio of 1:10); the injection port and transfer line temperatures were set at 280°C and 280°C, respectively. The oven temperature started at 60°C, followed by a temperature ramp of 10°C/min to 300°C held for 2 min. Total separation run time was 26.0 min. The ion source was maintained at 220°C and the quadrupole at 150°C. The mass spectrometer was operated with a filament current of 300 mA and an electron energy of 70 eV in the positive electron ionization mode. Selected ion monitoring mode was used with a dwell time of 80 ms. Three ions for each analyte and 1 ion for ISTD were chosen based on selectivity and abundance in order to maximize the signal-to-noise ratio in matrix extracts ([Table 4]). Agilent Enhanced ChemStation G1701DA software (Agilent Technologies) was used for data acquisition, data processing, and instrument control. The mass spectra were obtained by collecting the data at rate of 1.38 scan/s over the m/z range of 50–600. Compounds were identified by comparing the retention times of the chromatographic peaks with those of authentic compounds analyzed under the same conditions when available and through the National Institute of Standards and Technology (NIST 1998); Pfleger/Maurer/Weber: Mass Spectral Library of Drugs, Poisons, Pesticides, Pollutants and Their Metabolites (2011), and Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG 2019), MS spectral database.\nTable 4 Optimized identification parameters for compounds\nRetention Time (min)\nTime window (min)\nQuantification ion (m/z)\nQualifier ion 1 (m/z)\nDwell time (ms)\nPeak width (m/z units)\nΔ9-THC\nΔ9-THC-d3\nCBD cannabidiol, Δ9-THC Δ9-tetrahydrocannabinol, Δ9-THC-d3 Δ9-tetrahydrocannabinol-d3 and CBN cannabinol.\nCannabis oil was mixed by inversion prior to sample preparation. Then 10 μL of oil was diluted thousand-fold (1:1000 dilution) in 10 mL of diethyl ether and vortexed for 30 sec. Extracts were sonicated for 5 min and vortexed for 30 sec. The sonication and agitation cycles were performed twice more.\nOne hundred microliters (100 μL) of extract with 4 µL of ISTD (0.1 mg/mL) were evaporated to dryness under a gentle stream of nitrogen at 45°C. For the derivatization procedure, 50 μL of MSTFA were added to the dried residue and vortexed for 10 sec. The tubes were heated on a thermo block at 60°C for 20 min. A 2 μL aliquot of the resulting solution was injected into the GC–MS system.\nThe analytical method validation was performed in accordance with the guidelines of the FDA [30] and ICH [31]. The validation was performed following a 5-day validation protocol and included selectivity/specificity, linearity, limits, intra- and inter-day precision, and recovery.\nSince it is not possible to obtain cannabis oil that is devoid of cannabinoids, blank samples were prepared using olive oil (n =10). Samples were extracted and analyzed according to the previously described procedure.\nPeaks at the retention time of interest were compared with those from olive oil samples spiked with analytes at the LLOQ.\nThe acceptance criteria for compounds identification were according to the WADA [34]. The method would be considered selective if no analyte could be identified in the blank samples by applying those criteria.\nThe linearity of the method was established on aliquots of ethanol (100 μL) spiked with the corresponding working solution to obtain calibrator samples. Replicates (n =9) at each concentration were analyzed as described Fernandez et al. [35].\nThe lowest point of the calibration curve was the LLOQ of the method. The LLOQ was determined by analyzing 10 replicates of spiked blank olive oil samples (independent from those of the calibration curve). It was tested whether the signal-to-noise ratios (S/N) of all analytes was greater than 10. Furthermore, precision and accuracy data with a coefficient of variation (CV%) less than 20% and a relative error (RE%) within±20% of the nominal concentration were obtained.\nIn order to evaluate intra- and inter-day precision, different authentic samples containing different cannabinoid profiles were evaluated on 5 separate days as well as 5 times on the same day.\nPrecision, expressed as % RSD, was determined by calculating the percent ratio of the standard deviation divided by the calculated mean concentration times 100. Data were evaluated using a 1-way analysis of variance (ANOVA) with day as the grouping variable. RSD values below 15% and at LLOQ below 20% were acceptable for quantitative analysis.\nFor the analysis of recovery, 2 sets of samples (n =5) were prepared at LLOQ: sample set 1 representing the neat standard/ISTD and sample set 2 consisting of blank olive oil spiked before dilution. The ISTD were added to sample set 2 after dilution. The recovery results were obtained by comparison of peak areas ratio of sample set 1 to those of the corresponding peaks in sample set 2.\n1 Gonçalves J, Rosado T, Soares S, Simão AY, Caramelo D, Luís Â, Fernández N, Barroso M, Gallardo E, Duarte AP. Cannabis and its secondary metabolites: their use as therapeutic drugs, toxicological aspects, and analytical determination. Medicines 2019; 6: 31\n2 Garb S. Cannabinoids in the management of severe nausea and vomiting from cancer chemotherapy. Some additional considerations. J Clin Pharmacol 1981; 21: 57S-59S\n3 Lewis DY, Brett RR. Activity-based anorexia in C57/BL6 mice: Effects of the phytocannabinoid, 9-tetrahydrocannabinol (THC), and the anandamide analog, OMDM-2. Eur Neuropsychopharmacol 2010; 20: 622-631\n4 De Lago E, Gomez-Ruiz M, Moreno-Martet M, Fernandez-Ruiz J. Cannabinoids, multiple sclerosis, and neuroprotection. Exp Rev Clin Pharmacol 2009; 2: 645-660\n5 Maurer M, Henn V, Dittrich A, Hofmann A. 9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatr Clin Neurosci 1990; 240: 1-4\n6 Flores-Sanchez IJ, Verpoorte R. Secondary metabolism in cannabis. Phytochem Rev 2008; 7: 615-639\n7 Rong C, Lee Y, Carmona NE, Cha DS, Ragguett RM, Rosenblat JD, Mansur RB, Ho RC, McIntyre RS. Cannabidiol in medical marijuana: Research vistas and potential opportunities. Pharmacol Res 2017; 121: 213-218\n8 Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag 2008; 4: 245-459\n9 Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015; 313: 2456-2473\n10 Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013; 33: 195-209\n11 Pisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, Cuomo G, Abate M, Faggiana G, Proto MC, Fiore D, Laezza C, Bifulco M. Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacol Ther 2017; 175: 133-150\n12 Lercker G, Bocci F, Frega N, Bortolomeazzi R. Cannabinoid acids analysis. Farmaco 1992; 47: 367-378\n13 Perrotin-Brunel H, Buijs W, van Spronsen J, van Roosmalen MJE, Peters CJ, Verpoorte R, Witkamp GJ. Decarboxylation of Δ9-tetrahydrocannabinol: kinetics and molecular modelling. J Mol Struct 2011; 987: 67-73\n14 Politi M, Peschel W, Wilson N, Zloh M, Prieto JM, Heinrich M. Direct NMR analysis of cannabis water extracts and tinctures and semi-quantitative data on Δ9-THC and Δ9-THC-acid. Phytochemistry 2008; 69: 562-570\n15 Veress T, Szanto JI, Leisztner L. Determination of cannabinoid acids by high-performance liquid chromatography of their neutral derivatives formed by thermal decarboxylation: I. Study of the decarboxylation process in open reactors. J Chromatogr A 1990; 520: 339-347\n16 Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R. Cannabis tea revisited: a systematic evaluation of the cannabinoid composition of cannabis tea. J Ethnopharm 2007; 113: 85-90\n17 Fischedick JT, Hazekamp A, Erkelens T, Choi YH, Verpoorte R. Metabolic fingerprinting of cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochem 2010; 71: 2058-2073\n18 US Food and Drug Administration (FDA). Warning letters and test results for cannabidiol-related products. Available at https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products Accessed March 03, 2020.\n19 Ley 17818 De estupefacientes. Available at: http://www.anmat.gov.ar/webanmat/Legislacion/Medicamentos/ley17818.pdf; Accessed July 22, 2019.\n20 Ley 27350 Investigación médica y científica de uso medicinal de la planta de Cannabis y sus derivados. Available at: http://servicios.infoleg.gob.ar/infolegInternet/anexos/270000-74999/273801/norma.htm Accessed July 22, 2019.\n21 Pellegrini M, Marchei E, Pacifici R, Pichini S. A rapid and simple procedure for the determination of cannabinoids in hemp food products by gas chromatography-mass spectrometry. J Pharm Biomed Anal 2005; 36: 939-946\n22 Nahar L, Guo M, Sarker SD. Gas chromatographic analysis of naturally occurring cannabinoids: a review of literature published during the past decade. Phytochem Anal 2019; 1-12\n23 Ciolino LA, Ranieri TL, Taylor AM. Commercial cannabis consumer products part 1 : GC-MS qualitative analysis of cannabis cannabinoids. Forensic Sci Int 2018; 289: 429-437\n24 Citti C, Braghiroli D, Vandelli MA, Cannazza G. Pharmaceutical and biomedical analysis of cannabinoids: a critical review. J Pharm Biomed Anal 2018; 147: 565-579\n25 Meng Q, Buchanan B, Zuccolo J, Poulin M, Gabriele J, Baranowski DC. A reliable and validated LC-MS/MS method for the simultaneous quantification of 4 cannabinoids in 40 consumer products. PLoS One 2018; 13: e0196396\n26 Pacifici R, Marchei E, Salvatore F, Guandalini L, Busardò FP, Pichini S. Evaluation of long-term stability of cannabinoids in standardized preparations of cannabis flowering tops and cannabis oil by ultra-high-performance liquid chromatography tandem mass spectrometry. Clin Chem Lab Med 2018; 56: e94-e96\n27 Davis TWM, Farmilo CG, Osadchuk W. Identification and origin determinations of Cannabis by gas and paper chromatography. Anal Chem 1963; 35: 751-754\n28 Fetterman PS, Doorenbos NJ, Keith ES, Quimby MW. A simple gas liquid chromatography procedure for determination of cannabidiolic acids in Cannabis sativa L. Experientia 1971; 27: 988-990\n29 Parker JM, Stembal BL. Review of gas-liquid chromatography of marihuana. Journal of the AOAC 1974; 57: 888-892\n30 Food and Drug Administration (FDA) Bioanalytical Method Validation. Guidance for Industry. U.S. Department of Health and Human Services, Food and Drug Administration, FDA; 2018\n31 International Conference on Harmonization (ICH) Guidance for Industry, Q2B Validation of Analytical Procedures: Methodology. 1996\n32 Mudge EM, Murch SJ, Brown PN. Leaner and greener analysis of cannabinoids. Anal Bioanal Chem 2017; 409: 3153-3163\n33 Rutha AC, Gryniewicz-Ruzickaa CM, Trehya ML, Kornspanb N, Coodyb G. Consistency of label claims of internet-purchased hemp oil and cannabis products as determined using IMS and LC-MS: A marketplace survey. Journal of Regulatory Science 2016; 03: 1-6\n34 Word Anti-Doping Agency (WADA) Minimum criteria for chromatographic-mass spectrometric confirmation of the identity of analytes for doping control purposes. 2015\n35 Fernández N, Cabanillas LM, Olivera NM, Quiroga PN. Optimization and validation of simultaneous analyses of ecgonine, cocaine, and 7 metabolites in human urine by gas chromatography-mass spectrometry using a one-step solid-phase extraction. Drug Test Anal 2019; 11: 361-373\n36 Citti C, Pacchetti B, Vandelli MA, Forni F, Cannazza G. Analysis of cannabinoids in commercial hemp seed oil and decarboxylation kinetics studies of cannabidiolic acid (CBDA). J Pharm Biomed Anal 2018; 49: 532-540\n37 Bettiol A, Lombardi N, Crescioli G, Maggini V, Gallo E, Mugelli A, Firenzuoli F, Baronti R, Vannacci A. Galenic preparations of therapeutic cannabis sativa differ in cannabinoids concentration: A quantitative analysis of variability and possible clinical implications. Front Pharmacol 2019; 9: 1543\n38 Deiddaa R, Avohou HT, Baronti R, Davolioc PL, Pasquini B, Del Bubba M, Huberta C, Huberta P, Orlandinid S, Furlanetto S. Analytical quality by design: Development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts. J Pharm Biomed Anal 2019; 166: 326-335\n39 Crippa JA, Crippa AC, Hallak JE, Martín-Santos R, Zuardi AW. Δ 9-THC Intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: Full remission after switching to purified cannabidiol. Front Pharmacol 2016; 7: 359\n40 Ross SA. ElSohly MACBN and D9-THC concentration ratio as an indicator of the age of stored marijuana samples. Bull Narc. 1997; 49: 139-147\n41 Bonn-Miller MO, Loflin MJ, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling accuracy of cannabidiol extracts sold online. JAMA 2017; 318: 1708-1709\n42 Pavlovic R, Nenna G, Calvi L, Panseri S, Borgonovo G, Giupponi L, Cannazza G, Giorgi A. Quality traits of \"cannabidiol oils\": Cannabinoids content, terpene fingerprint and oxidation stability of European commercially available preparations. Molecules 2018; 23: 1230\nPatricia Noemi Quiroga\nFacultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Cátedra de Toxicología y Química Legal CENATOXA, Junín 956 7mo piso (C1113AAD), Ciudad Autónoma de Buenos Aires (CABA)\nEmail: arpquiroga@ffyb.uba.ar"

"Pesticide Kits\nBy Research Area >>\nCardiovascular >>\nImmunology >>\nAsthma Research\nImmune Cell Signaling\nNeuroscience >>\nEpilepsy Research\nOncology >>\nCancer Immunology\nCancer Stem Cell\nNeovascularization\nPulmonology >>\nCannabis Testing Products\nPesticide Detection\nMycotoxins Analysis\nTerpene Analysis\nCB1 Receptor\nSynthetic Cannabinoids\nJWH Cannabinoid\nSynfine Research Limited\nAll Products are stable to be shipped at room temperature, unless otherwise specified.\n$ 110.00 0.0\nExact Weight Packaging\n$ 75.00 / Vial 0.0\nTotal $ 0.0\nProduct successfully added to cart.\nRequest another packsize ? Click here.\nInventory Status : Pending QC\nShips On: 02/03/2020\nBulk Order Request for A795205\nFull Name: Company/ Institution: Email Address:\n1. Select mg g kg µg ml L Kit\nCatalogue Number: A795205\nChemical Name: (1R)-(-)-2-Azabicyclo[2.2.1]hept-5-en-3-one\nSynonyms: (1R,4S)-2-Azabicyclo[2.2.1]hept-5-en-3-one; (-)-2-Azabicyclo[2.2.1]hept-5-en-3-one; (-)-Vince Lactam; Abacavir - In House Impurity; Abacavir Impurities\nImpurity: Abacavir - In House Impurity\nMolecular Formula: C₆H₇NO\nAppearance: Off-White Solid\nMelting Point: 95-98ºC\nStorage: Refrigerator\nSolubility: Chloroform (Slightly, Heated), DMSO (Slightly), Methanol (Slightly)\nCategory: Building Blocks; Chiral Molecules;\nApplications: (1R)-(-)-2-Azabicyclo[2.2.1]hept-5-en-3-one (Abacavir - In House Impurity) is an Abacavir (A105000) intermediate (1). It is also an intermediate in the synthesis of carbocyclic sugar amines, carbanucleosides, and carbocyclic dinucleotide analogues (2).\nReferences (1) Jackson, A., et al.: Antivir Ther. 17, 19 (2012)\nDownload MSDS File\nrac 2-Azabicyclo[2.2.1]hept-5-en-3-one\n(1R)-(-)-2-Azabicyclo[2.2.1]hept-5-en-3-one\n2-Azabicyclo[4.2.0]octa-4,6(1)-dien-3-one\n(1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carboxamide\n(1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carboxamide Hydrochloride\n20 Martin Ross Avenue\nCanada, M3J 2K8\nUS & Canada: +1(800)727-9240\nWe have over 200,000 products in our ever expanding catalogue.\nCopyright © 2017 trc-canada.com All Rights Reserved. Reproduction of any materials from the site is strictly forbidden without permission. Toronto Research Chemical products are sold exclusively through TRC-Canada and approved distributors. Site Use Terms & Conditions | Privacy"

"Subjectsfractional differential equations (17)numerical methods (14)Error estimates (9)stability (8)error estimates (7)Caputo derivative (6)delay differential equations (6)integral equations (6)bifurcations (5)Finite difference method (5)View MoreJournalJournal of Computational and Applied Mathematics (11)Applied Numerical Mathematics (8)Journal of computational and applied mathematics (5)Computational Methods in Applied Mathematics (3)Nonlinearity (3)View MoreAuthorsFord, Neville J. (75)Yan, Yubin (33)Baker, Christopher T. H. (22)Gildea, Joe (17)Lumb, Patricia M. (14)Diethelm, Kai (12)Kavallaris, Nikos I. (11)Roberts, Jason A. (11)Antonopoulou, Dimitra (10)Lima, Pedro M. (10)View MoreTypesArticle (130)Technical Report (17)Book chapter (8)Preprint (8)Meetings & Proceedings (4)View More\nTitleAuthorsPublication DateSubmit DateSubjectsPublisherJournal\nWe are an active university Mathematics Department with a strong teaching and research reputation. We offer students the chance to study at undergraduate or postgraduate level on degree programmes leading to: BSc in Mathematics, BSc/BA joint courses in Mathematics or Applied Statistics and a wide range of other subjects. We have an active research group focusing on Computational Applied Mathematics, with research students studying for the degrees of MPhil and PhD, postdoctoral workers and associated collaborators from across the world.\nThis collection is licenced under a Creative Commons licence. The collection may be reproduced for non-commerical use and without modification, providing that copyright is acknowledged.\nDeveloping A High-performance Liquid Chromatography Method for Simultaneous Determination of Loratadine and its Metabolite Desloratadine in Human Plasma.\nSebaiy, Mahmoud M; Ziedan, Noha I (2019-11-24)\nAllergic diseases are considered among the major burdons of public health with increased prevalence globally. Histamine H1-receptor antagonists are the foremost commonly used drugs in the treatment of allergic disorders. Our target drug is one of this class, loratadine and its biometabolite desloratadine which is also a non sedating H1 receptor antagonist with anti-histaminic action of 2.5 to 4 times greater than loratadine. To develop and validate a novel isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method for rapid and simultaneous separation and determination of loratadine and its metabolite, desloratadine in human plasma. The drug extraction method from plasma was based on protein precipitation technique. The separation was carried out on a Thermo Scientific BDS Hypersil C18 column (5µm, 250 x 4.60 mm) using a mobile phase of MeOH : 0.025M KH2PO4 adjusted to pH 3.50 using orthophosphoric acid (85 : 15, v/v) at ambient temperature. The flow rate was maintained at 1 mL/min and maximum absorption was measured using PDA detector at 248 nm. The retention times of loratadine and desloratadine in plasma samples were recorded to be 4.10 and 5.08 minutes respectively, indicating a short analysis time. Limits of detection were found to be 1.80 and 1.97 ng/mL for loratadine and desloratadine, respectively, showing a high degree of method sensitivity. The method was then validated according to FDA guidelines for the determination of the two analytes in human plasma. The results obtained indicate that the proposed method is rapid, sensitive in the nanogram range, accurate, selective, robust and reproducible compared to other reported methods. [Abstract copyright: Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.]\nDouble Bordered Constructions of Self-Dual Codes from Group Rings over Frobenius Rings\nGildea, Joe; Kaya, Abidin; Taylor, Rhian; Tylyshchak, Alexander; University of Chester; Sampoerna University; Uzhgorod State University\nIn this work, we describe a double bordered construction of self-dual codes from group rings. We show that this construction is effective for groups of order 2p where p is odd, over the rings F2 + uF2 and F4 + uF4. We demonstrate the importance of this new construction by finding many new binary self-dual codes of lengths 64, 68 and 80; the new codes and their corresponding weight enumerators are listed in several tables\nOn the behavior of the solutions for linear autonomous mixed type difference equation\nYan, Yubin; Yenicerioglu, Ali Fuat; Pinelas, Sandra; University of Chester; Kocaeli University, Turkey; RUDN University, Russia (Springer Link, 2019-07-30)\nA class of linear autonomous mixed type difference equations is considered, and some new results on the asymptotic behavior and the stability are given, via a positive root of the corresponding characteristic equation.\nG-codes over Formal Power Series Rings and Finite Chain Rings\nDougherty, Steven; Gildea, Joe; Korban, Adrian; University of Scranton; University of Chester\nIn this work, we define $G$-codes over the infinite ring $R_\\infty$ as ideals in the group ring $R_\\infty G$. We show that the dual of a $G$-code is again a $G$-code in this setting. We study the projections and lifts of $G$-codes over the finite chain rings and over the formal power series rings respectively. We extend known results of constructing $\\gamma$-adic codes over $R_\\infty$ to $\\gamma$-adic $G$-codes over the same ring. We also study $G$-codes over principal ideal rings.\nA Modified Bordered Construction for Self-Dual Codes from Group Rings\nKaya, Abidin; Tylyshchak, Alexander; Yildiz, Bahattin; Gildea, Joe; University of Chester; Sampoerna University; Uzhgorod State University; Northern Arizona University (Jacodesmath Institute, 2019)\nWe describe a bordered construction for self-dual codes coming from group rings. We apply the constructions coming from the cyclic and dihedral groups over several alphabets to obtain extremal binary self-dual codes of various lengths. In particular we find a new extremal binary self-dual code of length 78.\nComposite Constructions of Self-Dual Codes from Group Rings and New Extremal Self-Dual Binary Codes of Length 68\nDougherty, Steven; Gildea, Joe; Kaya, Abidin; Korban, Adrian; University of Scranton; University of Chester; Sampoerna University ; University of Chester (American Institute of Mathematical Sciences, 2019)\nWe describe eight composite constructions from group rings where the orders of the groups are 4 and 8, which are then applied to find self-dual codes of length 16 over F4. These codes have binary images with parameters [32, 16, 8] or [32, 16, 6]. These are lifted to codes over F4 + uF4, to obtain codes with Gray images extremal self-dual binary codes of length 64. Finally, we use a building-up method over F2 + uF2 to obtain new extremal binary self-dual codes of length 68. We construct 11 new codes via the building-up method and 2 new codes by considering possible neighbors.\nNumerical methods for solving space fractional partial differential equations by using Hadamard finite-part integral approach\nYan, Yubin; Wang, Yanyong; Hu, Ye; University of Chester; Lvliang University (Springer, 2019-07-26)\nWe introduce a novel numerical method for solving two-sided space fractional partial differential equation in two dimensional case. The approximation of the space fractional Riemann-Liouville derivative is based on the approximation of the Hadamard finite-part integral which has the convergence order $O(h^{3- \\alpha})$, where $h$ is the space step size and $\\alpha\\in (1, 2)$ is the order of Riemann-Liouville fractional derivative. Based on this scheme, we introduce a shifted finite difference method for solving space fractional partial differential equation. We obtained the error estimates with the convergence orders $O(\\tau +h^{3-\\alpha}+ h^{\\beta})$, where $\\tau$ is the time step size and $\\beta >0$ is a parameter which measures the smoothness of the fractional derivatives of the solution of the equation. Unlike the numerical methods for solving space fractional partial differential equation constructed by using the standard shifted Gr\\\"unwald-Letnikov formula or higher order Lubich'e methods which require the solution of the equation satisfies the homogeneous Dirichlet boundary condition in order to get the first order convergence, the numerical method for solving space fractional partial differential equation constructed by using Hadamard finite-part integral approach does not require the solution of the equation satisfies the Dirichlet homogeneous boundary condition. Numerical results show that the experimentally determined convergence order obtained by using the Hadamard finite-part integral approach for solving space fractional partial differential equation with non-homogeneous Dirichlet boundary conditions is indeed higher than the convergence order obtained by using the numerical methods constructed with the standard shifted Gr\\\"unwald-Letnikov formula or Lubich's higer order approximation schemes.\nNumerical Approximation of Stochastic Time-Fractional Diffusion\nYan, Yubin; Jin, Bangti; Zhou, Zhi; University of Chester; University College London; The Hong Kong Polytechnic University\nWe develop and analyze a numerical method for stochastic time-fractional diffusion driven by additive fractionally integrated Gaussian noise. The model involves two nonlocal terms in time, i.e., a Caputo fractional derivative of order $\\alpha\\in(0,1)$, and fractionally integrated Gaussian noise (with a Riemann-Liouville fractional integral of order $\\gamma \\in[0,1]$ in the front). The numerical scheme approximates the model in space by the standard Galerkin method with continuous piecewise linear finite elements and in time by the classical Gr\\\"unwald-Letnikov method, and the noise by the $L^2$-projection. Sharp strong and weak convergence rates are established, using suitable nonsmooth data error estimates for the deterministic counterpart. One- and two-dimensional numerical results are presented to support the theoretical findings.\nA discrete mutualism model: analysis and exploration of a financial application\nRoberts, Jason A.; Kavallaris, Nikos I.; Rowntree, Andrew P.; University of Chester (Elsevier, 2019-09-16)\nWe perform a stability analysis on a discrete analogue of a known, continuous model of mutualism. We illustrate how the introduction of delays affects the asymptotic stability of the system's positive nontrivial equilibrium point. In the second part of the paper we explore the insights that the model can provide when it is used in relation to interacting financial markets. We also note the limitations of such an approach.\nAn Altered Four Circulant Construction for Self-Dual Codes from Group Rings and New Extremal Binary Self-dual Codes I\nGildea, Joe; Kaya, Abidin; Yildiz, Bahattin; University of Chester; Sampoerna University; Northern Arizona University (Elsevier, 2019-08-07)\nWe introduce an altered version of the four circulant construction over group rings for self-dual codes. We consider this construction over the binary field, the rings F2 + uF2 and F4 + uF4; using groups of order 4 and 8. Through these constructions and their extensions, we find binary self-dual codes of lengths 16, 32, 48, 64 and 68, many of which are extremal. In particular, we find forty new extremal binary self-dual codes of length 68, including twelve new codes with \\gamma=5 in W68,2, which is the first instance of such a value in the literature.\nCharacteristic functions of differential equations with deviating arguments\nBaker, Christopher T. H.; Ford, Neville J.; University of Manchester; University of Chester (Elsevier, 2019-04-24)\nThe material here is motivated by the discussion of solutions of linear homogeneous and autonomous differential equations with deviating arguments. If $a, b, c$ and $\\{\\check{\\tau}_\\ell\\}$ are real and ${\\gamma}_\\natural$ is real-valued and continuous, an example with these parameters is \\begin{equation} u'(t) = \\big\\{a u(t) + b u(t+\\check{\\tau}_1) + c u(t+\\check{\\tau}_2) \\big\\} { \\red +} \\int_{\\check{\\tau}_3}^{\\check{\\tau}_4} {{\\gamma}_\\natural}(s) u(t+s) ds \\tag{\\hbox{$\\rd{\\star}$}} . \\end{equation} A wide class of equations ($\\rd{\\star}$), or of similar type, can be written in the {\\lq\\lq}canonical{\\rq\\rq} form \\begin{equation} u'(t) =\\DSS \\int_{\\tau_{\\rd \\min}}^{\\tau_{\\rd \\max}} u(t+s) d\\sigma(s) \\quad (t \\in \\Rset), \\hbox{ for a suitable choice of } {\\tau_{\\rd \\min}}, {\\tau_{\\rd \\max}} \\tag{\\hbox{${\\rd \\star\\star}$}} \\end{equation} where $\\sigma$ is of bounded variation and the integral is a Riemann-Stieltjes integral. For equations written in the form (${\\rd{\\star\\star}}$), there is a corresponding characteristic function \\begin{equation} \\chi(\\zeta) ):= \\zeta - \\DSS \\int_{\\tau_{\\rd \\min}}^{\\tau_{\\rd \\max}} \\exp(\\zeta s) d\\sigma(s) \\quad (\\zeta \\in \\Cset), \\tag{\\hbox{${\\rd{\\star\\star\\star}}$}} \\end{equation} %%($ \\chi(\\zeta) \\equiv \\chi_\\sigma (\\zeta)$) whose zeros (if one considers appropriate subsets of equations (${\\rd \\star\\star}$) -- the literature provides additional information on the subsets to which we refer) play a r\\^ole in the study of oscillatory or non-oscillatory solutions, or of bounded or unbounded solutions. We show that the related discussion of the zeros of $\\chi$ is facilitated by observing and exploiting some simple and fundamental properties of characteristic functions.\nQuadruple Bordered Constructions of Self-Dual Codes from Group Rings\nDougherty, Steven; Gildea, Joe; Kaya, Abidin; University of Scranton; University of Chester; Sampoerna University (Springer Verlag, 2019-07-05)\nIn this paper, we introduce a new bordered construction for self-dual codes using group rings. We consider constructions over the binary field, the family of rings Rk and the ring F4 + uF4. We use groups of order 4, 12 and 20. We construct some extremal self-dual codes and non-extremal self-dual codes of length 16, 32, 48, 64 and 68. In particular, we construct 33 new extremal self-dual codes of length 68.\nAnalysis of transient Rivlin-Ericksen fluid and irreversibility of exothermic reactive hydromagnetic variable viscosity\nOlakunle, Salawu; Kareem, Rasaq; Yan, Yubin; Landmark University, Nigeria; Lagos State Polytechnic, Nigeria; University of Chester, UK (Shahid Chamran University of Ahvaz, 2019-03-15)\nThe study analysed unsteady Rivlin-Ericksen fluid and irreversibility of exponentially temperature dependent variable viscosity of hydromagnetic two-step exothermic chemical reactive flow along the channel axis with walls convective cooling. The non-Newtonian Hele-Shaw flow of Rivlin-Erickson fluid is driven by bimolecular chemical kinetic and unvarying pressure gradient. The reactive fluid is induced by periodic changes in magnetic field and time. The Newtons law of cooling is satisfied by the constant heat coolant convection exchange at the wall surfaces with the neighboring regime. The dimensionless non-Newtonian reactive fluid equations are numerically solved using a convergent and consistence semi-implicit finite difference technique which are confirmed stable. The response of the reactive fluid flow to variational increase in the values of some entrenched fluid parameters in the momentum and energy balance equations are obtained. A satisfying equations for the ratio of irreversibility, entropy generation and Bejan number are solved with the results presented graphically and discussed quantitatively. From the study, it was obtained that the thermal criticality conditions with the right combination of thermo-fluid parameters, the thermal runaway can be prevented. Also, the entropy generation can minimize by at low dissipation rate and viscosity.\nSpace-Time Discontinuous Galerkin Methods for the '\\eps'-dependent Stochastic Allen-Cahn Equation with mild noise\nAntonopoulou, Dimitra; Department of Mathematics, University of Chester, UK (Oxford University Press, 2019-04-08)\nWe consider the $\\eps$-dependent stochastic Allen-Cahn equation with mild space- time noise posed on a bounded domain of R^2. The positive parameter $\\eps$ is a measure for the inner layers width that are generated during evolution. This equation, when the noise depends only on time, has been proposed by Funaki in [15]. The noise although smooth becomes white on the sharp interface limit as $\\eps$ tends to zero. We construct a nonlinear dG scheme with space-time finite elements of general type which are discontinuous in time. Existence of a unique discrete solution is proven by application of Brouwer's Theorem. We first derive abstract error estimates and then for the case of piece-wise polynomial finite elements we prove an error in expectation of optimal order. All the appearing constants are estimated in terms of the parameter $\\eps$. Finally, we present a linear approximation of the nonlinear scheme for which we prove existence of solution and optimal error in expectation in piece-wise linear finite element spaces. The novelty of this work is based on the use of a finite element formulation in space and in time in 2+1-dimensional subdomains for a nonlinear parabolic problem. In addition, this problem involves noise. These type of schemes avoid any Runge-Kutta type discretization for the evolutionary variable and seem to be very effective when applied to equations of such a difficulty.\nNumerical analysis of a two-parameter fractional telegraph equation\nFord, Neville J.; Rodrigues, M. M.; Xiao, Jingyu; Yan, Yubin; University of Chester, Harbin Institute of Technology, University of Aveiro, Campus Universitario de Santiago (Elsevier, 2013-09-26)\nIn this paper we consider the two-parameter fractional telegraph equation of the form $$-\\, ^CD_{t_0^+}^{\\alpha+1} u(t,x) + \\, ^CD_{x_0^+}^{\\beta+1} u (t,x)- \\, ^CD_{t_0^+}^{\\alpha}u (t,x)-u(t,x)=0.$$ Here $\\, ^CD_{t_0^+}^{\\alpha}$, $\\, ^CD_{t_0^+}^{\\alpha+1}$, $\\, ^CD_{x_0^+}^{\\beta+1}$ are operators of the Caputo-type fractional derivative, where $0\\leq \\alpha < 1$ and $0 \\leq \\beta < 1$. The existence and uniqueness of the equations are proved by using the Banach fixed point theorem. A numerical method is introduced to solve this fractional telegraph equation and stability conditions for the numerical method are obtained. Numerical examples are given in the final section of the paper.\nStabilizing a mathematical model of plant species interaction\nYan, Yubin; Ekaka-A, Enu-Obari N.; University of Chester, University of Ibadan (Elsevier, 2011-09-03)\nIn this paper, we will consider how to stabilize a mathematical model of plant species interaction which is modelled by using Lotka-Volterra system. We first identify the unstable steady states of the system, then we use the feedback control based on the solutions of the Riccati equation to stabilize the linearized system. We further stabilize the nonlinear system by using the feedback controller obtained in the stabilization of the linearized system. We introduce the backward Euler method to approximate the feedback control nonlinear system and obtain the error estimates. Four numerical examples are given which come from the application areas.\nStability of a numerical method for a fractional telegraph equation\nYan, Yubin; Xiao, Jingyu; Ford, Neville J.; University of Chester, Harbin Institute of Technology (De Gruyter, 2012-03)\nIn this paper, we introduce a numerical method for solving the time-space fractional telegraph equations. The numerical method is based on a quadrature formula approach and a stability condition for the numerical method is obtained. Two numerical examples are given and the stability regions are plotted.\nOn hereditary reducibility of 2-monomial matrices over commutative rings\nBondarenko, Vitaliy M.; Gildea, Joe; Tylyshchak, Alexander; Yurchenko, Natalia; Institute of Mathematic, Kyiv; University of Chester; Uzhgorod National University (Taras Shevchenko National University of Luhansk, 2019)\nA 2-monomial matrix over a commutative ring $R$ is by definition any matrix of the form $M(t,k,n)=\\Phi\\left(\\begin{smallmatrix}I_k&0\\\\0&tI_{n-k}\\end{smallmatrix}\\right)$, $0<k<n$, where $t$ is a non-invertible element of $R$, $\\Phi$ the compa\\-nion matrix to $\\lambda^n-1$ and $I_k$ the identity $k\\times k$-matrix. In this paper we introduce the notion of hereditary reducibility (for these matrices) and indicate one general condition of the introduced reducibility.\nA high order numerical method for solving nonlinear fractional differential equation with non-uniform meshes\nFan, Lili; Yan, Yubin; University of Chester; Lvliang University (Springer Link, 2019-01-18)\nWe introduce a high-order numerical method for solving nonlinear fractional differential equation with non-uniform meshes. We first transform the fractional nonlinear differential equation into the equivalent Volterra integral equation. Then we approximate the integral by using the quadratic interpolation polynomials. On the first subinterval $[t_{0}, t_{1}]$, we approximate the integral with the quadratic interpolation polynomials defined on the nodes $t_{0}, t_{1}, t_{2}$ and in the other subinterval $[t_{j}, t_{j+1}], j=1, 2, \\dots N-1$, we approximate the integral with the quadratic interpolation polynomials defined on the nodes $t_{j-1}, t_{j}, t_{j+1}$. A high-order numerical method is obtained. Then we apply this numerical method with the non-uniform meshes with the step size $\\tau_{j}= t_{j+1}- t_{j}= (j+1) \\mu$ where $\\mu= \\frac{2T}{N (N+1)}$. Numerical results show that this method with the non-uniform meshes has the higher convergence order than the standard numerical methods obtained by using the rectangle and the trapzoid rules with the same non-uniform meshes.\nNew Self-Dual and Formally Self-Dual Codes from Group Ring Constructions\nDougherty, Steven; Gildea, Joe; Kaya, Abidin; Yildiz, Bahattin; University of Scranton; University of Chester; Sampoerna Academy; University of Chester; Northern Arizona University (American Institute of Mathematical Sciences, 2019-08-31)\nIn this work, we study construction methods for self-dual and formally self-dual codes from group rings, arising from the cyclic group, the dihedral group, the dicyclic group and the semi-dihedral group. Using these constructions over the rings $_F2 +uF_2$ and $F_4 + uF_4$, we obtain 9 new extremal binary self-dual codes of length 68 and 25 even formally self-dual codes with parameters [72,36,14]."

"Medication name\nEuropean prescription medicines info\nHome / D / Dacogen\nDacogen (decitabine) – Summary of product characteristics - L01BC08\nMedication name Dacogen\nATC Code L01BC08\nSubstance decitabine\nManufacturer Janssen-Cilag International N V\nDacogen\nDacogen: Summary of product characteristics\nDacogen: Conditions or restrictions regarding supply and use\nDacogen: Labelling\nDacogen: Package leaflet\n4.1 Therapeutic indications\n4.2 Posology and method of administration\n4.3 Contraindications\n4.4 Special warnings and precautions for use\n4.5 Interaction with other medicinal products and other forms of interaction\n4.6 Fertility, pregnancy and lactation\n4.7 Effects on ability to drive and use machines\n4.8 Undesirable effects\n4.9 Overdose\n5.1 Pharmacodynamic properties\n5.2 Pharmacokinetic properties\n5.3 Preclinical safety data\n6.1 List of excipients\n6.2 Incompatibilities\n6.3 Shelf life\n6.4 Special precautions for storage\n6.5 Nature and contents of container\n6.6 Special precautions for disposal and other handling\n1 NAME OF THE MEDICINAL PRODUCT\nDacogen 50 mg powder for concentrate for solution for infusion.\n2 QUALITATIVE AND QUANTITATIVE COMPOSITION\nEach vial of powder for concentrate for solution for infusion contains 50 mg decitabine.\nAfter reconstitution with 10 ml of water for injections, each ml of concentrate contains 5 mg of decitabine.\nExcipients with known effect\nEach vial contains 0.5 mmol potassium (E340) and 0.29 mmol sodium (E524).\nFor the full list of excipients, see section 6.1.\n3 PHARMACEUTICAL FORM\nPowder for concentrate for solution for infusion (powder for infusion).\nWhite to almost white lyophilized powder.\n4 CLINICAL PARTICULARS\n4.1Therapeutic indications\nDacogen is indicated for the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification, who are not candidates for standard induction chemotherapy.\n4.2Posology and method of administration\nDacogen administration must be initiated under the supervision of physicians experienced in the use of chemotherapeutic medicinal products.\nPosology\nIn a treatment cycle, Dacogen is administered at a dose of 20 mg/m2 body surface area by intravenous infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose must not exceed 20 mg/m2 and the total dose per treatment cycle must not exceed 100 mg/m2. If a dose is missed, treatment should be resumed as soon as possible. The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. It is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial remission may take longer than 4 cycles to be obtained. Treatment may be continued as long as the patient shows response, continues to benefit or exhibits stable disease, i.e., in the absence of overt progression.\nIf after 4 cycles, the patient's haematological values (e.g., platelet counts or absolute neutrophil count), have not returned to pre-treatment levels or if disease progression occurs (peripheral blast counts are increasing or bone marrow blast counts are worsening), the patient may be considered to be a non-responder and alternative therapeutic options to Dacogen should be considered.\nPre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required.\nManagement of myelosuppression and associated complications\nMyelosuppression and adverse events related to myelosuppression (thrombocytopaenia, anaemia, neutropaenia, and febrile neutropaenia) are common in both treated and untreated patients with AML. Complications of myelosuppression include infections and bleeding. Treatment may be delayed at the discretion of the treating physician, if the patient experiences myelosuppression-associated complications, such as those described below:\nFebrile neutropaenia (temperature ≥ 38.5°C and absolute neutrophil count < 1,000/µL)\nActive viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensive supportive care)\nHaemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25,000/µL or any central nervous system haemorrhage)\nTreatment with Dacogen may be resumed once these conditions have improved or have been stabilised with adequate treatment (anti-infective therapy, transfusions, or growth factors).\nIn clinical studies, approximately one-third of patients receiving Dacogen required a dose-delay. Dose reduction is not recommended.\nPaediatric population\nThe safety and efficacy of Dacogen in children aged < 18 years have not yet been established. No data are available.\nStudies in patients with hepatic impairment have not been conducted. The need for dose adjustment in patients with hepatic impairment has not been evaluated. If worsening hepatic function occurs, patients should be carefully monitored (see sections 4.4 and 5.2).\nRenal impairment\nStudies in patients with renal impairment have not been conducted. The need for dose adjustment in patients with renal impairment has not been evaluated (see section 4.4 and 5.2).\nMethod of administration\nDacogen is administered by intravenous infusion. A central venous catheter is not required.\nFor instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.\n4.3Contraindications\nHypersensitivity to decitabine or to any of the excipients, listed in section 6.1.\nBreast-feeding (see section 4.6)\n4.4Special warnings and precautions for use\nMyelosuppression\nMyelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with AML may be exacerbated with Dacogen treatment. Therefore patients are at increased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), with potentially fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated promptly.\nIn clinical studies, the majority of patients had baseline Grade 3/4 myelosuppression. In patients with baseline Grade 2 abnormalities, worsening of myelosuppression was seen in most patients and more frequently than in patients with baseline Grade 1 or 0 abnormalities. Myelosuppression caused by Dacogen is reversible. Complete blood and platelet counts should be performed regularly, as clinically\nindicated and prior to each treatment cycle. In the presence of myelosuppression or its complications, treatment with Dacogen may be interrupted and/or supportive measures instituted (see sections 4.2 and 4.8).\nRespiratory, thoracic and mediastinal disorders\nCases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section 4.8).\nUse in patients with hepatic impairment has not been established. Caution should be exercised in the administration of Dacogen to patients with hepatic impairment and patients should be monitored closely (see sections 4.2 and 5.2).\nUse in patients with severe renal impairment has not been studied. Caution should be exercised in the administration of Dacogen to patients with severe renal impairment (Creatinine Clearance [CrCl]\n< 30 ml/min) and these patients should be monitored closely (see section 4.2).\nPatients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore the safety and efficacy of Dacogen in these patients has not been established.\nThis medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially 'potassium- free'.\nThis medicine contains 0.29 mmol sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains between 0.6-6 mmol sodium per dose depending on the infusion fluid for dilution. To be taken into consideration by patients on a controlled sodium diet.\n4.5Interaction with other medicinal products and other forms of interaction\nNo formal clinical drug interaction studies with decitabine have been conducted.\nThere is the potential for a drug-drug interaction with other agents which are also activated by sequential phosphorylation (via intracellular phosphokinase activities) and/or metabolised by enzymes implicated in the inactivation of decitabine (e.g., cytidine deaminase). Therefore, caution should be exercised if these active substances are combined with decitabine.\nImpact of co-administered medicinal products on decitabine\nCytochrome (CYP) 450-mediated metabolic interactions are not anticipated as decitabine metabolism is not mediated by this system but by oxidative deamination.\nImpact of decitabine on co-administered medicinal products\nGiven its low in vitro plasma protein binding ( 1%), decitabine is unlikely to displace co-administered medicinal products from their plasma protein binding. Decitabine has been shown to be a weak inhibitor of P-gp mediated transport in vitro and is therefore also not expected to affect P-gp mediated transport of co-administered medicinal products (see section 5.2).\n4.6Fertility, pregnancy and lactation\nWomen of childbearing potential/Contraception in males and females\nWomen of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with Dacogen. The time period following treatment with Dacogen where\nit is safe to become pregnant is unknown. Men should use effective contraceptive measures and be advised to not father a child while receiving Dacogen, and for 3 months following completion of treatment (see section 5.3).\nThe use of decitabine with hormonal contraceptives has not been studied.\nThere are no adequate data on the use of Dacogen in pregnant women. Studies have shown that decitabine is teratogenic in rats and mice (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Dacogen should not be used during pregnancy and in women of childbearing potential not using effective contraception. If Dacogen is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.\nIt is not known whether decitabine or its metabolites are excreted in breast milk. Dacogen is contraindicated during breast-feeding; therefore if treatment with this medicine is required, breast-feeding must be discontinued (see section 4.3).\nNo human data on the effect of decitabine on fertility are available. In non-clinical animal studies, decitabine alters male fertility and is mutagenic. Because of the possibility of infertility as a consequence of Dacogen therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiation of treatment.\n4.7Effects on ability to drive and use machines\nDacogen has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects such as anaemia during treatment. Therefore, caution should be recommended when driving a car or operating machines.\n4.8Undesirable effects\nSummary of the safety profile\nThe most common adverse drug reactions (≥ 35%) reported are pyrexia, anaemia and thrombocytopaenia.\nThe most common Grade 3/4 adverse drug reactions (≥ 20%) included pneumonia, thrombocytopaenia, neutropaenia, febrile neutropaenia and anaemia.\nIn clinical studies, 30% of patients treated with Dacogen and 25% of patients treated in the comparator arm had adverse events with an outcome of death during treatment or within 30 days after the last dose of study drug.\nIn the Dacogen treatment group, there was a higher incidence of treatment discontinuation due to adverse events in women compared to men (43% versus 32%).\nTabulated list of adverse drug reactions\nAdverse drug reactions reported in 293 AML patients treated with Dacogen are summarised in Table 1. The following table reflects data from AML clinical studies and from post-marketing experience. The adverse drug reactions are listed by frequency category. Frequency categories are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).\nWithin each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.\nTable 1: Adverse drug reactions identified with Dacogen\nAll Gradesa\nGrades 3-4a\nSystem Organ Class\n(all Grades)\nInfections and\nVery common\npneumonia*\ninfestations\nurinary tract infection*\nAll other infections (viral,\nbacterial, fungal)*, b, c, d\nseptic shock*\nsepsis*\nBlood and lymphatic\nfebrile neutropaenia*\nneutropaenia*\nthrombocytopaenia*, e\nleukopaenia\npancytopaenia*\nhypersensitivity including\nanaphylactic reactionf\nRespiratory, thoracic\nand mediastinal\nenterocolitis, including\nneutropaenic colitis,\ncaecitis*\nSkin and\nacute febrile neutrophilic\nsubcutaneous tissue\ndermatosis (Sweet's\nsyndrome)\nGeneral disorders and\nadministration site\naWorst National Cancer Institute Common Terminology Criteria for Adverse Events Grade.\nbExcluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis.\ncThe most frequently reported \"other infections\" in study DACO-016 were: oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis.\ndIncluding enterocolitis infectious.\neIncluding haemorrhage associated with thrombocytopaenia, including fatal cases.\nfIncluding preferred terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.\n* Includes events with a fatal outcome. NA = Not applicable\nDescription of selected adverse drug reactions\nHaematologic adverse drug reactions\nThe most commonly reported haematologic adverse drug reactions associated with Dacogen treatment included febrile neutropaenia, thrombocytopaenia, neutropaenia, anaemia and leukopaenia.\nSerious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as central nervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the context of severe thrombocytopaenia, were reported in patients receiving decitabine.\nHaematological adverse drug reactions should be managed by routine monitoring of complete blood counts and early administration of supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia and transfusions for anaemia or thrombocytopaenia according to institutional guidelines. For situations where decitabine administration should be delayed, see section 4.2.\nInfections and infestations adverse drug reactions\nSerious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving decitabine.\nOccurrences of enterocolitis, including neutropaenic colitis, caecitis have been reported during treatment with decitabine. Enterocolitis may lead to septic complications and may be associated with fatal outcome.\nPrescription drugs listed:\nKarvezide\nNimvastid\nEklira genuair\nRasilez\nRivastigmine actavis\nEvoltra\nCases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine.\nReporting of suspected adverse reactions\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.\n4.9Overdose\nThere is no direct experience of human overdose and no specific antidote. However, early clinical study data in published literature at doses greater than 20 times higher than the current therapeutic dose, reported increased myelosuppression including prolonged neutropaenia and thrombocytopaenia. Toxicity is likely to manifest as exacerbations of adverse drug reactions, primarily myelosuppression. Treatment for overdose should be supportive.\n5 PHARMACOLOGICAL PROPERTIES\n5.1Pharmacodynamic properties\nPharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues; ATC Code: L01BC08\nDecitabine (5-aza-2-deoxycytidine) is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result in reactivation of tumour suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.\nThe use of Dacogen was studied in an open-label, randomised, multicentre Phase III study (DACO-016) in subjects with newly diagnosed de novo or secondary AML according to the WHO\nclassification. Dacogen (n = 242) was compared to treatment choice (TC, n = 243) which consisted of patient's choice with physician's advice of either supportive care alone (n = 28, 11.5%) or 20 mg/m2 cytarabine subcutaneously once daily for 10 consecutive days repeated every 4 weeks\n(n = 215, 88.5%). Dacogen was administered as a 1-hour intravenous infusion of 20 mg/m2 once daily for 5 consecutive days repeated every 4 weeks.\nSubjects who were considered candidates for standard induction chemotherapy were not included in the study as shown by the following baseline characteristics. The median age for the intent-to-treat (ITT) population was 73 years (range 64 to 91 years). Thirty-six percent of subjects had poor-risk cytogenetics at baseline. The remainder of the subjects had intermediate-risk cytogenetics. Patients with favourable cytogenetics were not included in the study. Twenty-five percent of subjects had an ECOG performance status ≥ 2. Eighty-one percent of subjects had significant comorbidities (e.g., infection, cardiac impairment, pulmonary impairment). The number of patients treated with Dacogen by racial group was White 209 (86.4%) and Asian 33 (13.6%).\nThe primary endpoint of the study was overall survival. The secondary endpoint was complete remission rate that was assessed by independent expert review. Progression-free survival and Event-free survival were tertiary endpoints.\nThe median overall survival in the --ITT population was 7.7 months in subjects treated with Dacogen compared to 5.0 months for subjects in the TC arm (hazard ratio 0.85; 95% CI: 0.69, 1.04,\np = 0.1079). The difference did not reach statistical significance, however, there was a trend for improvement in survival with a 15% reduction in the risk of death for subjects in the Dacogen arm (Figure 1). When censored for potentially disease modifying subsequent therapy (i.e., induction chemotherapy or hypomethylating agent) the analysis for overall survival showed a 20% reduction in the risk of death for subjects in the Dacogen arm [HR = 0.80, (95% CI: 0.64, 0.99),\np-value = 0.0437)].\nFigure 1. Overall survival (ITT population).\nDeath (%)\n(6.2, 9.2)\nTotal TC\nHR (95% CI):\n0.85 (0.69, 1.04)\nLogrank p-value:\nof Subjects\nTime (Months)\nNo. of Subjects at Risk\nIn an analysis with an additional 1 year of mature survival data, the effect of Dacogen on overall survival demonstrated a clinical improvement compared to the TC arm (7.7 months vs. 5.0 months, respectively, hazard ratio = 0.82, 95% CI: 0.68, 0.99, nominal p-value = 0.0373, Figure 2).\nFigure 2. Analysis of mature overall survival data (ITT population).\nBased on the initial analysis in the ITT population, a statistically significant difference in complete remission rate (CR + CRp) was achieved in favour of subjects in the Dacogen arm, 17.8% (43/242) compared to the TC arm, 7.8% (19/243); treatment difference 9.9% (95% CI: 4.07; 15.83), p = 0.0011. The median time to best response and median duration of best response in patients who achieved a CR or CRp were 4.3 months and 8.3 months, respectively. Progression-free survival was significantly longer for subjects in the Dacogen arm, 3.7 months (95% CI: 2.7, 4.6) compared with subjects in the TC arm, 2.1 months (95% CI: 1.9, 3.1); hazard ratio 0.75 (95% CI: 0.62, 0.91), p = 0.0031. These results as well as other endpoints are shown in Table 2.\nOther efficacy endpoints for Study DACO-016 (ITT population)\nTC (combined\nCR + CRp\nOR = 2.5\n(1.40, 4.78)b\n(2.5, 4.1)b\nHR = 0.75\nPFSa\nHR = 0.75 (0.62, 0.91)b\nCR = complete remission; CRp = complete remission with incomplete platelet recovery, EFS = event-free survival, PFS = progression-free survival, OR = odds ratio, HR = hazard ratio\n- = Not evaluable\naReported as median months\nb95% confidence intervals\nOverall survival and complete remission rates in pre-specified disease-related sub-groups (i.e., cytogenetic risk, Eastern Cooperative Oncology Group [ECOG] score, age, type of AML, and baseline bone marrow blast count) were consistent with results for the overall study population.\nDacogen-treated subjects (11%, 24/223) experienced worsening of hyperglycaemia compared with subjects in the TC arm (6%, 13/212).\nThe use of Dacogen as initial therapy was also evaluated in an open-label, single-arm, Phase II study (DACO-017) in 55 subjects > 60 years with AML according to the WHO classification. The primary endpoint was complete remission (CR) rate that was assessed by independent expert review. The secondary endpoint of the study was overall survival. Dacogen was administered as a 1-hour intravenous infusion of 20 mg/m2 once daily for 5 consecutive days repeated every 4 weeks. In the ITT analysis, a CR rate of 23.6% (95% CI: 13.2, 37) was observed in 13/55 subjects treated with Dacogen. The median time to CR was 4.1 months, and the median duration of CR was 18.2 months. The median overall survival in the ITT population was 7.6 months (95% CI: 5.7, 11.5).\nThe efficacy and safety of Dacogen has not been evaluated in patients with acute promyelocytic leukaemia or CNS leukaemia.\nThe European Medicines Agency has deferred the obligation to submit the results of studies with Dacogen in one or more subsets of the paediatric population for the treatment of acute myeloid leukaemia (see section 4.2 for information on paediatric use).\n5.2Pharmacokinetic properties\nThe population pharmacokinetic (PK) parameters of decitabine were pooled from 3 clinical studies in 45 patients with AML or myelodysplastic syndrome (MDS) utilizing the 5-Day regimen. In each study, decitabine PK was evaluated on the fifth day of the first treatment cycle.\nThe pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion were described by a linear two-compartment model, characterised by rapid elimination from the central compartment and by relatively slow distribution from the peripheral compartment. For a typical patient (weight 70 kg/body surface area 1.73 m2) the decitabine pharmacokinetic parameters are listed in the Table 3 below.\nTable 3: Summary of population PK analysis for a typical patient receiving daily 1-hour infusions of Dacogen 20 mg/m2 over 5 days every 4 weeks\nParameter a\nPredicted Value\nCmax (ng/ml)\n88.5 - 129\nAUCcum (ng.h/ml)\nt1/2 (min)\nVdss (L)\nCL (L/h)\na The total dose per cycle was 100 mg/m2\nDecitabine exhibits linear PK and following the intravenous infusion, steady-state concentrations are reached within 0.5 hour. Based on model simulation, PK parameters were independent of time (i.e.,\ndid not change from cycle to cycle) and no accumulation was observed with this dosing regimen. Plasma protein binding of decitabine is negligible (< 1%). Decitabine Vdss in cancer patients is large indicating distribution into peripheral tissues. There was no evidence of dependencies on age, creatinine clearance, total bilirubin, or disease.\nIntracellularly, decitabine is activated through sequential phosphorylation via phosphokinase activities to the corresponding triphosphate, which is then incorporated by the DNA polymerase. In vitro metabolism data and the human mass balance study results indicated that the cytochrome P450 system is not involved in the metabolism of decitabine. The primary route of metabolism is likely through deamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood. Results from the human mass-balance study showed that unchanged decitabine in plasma accounted for approximately 2.4% of total radioactivity in plasma. The major circulating metabolites are not believed to be pharmacologically active. The presence of these metabolites in urine together with the high total body clearance and low urinary excretion of unchanged decitabine in the urine (~4% of the dose) indicate that decitabine is appreciably metabolized in vivo. In vitro studies show that decitabine does not inhibit nor induce CYP 450 enzymes up to more than 20-fold of the therapeutic maximum observed plasma concentration (Cmax). Thus; CYP-mediated metabolic drug interactions are not anticipated, and decitabine is unlikely to interact with agents metabolized through these pathways. In addition, in vitro data show that decitabine is a poor P-gp substrate.\nMean plasma clearance following intravenous administration in cancer subjects was > 200 L/h with moderate inter-subject variability (coefficient of variation [CV] is approximately 50%). Excretion of unchanged drug appears to play only a minor role in the elimination of decitabine.\nResults from a mass balance study with radioactive 14C-decitabine in cancer patients showed that 90% of the administered dose of decitabine (4% unchanged drug) is excreted in the urine.\nAdditional information on special populations\nThe effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine have not been formally studied. Information on special populations was derived from pharmacokinetic data from the 3 studies noted above, and from one Phase I study in MDS subjects, (N = 14;\n15 mg/m2 x 3-hours q8h x 3 days).\nPopulation pharmacokinetic analysis showed that decitabine pharmacokinetics are not dependent on age (range studied 40 to 87 years; median 70 years).\nPopulation pharmacokinetic analysis of decitabine did not show any clinically relevant difference between men and women.\nMost of the patients studied were Caucasian. However, the population pharmacokinetic analysis of decitabine indicated that race had no apparent effect on the exposure to decitabine.\nThe PK of decitabine have not been formally studied in patients with hepatic impairment. Results from a human mass-balance study and in vitro experiments mentioned above indicated that the CYP enzymes are unlikely to be involved in the metabolism of decitabine. In addition, the limited data from the population PK analysis indicated no significant PK parameter dependencies on total bilirubin concentration despite a wide range of total bilirubin levels. Thus, decitabine exposure is not likely to be affected in patients with impaired hepatic function.\nThe PK of decitabine have not been formally studied in patients with renal insufficiency. The population PK analysis on the limited decitabine data indicated no significant PK parameter dependencies on normalized creatinine clearance, an indicator of renal function. Thus, decitabine exposure is not likely to be affected in patients with impaired renal function.\n5.3Preclinical safety data\nFormal carcinogenicity studies have not been performed with decitabine. Evidence from the literature indicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studies provide sufficient evidence that decitabine has genotoxic potential. Data from the literature also indicate that decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryo-foetal development and post-natal development. Multi-cycle repeat-dose toxicity studies in rats and rabbits indicated that the primary toxicity was myelosuppression, including effects on bone marrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observed and in males, testicular atrophy which did not reverse over the scheduled recovery periods. Decitabine administration to neonatal/juvenile rats showed a comparable general toxicity profile as in older rats. Neurobehavioural development and reproductive capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression. See section 4.2 for information on paediatric use.\n6 PHARMACEUTICAL PARTICULARS\n6.1List of excipients\nPotassium dihydrogen phosphate (E340)\nSodium hydroxide (E524)\nHydrochloric acid (for pH adjustment)\n6.2Incompatibilities\nThis medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.\n6.3Shelf life\nUnopened vial 3 years.\nReconstituted and diluted solution\nWithin 15 minutes of reconstitution, the concentrate (in 10 ml of sterile water for injections) must be further diluted with cold (2°C - 8°C) infusion fluids. This prepared diluted solution for intravenous infusion can be stored at 2°C - 8°C for up to a maximum of 3 hours, followed by up to 1 hour at room temperature (20°C - 25°C) before administration.\nFrom a microbiological point of view, the product should be used within the time period recommended above. It is the responsibility of the user to follow the recommended storage times and conditions and ensure that reconstitution has taken place in aseptic conditions.\n6.4Special precautions for storage\nDo not store above 25 C.\nFor storage conditions of the reconstituted and diluted medicinal product, see section 6.3.\n6.5Nature and contents of container\n20 ml clear colourless Type I glass vial sealed with a butyl rubber stopper and an aluminium seal with plastic flip-off cap containing 50 mg decitabine.\nPack size: 1 vial.\n6.6Special precautions for disposal and other handling\nRecommendations for safe handling\nSkin contact with the solution should be avoided and protective gloves must be worn. Standard procedures for dealing with cytotoxic medicinal products should be adopted.\nReconstitution procedure\nThe powder should be aseptically reconstituted with 10 ml of water for injections. Upon reconstitution, each ml contains approximately 5 mg of decitabine at pH 6.7 to 7.3. Within 15 minutes of reconstitution, the solution must be further diluted with cold infusion fluids (sodium chloride\n9 mg/ml [0.9%] solution for injection or 5% glucose solution for injection) to a final concentration of 0.1 to 1.0 mg/ml. For the shelf-life and the precaution for storage after reconstitution, see section 6.3.\nDacogen should not be infused through the same intravenous access/line with other medicinal products.\nThis medicinal product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.\n7 MARKETING AUTHORISATION HOLDER\nJanssen-Cilag International NV\nTurnhoutseweg 30\nB-2340 Beerse\n8 MARKETING AUTHORISATION NUMBER\nEU/1/12/792/001\n9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION\nDate of first authorisation: 20 September 2012\nDate of latest renewal:\n10 DATE OF REVISION OF THE TEXT\nDetailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/\nprescription drugs listed\nHome AdvertisingPrivacyContact usCookie Policy"

"Search Drugs.com\nAll Select the section you want to search in All Consumer Professional Pill ID Interactions News FDA Alerts Approvals Pipeline Clinical Trials Care Notes Natural Products\nBrowse all medications: a b c d e f g h i j k l m n o p q r s t u v w x y z 0-9\nInteractions Checker\nAHFS Monographs\nClass: Biguanides\nATC Class: A10BA02\nVA Class: HS502\nChemical Name: 1,1-Dimethylbiguanide monohydrochloride\nMolecular Formula: C4H11N5 • HCl\nBrands: Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet\nMedically reviewed by Drugs.com. Last updated on Nov 18, 2019.\nLactic Acidosis\nLactic acidosis rare but potentially fatal.6 18 20 27 29 30 62 89 96 158 Increased risk of lactic acidosis in patients with renal impairment and advanced age.1 2 62 96 119\nGenerally has occurred in diabetic patients with severe renal insufficiency who frequently had concomitant medical and/or surgical problems and were receiving multiple drugs; metformin plasma concentrations >5 mcg/mL often found in patients with lactic acidosis.1 2 3 20 50 62 64 76 96 123 158 164 165\nPeriodically monitor renal function and use the minimum effective dosage.1 32 62 63 65 76 85 91 93 96 123 124 158 164 165 247 258 313 314 Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.1 2 62 63 93 313 Avoid use in patients with clinical or laboratory evidence of hepatic impairment.1 2 63 65 85 91 93 156 158 313 314 Manufacturers state to temporarily discontinue metformin therapy before or at the time of an iodinated contrast imaging procedure in patients with eGFR of 30–60 mL/minute per 1.73 m2 and in patients with a history of liver disease, alcoholism, or heart failure.1 330 336 Withhold metformin temporarily in patients undergoing surgery or receiving intra-arterial iodinated contrast agents. 1 2 30 62 63 93 158 234 247 254 261 313 314 330 336 Drugs that may affect renal function or alter metformin elimination should be used with caution.1\nHowever, the American College of Radiology states that in patients with no evidence of acute kidney injury and eGFR ≥30 mL/minute per 1.73 m2, there is no need to discontinue metformin either before or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function after the test or procedure.335\nAdvise patients not to consume excessive amounts of alcohol.1 2 63 76 91 93 158\nIf lactic acidosis occurs, discontinue metformin.1 30 313 314 Treat as medical emergency; immediate hospitalization and treatment required; hemodialysis recommended.1 23 32 62 117 119 313 314\nAntidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.1 2 3 4 18 20 22 23 27 28 29 30 33 72 146 243 245 246\nUses for metFORMIN\nUsed as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 3 4 6 8 15 16 17 18 19 20 27 29 95 166 243 245 246\nMay be used in combination with a sulfonylurea, repaglinide, a thiazolidinedione antidiabetic agent, a dipeptidyl peptidase-4 [DPP-4] inhibitor, a glucagon-like peptide-1 (GLP-1) agonist, or a sodium-glucose cotransporter-2 [SGLT2] inhibitor for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs.1 3 6 15 18 20 22 27 29 30 48 59 78 88 95 97 99 112 134 166 191 234 237 238 239 241 242 243 245 246 249 250 260 352 355 362 368 370 372 374 376 378 598 604 610 Also used concomitantly with nateglinide.248\nMay be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.1 3 6 88 90 94 95 146\nCommercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise in adults with type 2 diabetes mellitus.234 254 May add a thiazolidinedione antidiabetic agent if patient has inadequate glycemic control with fixed-combination metformin/glyburide therapy.234\nCommercially available in fixed combination with rosiglitazone for use when treatment with both rosiglitazone and metformin is appropriate.247\nCommercially available in fixed combination with pioglitazone (as immediate- or extended-release tablets) for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components.260\nCommercially available in fixed combination with repaglinide for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who are already receiving repaglinide and metformin concurrently as separate components or in those who have inadequate glycemic control with repaglinide or metformin monotherapy.313\nCommercially available in fixed combination with the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, or sitagliptin for use as an adjunct to diet and exercise when treatment with both drug components is appropriate.314 352 368 376 378 610\nCommercially available in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both drugs components is appropriate.355 362 372 370\nMetformin generally is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.264 Potential advantages of metformin compared with sulfonylureas or insulin include minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain.1 2 3 6 16 17 18 19 20 27 30 42 60 68 102 134 146 166 264\nNot effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.1 6 30 146 191 192\nHas been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome†.289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312\nmetFORMIN Dosage and Administration\nWhen therapy is transferred from most sulfonylurea antidiabetic agents to metformin, sulfonylurea agent may be abruptly discontinued (no transition period generally required).1 2\nPatients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.1 2 30\nGoal of therapy should be to reduce both fasting glucose and HbA1c values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent.1 8 13 14 78 85 88 105 134 146 166 234 235 243 245 246\nOral Administration\nAdminister orally with meals to reduce adverse GI effects.1 2 3 18 53 85 243 245 246\nAdminister immediate-release tablets 2 or 3 times daily.1 243 245 246 Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.1\nAdminister extended-release tablets once daily with the evening meal; swallow whole and do not chew, cut, or crush.1 258 259 260 261 In addition, administer Fortamet extended-release tablets with a full glass of water.258\nAdminister immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, rosiglitazone, repaglinide, alogliptin, linagliptin, or sitagliptin in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.247 260 313 314 355 362 370 372 376 610\nAdminister metformin/repaglinide fixed-combination tablets within 15 minutes before meals.313 If a meal is skipped, omit dose for that meal.313\nAdminister extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin once daily with the morning meal.362 370 374\nAdminister the fixed combination of extended-release metformin hydrochloride and linagliptin once daily with a meal.378 Administer the fixed combination of extended-release metformin hydrochloride and sitagliptin once daily with a meal, preferably the evening meal.352 Administer extended-release metformin hydrochloride in fixed combination with saxagliptin once daily with the evening meal.368\nAvailable as metformin hydrochloride; dosage expressed in terms of the salt.1\nIndividualize dosage carefully based on patient's glycemic response and tolerance.1 4 243 245 246\nImmediate-release tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals.1 257 Increase daily dosage in increments of 500 mg at weekly intervals to a maximum of 2 g daily given in divided doses.1 257\nMetformin Hydrochloride Monotherapy\nImmediate-release tablets or oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals.1 257 Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals up to a maximum of 2 g daily given in divided doses.1 257 May increase dosage from 500 mg twice daily to 850 mg twice daily after 2 weeks.1 257 Clinically important responses generally not observed at dosages <1.5 g daily.1 257\nInitial dosage of 500 mg once daily suggested by some experts.264\nFor additional glycemic control, increase dosage (as immediate-release tablets or oral solution) up to a maximum daily dosage of 2.55 g given in divided doses.1 257\nExtended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal.1 259 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g daily.1 259 If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.1 259 If >2 g daily is required, switch to immediate-release tablet formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses per day for daily dosages >2 g).1 259\nExtended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g once daily with the evening meal; 500 mg once daily may be used when clinically appropriate.258 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2.5 g daily with the evening meal.258\nImmediate-release Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)\nPatients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.254 For more severe hyperglycemia (fasting plasma glucose concentrations of 280–320 mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily.254 Increase daily dosage in increments of one tablet (using the tablet strength at which therapy was initiated) at 2-week intervals until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.254 256\nEfficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL.254 No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.254\nPatients with inadequate glycemic control on either a sulfonylurea or metformin alone: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals.254 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of metformin hydrochloride or glipizide (or equivalent dosage of another sulfonylurea).254 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate glycemic control achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254\nPatients currently receiving combined therapy with separate metformin and glipizide (or another sulfonylurea) preparations: May switch to 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide; initial dosage of the fixed-combination preparation should not exceed the patient's current daily dosage of metformin hydrochloride and glipizide (or equivalent dosage of another sulfonylurea).254 Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.254 Titrate daily dosage in increments not exceeding until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254\nImmediate-release Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)\nPatients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal.234 For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or HbA1c >9%), may consider initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meals.234 Titrate daily dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide at 2-week intervals until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide is reached.234\nDo not use the fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg as initial therapy due to an increased risk of hypoglycemia.234\nPatients with inadequate glycemic control on a sulfonylurea and/or metformin: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily.234 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride.234 Increase daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.234\nPatients currently receiving combined therapy with separate metformin and glyburide (or another sulfonylurea agent) preparations: Initial dosage of the fixed combination should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea).234 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 of mg glyburide is reached.234\nFor patients whose hyperglycemia is not adequately controlled on the fixed combination, may add a thiazolidinedione (e.g., pioglitazone, rosiglitazone) at its recommended initial dosage and continue same dosage of the fixed combination.234 In patients requiring further glycemic control, increase thiazolidinedione dosage as recommended.234\nImmediate-release Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)\nDosage of the fixed combination is based on the patient's current dosages of metformin hydrochloride and/or rosiglitazone.247 (See Table 1.) In rosiglitazone-naive patients, initiate rosiglitazone component at the lowest recommended dosage.247\nIn patients currently receiving metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given in divided doses with patient's existing dosage of metformin hydrochloride.247\nIn patients currently receiving rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given in divided doses with patient's existing dosage of rosiglitazone.247\nIndividualize therapy in patients already receiving metformin hydrochloride at doses not available in the fixed combination (i.e., doses other than 1 or 2 g).247\nTable 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and Rosiglitazone (Avandamet)247\nPrior Therapy\nUsual Initial Dosage of Avandamet\nTotal Daily Dosage\nTablet Strength\nNumber of Tablets\n2 mg/500 mg\n1 tablet twice daily\n2 mg/1 g\nFor patients switching from combined therapy with separate metformin and rosiglitazone preparations, the usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.247\nIf additional glycemic control is needed following transfer, increase daily dosage in increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.247 Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. 247 Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.247\nImmediate-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met)\nIndividualize dosage based on the patient's current dosage regimen, effectiveness, and tolerability.260\nUsual initial dosage is 500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone given once or twice daily.260\nGradually titrate dosage as needed based on therapeutic response.260 Allow sufficient time (e.g., 8–12 weeks) to assess response.260\nSafety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met not established; undertake any such change with caution and appropriate monitoring.260\nExtended-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met XR)\nUsual initial dosage is 1 g of metformin hydrochloride and 15 or 30 mg of pioglitazone given once daily.260\nSafety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met XR not established; undertake any such change with caution and appropriate monitoring.260\nImmediate-release Metformin Hydrochloride in Fixed Combination with Repaglinide (PrandiMet)\nPatients with inadequate glycemic control on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 1 mg of repaglinide twice daily with meals; gradually increase dosage as needed.313\nPatients with inadequate glycemic control on repaglinide monotherapy: Initially, 500 mg of the metformin hydrochloride component (given in fixed combination with repaglinide) twice daily; gradually increase dosage as needed.313\nPatients switching from combined therapy with separate metformin and repaglinide preparations: Initiate with dosages that are similar to (but do not exceed) patient's existing dosages of the individual drugs.313\nSafety and efficacy of transferring to PrandiMet from therapy with other oral antidiabetic agents not established; undertake any such change with caution and appropriate monitoring.313\nImmediate-release Metformin Hydrochloride in Fixed Combination with Alogliptin (Kazano)\nIndividualize dosage based on current antidiabetic regimen, effectiveness, and patient tolerability.610 Increase dosage gradually to minimize adverse GI effects, up to a maximum daily dosage of 2 g of metformin hydrochloride and 25 mg of alogliptin.610\nImmediate-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto)\nIndividualize dosage based on effectiveness and patient tolerability.376 May increase dosage up to a maximum daily dosage of 2 g of metformin hydrochloride and 5 mg of linagliptin.376\nPatients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin administered in 2 divided doses.376\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered in 2 divided doses.376\nPatients currently receiving linagliptin and metformin hydrochloride: Initially, same total daily dosage of each component administered in 2 divided doses daily.376\nExtended-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto XR)\nPatients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin once daily.378\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered once daily.378\nPatients currently receiving linagliptin and metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 5 mg of linagliptin, administered once daily.378\nExtended-release Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)\nPatients inadequately controlled on monotherapy with saxagliptin 5 mg daily: Initially, 500 mg of metformin hydrochloride and 5 mg of saxagliptin once daily; increase dosage gradually to minimize adverse GI effects of metformin.368\nPatients inadequately controlled on monotherapy with extended-release metformin hydrochloride: Dosage of the fixed combination should provide metformin hydrochloride at the current dosage or the nearest therapeutically appropriate dosage.368\nFollowing a switch from immediate-release to extended-release metformin hydrochloride, closely monitor glycemic control and adjust dosage accordingly.368\nPatients inadequately controlled on monotherapy with saxagliptin 2.5 mg daily: Initially, 1 g of metformin hydrochloride and 2.5 mg of saxagliptin daily.368 Use the individual components in patients who require 2.5 mg of saxagliptin and are either metformin naive or require a metformin hydrochloride dose >1 g.368\nIf used with a potent CYP3A4/5 inhibitor, limit dosage of saxagliptin to 2.5 mg once daily.368\nImmediate-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet)\nPatients not currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily.314\nPatients currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily or 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily, depending on the patient's existing dosage of metformin hydrochloride.314\nPatients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily.314\nMaintain the same total daily dosage of sitagliptin and metformin hydrochloride when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride (Janumet) and the fixed combination of sitagliptin and extended-release metformin hydrochloride (Janumet XR).352\nEfficacy and safety of switching therapy from oral antidiabetic agents other than sitagliptin or metformin hydrochloride to the fixed combination of sitagliptin and metformin hydrochloride not established.314\nExtended-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet XR)\nPatients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily.352\nPatients currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily or 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily, depending on the patient's existing dosage of metformin hydrochloride.352\nPatients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily.314 352\nImmediate-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet)\nIndividualize dosage based on patient's current antidiabetic regimen.370 May increase dosage gradually based on effectiveness and tolerability.370\nPatients not currently receiving either canagliflozin or metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of canagliflozin twice daily.370\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered in 2 divided doses.370 In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.370\nPatients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered in 2 divided doses.370\nPatients currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered in 2 divided doses.370\nExtended-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet XR)\nIndividualize dosage of based on patient's current antidiabetic regimen.370 May increase dosage gradually based on effectiveness and tolerability.370\nPatients not currently receiving either canagliflozin or metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of canagliflozin once daily.370\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered once daily.370 In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.370\nPatients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered once daily.370\nPatients currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered once daily.370\nExtended-release Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)\nInitial dosage based on patient's current regimen with metformin hydrochloride and/or dapagliflozin.362 May increase dosage gradually based on effectiveness and tolerability.362\nPatients not currently receiving dapagliflozin: Initially, 5 mg of the dapagliflozin component once daily.362 Titrate gradually based on effectiveness and tolerability, up to a maximum daily dosage of 2 g of extended-release metformin and 10 mg of dapagliflozin.362\nPatients already receiving extended-release metformin hydrochloride in the evening who are switching to the fixed combination of metformin hydrochloride and dapagliflozin: Skip last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.362\nImmediate-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy)\nIndividualize dosage based on the patient's current antidiabetic regimen.372 May increase dosage gradually based on effectiveness and tolerability.372\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered in 2 divided doses.372\nPatients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered in 2 divided doses.372\nPatients currently receiving empagliflozin and metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered in 2 divided doses.372\nExtended-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy XR)\nPatients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered once daily.374\nPatients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered once daily.374\nPatients currently receiving empagliflozin and metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered once daily.374\nImmediate-release Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)\nInitial dosage based on patient's current regimen with metformin hydrochloride and/or ertugliflozin.355 May increase dosage gradually based on effectiveness and tolerability.355\nPatients currently receiving metformin hydrochloride: Initially, total daily metformin hydrochloride dosage similar to patient's existing dosage and total daily dosage of 5 mg of ertugliflozin (administered as fixed combination with 2.5 mg of ertugliflozin), given in 2 divided doses daily.355\nPatients currently receiving ertugliflozin: Initially, total daily dosage of 1 g of metformin hydrochloride (administered as fixed combination with 500 mg of metformin hydrochloride) and a total daily ertugliflozin dosage similar to the patient's existing dosage, given in 2 divided doses daily.355\nPatients currently receiving metformin hydrochloride and ertugliflozin (administered as separate tablets): Initially, give fixed combination containing a total daily metformin hydrochloride dosage similar to patient's existing dosage and same total daily dose of ertugliflozin, in 2 divided doses daily.355\nMetformin Hydrochloride Dosage in Patients Transferred from Insulin\nInitially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (immediate-release tablets) or 2 g (extended-release tablets) is reached.1 Concurrent insulin dosage initially remains unchanged.1 When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.1\nPolycystic Ovary Syndrome†\nIn general, 1.5–2.25 g daily in divided doses.291 292 294 296 299 300 301 302 303 305 306 307\nPrescribing Limits\nChildren 10–16 years of age: Maximum 2 g daily as immediate-release tablets or oral solution.1 257\nMaximum 2.55 g daily as immediate-release tablets or oral solution, 2.5 g daily as Fortamet extended-release tablets, or 2 g daily as certain other extended-release tablets (e.g., Glucophage XR).1 2 3 4 14 18 22 85 257 258 259 Switch to immediate-release tablets for further dosage titration if required dosage exceeds 2 g daily.1 259\nMetformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)\nMaximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide.234\nNo experience with total daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide in clinical trials in patients receiving the fixed combination as initial therapy.234\nMetformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)\nMaximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glipizide.254 256\nMetformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto, Jentadueto XR)\nMaximum daily dosage is 2 g of metformin hydrochloride and 5 mg of linagliptin.376 378\nMetformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)\nMaximum daily dosage is 2 g of metformin hydrochloride and 5 mg of saxagliptin.368\nMetformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet, Janumet XR)\nMaximum daily dosage is 2 g of metformin hydrochloride and 100 mg of sitagliptin.314 352\nMetformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet, Invokamet XR)\nPatients with eGFR ≥60 mL/minute per 1.73 m2: Maximum daily dosage is 2 g of metformin hydrochloride and 300 mg of canagliflozin.370\nPatients with eGFR 45 to <60 mL/minute per 1.73 m2: Maximum daily dosage is 2 g of metformin hydrochloride and 100 mg of canagliflozin.370\nMetformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)\nMaximum daily dosage is 2 g of metformin hydrochloride and 10 mg of dapagliflozin.362\nMetformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy, Synjardy XR)\nMaximum daily dosage is 2 g of metformin hydrochloride and 25 mg of empagliflozin.372 374\nMetformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)\nMaximum daily dosage is 2 g of metformin hydrochloride and 15 mg of ertugliflozin.355\neGFR 30–45 mL/minute per 1.73 m2: Do not initiate metformin; assess benefits and risks of continued treatment in patients already receiving metformin.330 336 350\neGFR <30 mL/minute per 1.73 m2: Use contraindicated; discontinue in patients already receiving metformin.330 336 350\nNational Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) states that the exact GFR cutoff for metformin use is controversial.341 NKF-KDOQI suggests reviewing use of metformin in GFR <45 mL/minute per 1.73 m2.341 NKF-KDOQI and other clinicians suggest avoiding metformin therapy if GFR <30 mL/minute but suggest considering risk-benefit of such therapy if GFR stable.340 341\nAvoid use in those with hepatic disease.1\nGeriatric Patients\nIn general, do not titrate to the maximum dosage recommended for younger adults;1 2 3 4 165 243 245 246 314 limited data suggest reducing initial dosage by approximately 33% in geriatric patients.30 174\nMonitor renal function regularly to determine appropriate dosage.1 2 3 4 164 165 243 245 246 314\nCautions for metFORMIN\nAcute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1 2 234 247\nSevere renal impairment (eGFR <30 mL/minute per 1.73 m2),1 234 247 330 which may result from conditions such as cardiovascular collapse (shock), acute MI, or septicemia.1 234\nKnown hypersensitivity to metformin hydrochloride or any ingredient in the formulations.1 2 234 247 254\nSee Boxed Warning.\nUncommon in patients receiving metformin as monotherapy.1 15 30 78 94 99 Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.1 2 Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.1 2 Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.1 83 91 128 143 153 159 (See Specific Drugs under Interactions.)\nHematologic Effects\nDecreased serum vitamin B12 concentrations, 1 18 with or without clinical manifestations (e.g., anemia).1\nSymptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B12.1 3 6 20 30 70 77 82 134 Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B12 concentrations)1 82 114 122 134 148 prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.1 350\nConsider periodic supplementation with parenteral vitamin B12 in patients at high risk for developing subnormal serum vitamin B12 concentrations (e.g., alcoholics, patients with low calcium or vitamin B12 intake or absorption).1 82 114 122 134 148 598\nCardiovascular Effects\nPossible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin).1 191 192 200 The American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas pending the results of further studies of metformin alone or in combination with sulfonylureas.220 221 224\nUse of metformin in combination with rosiglitazone and insulin is not recommended; adverse cardiovascular events (e.g., edema, CHF) have occurred with combined rosiglitazone and insulin therapy.247\nConcurrent Illness\nEvaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.1 88 134 156 169\nTemporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.1\nUse of Fixed Combinations\nWhen used in fixed combination with other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).234 237 247 254 260 313 314 352 355 362 368 370 372 374 376 378 610\nCategory B.1\nMost clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.1 3 4 18 72 88 92\nDistributed into milk in rats; small amounts distributed into human milk.1 284 285 286 Discontinue nursing or the drug.1 3 4\nSafety and efficacy of metformin as immediate-release tablets or oral solution in children <10 years of age have not been established.1 257\nSafety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.1 258 259\nSafety and efficacy of metformin in fixed combination with glipizide, pioglitazone, repaglinide, rosiglitazone, or sitagliptin in children have not been established.1 3 4 30 134 247 254 260 313 314 Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide (Glucovance) with each drug as monotherapy did not reveal unexpected safety findings.234\nInsufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride immediate-release (Glucophage) and extended-release tablets (Glucophage XR, Glumetza) to determine if such patients respond differently than younger adults.1 261 314 With another extended-release preparation of metformin hydrochloride (Fortamet), no overall differences in safety or efficacy in geriatric patients were observed compared with younger adults.258\nUse with caution, since renal function declines with age.1 3 4 30 85 174 234 247 254 314\nMonitor renal function periodically.1 2 3 4 164 165 314\nDo not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Clcr.1 209 214 313 314\nGeriatric patients particularly susceptible to hypoglycemia,1 2 which may be difficult to recognize.1 83 91 128 143 153 159\nDo not use in patients with severe renal disease or dysfunction.1 330 (See Contraindications.)\nEvaluate renal function prior to initiation of therapy and at least annually thereafter.1 2 77 85 234\nMonitor more frequently if development of impaired renal function is anticipated (e.g., those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).156\nDiscontinue metformin if patient's eGFR <30 mL/minute per 1.73 m2; contraindicated in such patients.330\nGenerally avoid use in patients with clinical or laboratory evidence of hepatic disease.1 165 Elimination of lactate may be substantially reduced.1 (See Boxed Warning.)\nCommon Adverse Effects\nDiarrhea,1 31 48 49 53 78 109 118 122 135 nausea,1 31 53 78 109 118 122 vomiting,1 118 122 abdominal bloating, abdominal cramping or pain,1 31 35 42 53 118 122 flatulence,1 anorexia.1 3 6 18\nInteractions for metFORMIN\nCationic Agents Secreted by Proximal Renal Tubules\nPharmacokinetic interaction with cimetidine (decreased excretion of metformin).1 75\nPotential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).1 30\nMonitor carefully; consider dosage adjustment of either agent.1\nProtein-bound Drugs\nPharmacokinetic interaction unlikely.1\nDrugs That May Antagonize Hypoglycemic Effects\nCalcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.1 30 80 85 91 120 121 134 139 143 151 152 153 154 159 160\nSpecific Drugs or Foods\nAcute decrease in metformin bioavailability in single-dose study138 201\nACE inhibitors\nPotential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn131 132 134 152 155 160\nMonitor blood glucose concentrations during dosage adjustments with either agent130 131 132 134 152 155 160\nIncreased risk of hypoglycemia and lactic acidosis1 2 18 33 63 72 76 91 93 107 143\nAvoid excessive alcohol intake1\nAntidiabetic agents (e.g., sulfonylureas, meglitinides, insulin)\nPossible hypoglycemia1 15 78 94 99 260 313\nMay need to reduce dosage of concomitant antidiabetic agent1\nβ-Adrenergic blocking agents\nMay impair glucose tolerance; 73 143 152 153 159 may increase frequency or severity of hypoglycemia and hypoglycemia-induced complications91 127 153 159\nIf concomitant therapy necessary, a β1-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred36 143 152 160 173\nPossible decreased excretion of metformin1\nIncreased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics1\nCarefully monitor patient; consider need for dosage adjustment1\nClomiphene\nPossible resumption of ovulation in premenopausal patients with polycystic ovary syndrome210\nIncreased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study1\nPharmacokinetics and pharmacodynamics of metformin not altered in single-dose study1 260 261 314\nVariable decreases in AUC and peak blood concentration of glyburide1 260 314\nClinical importance uncertain1\nReduced and delayed GI absorption of metformin 18 85 99 106\nEnhanced absorption and increased urinary excretion of metformin; minimal effects on nifedipine pharmacokinetics1\nThiazide diuretics\nMay exacerbate diabetes mellitus1 91 139 143 151 152 153 154 159 160\nConsider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent73 134 152 153 154 159 160\nmetFORMIN Pharmacokinetics\nApproximately 50–60% (absolute) with dosages of 0.5–1.5 g.1 2 3 4 18 33 43 50 65 72 85 89\nFixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of rosiglitazone is bioequivalent to mg-equivalent dosages of individual components administered separately under fasted conditions.247\nTherapeutic response usually apparent within a few days to 1 week.18 53 72 98 134 Maximal glycemic response within 2 weeks.18 53 72 98 134\nBlood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.53 134\nFood decreases and slightly delays absorption of immediate-release tablets.1 2 3 4 18 208 314\nFood increases the extent of absorption of extended-release tablets (Glucophage XR, Fortamet).1 258 Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage XR) with food; 1 food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet).258\nPeak concentrations and AUC of the extended-release metformin hydrochloride component increased by approximately 98 and 85%, respectively, when Actoplus Met XR was given with food.260 Time to peak concentration prolonged by approximately 3 hours for pioglitazone and 2 hours for extended-release metformin hydrochloride under fed conditions.260\nFood increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution.257 Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.257\nRapidly distributed into peripheral body tissues and fluids, particularly GI tract.30 50 65 72 89 134 162 167\nSlowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).30 50 65 72 89 134 162 167\nPlasma Protein Binding\nNegligible.1 18 50 51 65 85 89\nNot metabolized in the liver or GI tract and not excreted into bile.1 50 51 89 No metabolites identified in humans.1 50 51 89 314\nElimination Route\nExcreted in urine (approximately 35–52%)50 51 89 and feces (20–33%).6 33 43 50 72 89 Eliminated as unchanged drug.1 2 6 33 50 63 65 75 85 89 314\nApproximately 6.2 hours.1 2 6 18 33 38 50 51 65 85 89 125 134 314\nRenal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function.1 33 51 174 Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.1 3 51 174\nImmediate-release tablets: Tight, light-resistant containers at 20–25°C (may be exposed to 15–30°C).1\nExtended-release tablets: Tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).1 258\nMetformin/glyburide fixed combination: Light-resistant containers at 25°C.234\nMetformin/glipizide fixed combination: 20–25° C (may be exposed to 15–30°C).254\nMetformin/rosiglitazone fixed combination: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).247\nMetformin/pioglitazone fixed combination: Tight (Actoplus Met) or tight, light-resistant (Actoplus Met XR) containers at 25°C (may be exposed to 15–30°C).260\nMetformin/repaglinide fixed combination: Tight containers at temperatures not exceeding 25°C.313\nMetformin/linagliptin fixed combination: 25°C (may be exposed to 15–30°C); protect from exposure to high humidity.376 378\nMetformin/saxagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).368\nMetformin/sitagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).314\nMetformin/canagliflozin fixed combination: 20–25°C (may be exposed to 15–30°C).370 Store and dispense in original container.370 May store in pillbox for ≤30 days.370\nMetformin/dapagliflozin: 20–25°C (may be exposed to 15–30°C).362\nMetformin/empagliflozin: 25°C (may be exposed to 15–30°C).372 374\nMetformin/ertugliflozin: 20–25°C (may be exposed to 15–30°C); protect from moisture and store in a dry place.355\n15–30°C.257\nLowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells.1 2 3 4 18 20 27 31 40 60 134 Ineffective in the absence of some endogenous or exogenous insulin.18 27 40 71 122\nUsually does not lower glucose concentrations below euglycemia, but hypoglycemia occasionally may occur with overdosage.1 2 18 20 27 28 29 72 102 103 111\nLowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1 2 18 22 Improves insulin sensitivity by decreasing hepatic glucose production and enhancing insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes).18 31 40 41 42 44 60 81 146 149 Insulin secretion usually remains unchanged.1 2 3 18 20 42 60 68 102 166\nAdvice to Patients\nImportance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, dietary or herbal supplements, and alcohol consumption, as well as any concomitant illnesses (e.g., renal disease).1 Importance of avoiding excessive alcohol consumption.1\nImportance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1\nImportance of adherence to diet and exercise regimens.1\nPossibility of primary and secondary failure with metformin therapy.1\nRisks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions.1\nImportance of regular laboratory evaluations, including fasting blood (or plasma) glucose determinations.1 2 85\nRisks of lactic acidosis and conditions that predispose to its development.1\nImportance of informing patients of other important precautionary information.1 (See Cautions.)\nExcipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.\nPlease refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.\n* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name\n500 mg/5 mL*\nmetFORMIN Hydrochloride Solution\nRiomet\nTablets, extended-release\n500 mg*\nFortamet\nShionogi Pharma\nGlucophage XR\nGlumetza\nDepomed\n1 g*\nTablets, film-coated\nmetFORMIN Hydrochloride Combinations\n500 mg with Immediate-release Canagliflozin (anhydrous) 50 mg\nInvokamet XR\n500 mg with Immediate-release Canagliflozin (anhydrous) 150 mg\n500 mg with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)\nXigduo XR\n500 mg with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)\n500 mg with Immediate-release Saxagliptin 5 mg\nKombiglyze XR\n500 mg with Immediate-release Sitagliptin 50 mg\nJanumet XR\n1 g with Immediate-release Canagliflozin 50 mg (anhydrous)\n1 g with Immediate-release Canagliflozin (anhydrous) 150 mg\n1 g with Immediate-release Dapagliflozin Propanediol 2.5 mg (of dapagliflozin)\n1 g with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)\n1 g with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)\n1 g with Immediate-release Empagliflozin 5 mg\nSynjardy XR\nBoehniger Ingelheim\n1 g with Immediate-release Empagliflozin 10 mg\n1 g with Immediate-release Empagliflozin 12.5 mg\n1 g with Immediate-release Linagliptin 2.5 mg\nJentadueto XR\n1 g with Immediate-release Linagliptin 5 mg\n1 g with Immediate-release Pioglitazone Hydrochloride 15 mg (of pioglitazone)\nActoplus Met XR\n1 g with Immediate-release Saxagliptin 2.5 mg\n1 g with Immediate-release Saxagliptin 5 mg\n1 g with Immediate-release Sitagliptin 50 mg\n1 g with Immediate-release Sitagliptin 100 mg\n250 mg with Glipizide 2.5 mg*\nMetaglip\nmetFORMIN Hydrochloride and Glipizide Tablets\n250 mg with Glyburide 1.25 mg*\nmetFORMIN Hydrochloride and Glyburide Tablets\n500 mg with Alogliptin Benzoate 12.5 mg (of alogliptin)\nKazano\n500 mg with Canagliflozin (anhydrous) 50 mg\nInvokamet\n500 mg with Canagliflozin (anhydrous) 150 mg\n500 mg with Empagliflozin 5 mg\nSynjardy\n500 mg with Empagliflozin 12.5 mg\n500 mg with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)\n500 mg with Glipizide 5 mg*\n500 mg with Glyburide 2.5 mg*\n500 mg with Glyburide 5 mg*\n500 mg with Linagliptin 2.5 mg\nJentadueto\n500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)\n500 mg with Repaglinide 1 mg\nPrandimet\n500 mg with Rosiglitazone Maleate 2 mg (of rosiglitazone)\nAvandamet\n500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin)\n1 g with Alogliptin Benzoate 12.5 mg (of alogliptin)\n1 g with Canagliflozin (anhydrous) 50 mg\n1 g with Canagliflozin (anhydrous) 150 mg\n1 g with Empagliflozin 5 mg\n1 g with Empagliflozin 12.5 mg\n1 g with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)\n1 g with Linagliptin 2.5 mg\n1 g with Rosiglitazone Maleate 2 mg (of rosiglitazone)\n1 g with Sitagliptin Phosphate 50 mg (of sitagliptin)\nAHFS DI Essentials™. © Copyright 2021, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.\n† Use is not currently included in the labeling approved by the US Food and Drug Administration.\n1. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets prescribing information. Princeton, NJ; 2009 Jan.\n2. Bristol-Myers Squibb Company. Product information form for American Hospital Formulary Service: Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.\n3. Bristol-Myers Squibb Company. Executive summary (product information) on Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.\n4. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets product monograph. Princeton, NJ; 1995 Apr.\n5. Marchetti P, Benzi L, Cecchetti P et al. Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clin Pharmacol Ther. 1987; 41:450-4. http://www.ncbi.nlm.nih.gov/pubmed/3829580?dopt=AbstractPlus\n6. Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992; 15:755-72. http://www.ncbi.nlm.nih.gov/pubmed/1600835?dopt=AbstractPlus\n7. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28:1039-57. http://www.ncbi.nlm.nih.gov/pubmed/510803?dopt=AbstractPlus\n8. Henry R R. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus\n9. DeFronzo RA. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988; 37:667-87. http://www.ncbi.nlm.nih.gov/pubmed/3289989?dopt=AbstractPlus\n10. Scientific Advisory Panel of the Executive Committee, American Diabetes Association. Policy statement: the UGDP controversy. Diabetes. 1979; 28:168-70.\n11. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996; 334:777-83. http://www.ncbi.nlm.nih.gov/pubmed/8592553?dopt=AbstractPlus\n12. American Diabetes Association. Office guide to diagnosis and classification of diabetes mellitus and other categories of glucose intolerance. Diabetes Care. 1995; 18(Suppl 1):4.\n13. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care. 1994; 17:1542-4. http://www.ncbi.nlm.nih.gov/pubmed/7882832?dopt=AbstractPlus\n14. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003; 26(Suppl 1):S33-50.\n15. Hermann LS, Scherstén B, Bitzén PO et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care. 1994; 17:1100-9. http://www.ncbi.nlm.nih.gov/pubmed/7821128?dopt=AbstractPlus\n16. Clarke BF, Campbell IW. Comparison of metformin and chlropropamide in non-obese, maturity-onset diabetics uncontrolled by diet. Br Med J. 1977; 2:1576-8. http://www.ncbi.nlm.nih.gov/pubmed/589351?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1632725&blobtype=pdf\n17. Clarke BF, Duncan LJP. Comparison of chlorpropamide and metformin treatment on weight and blood-glucose response of uncontrolled obese diabetics. Lancet. 1968; 1:123-6. http://www.ncbi.nlm.nih.gov/pubmed/4169605?dopt=AbstractPlus\n18. Dunn CJ, Peters DH. Metformin: a review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 1995; 49:721-49. http://www.ncbi.nlm.nih.gov/pubmed/7601013?dopt=AbstractPlus\n19. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ. 1995; 310:83-8. http://www.ncbi.nlm.nih.gov/pubmed/7833731?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2548496&blobtype=pdf\n20. Bailey CJ, Nattrass M. Treatment—metformin. Baillieres Clin Endocrinol Metab. 1988; 2:455-76. http://www.ncbi.nlm.nih.gov/pubmed/3075902?dopt=AbstractPlus\n21. Haupt E, Knick B, Koschinsky T et al. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabetes Metab. 1991; 17:224-31.\n22. Reaven GM, Johnston P, Hollenbeck CB et al. Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab. 1992; 74:1020-6. http://www.ncbi.nlm.nih.gov/pubmed/1569149?dopt=AbstractPlus\n23. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf. 1994; 11:223-41. http://www.ncbi.nlm.nih.gov/pubmed/7848543?dopt=AbstractPlus\n24. Anon. Diabetes mellitus. NIH Cons Dev Conf Statement. 1986; 6:1-7.\n25. Blake GH. Control of type II diabetes: reaping the rewards of exercise and weight loss. Postgrad Med. 1992; 92:129-32. http://www.ncbi.nlm.nih.gov/pubmed/1437899?dopt=AbstractPlus\n26. Kerr CP. Improving outcomes in diabetes: a review of the outpatient care of NIDDM patients. J Fam Pract. 1995; 40:63-75. http://www.ncbi.nlm.nih.gov/pubmed/7807040?dopt=AbstractPlus\n27. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989; 321:1231-45. http://www.ncbi.nlm.nih.gov/pubmed/2677730?dopt=AbstractPlus\n28. Kahn CR, Shechter Y. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Gilman AG, Rawl TW, Nies AS et al, eds. Goodman and Gilman's pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1463-95.\n29. Anon. Metformin for noninsulin-dependent diabetes mellitus. Med Lett Drugs Ther. 1995; 37:41-2. http://www.ncbi.nlm.nih.gov/pubmed/7739421?dopt=AbstractPlus\n30. Bristol-Myers Squibb, Princeton, NJ: personal communication.\n31. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in Obese and Lean Noninsulin-Dependent Diabetic Subjects. J Clin Endocrinol Metab. 1991; 73:1294-1300. http://www.ncbi.nlm.nih.gov/pubmed/1955512?dopt=AbstractPlus\n32. Gan SC, Barr J, Arieff AI et al. Biguanide-associated lactic acidosis. Arch Intern Med. 1992; 152:2333-36. http://www.ncbi.nlm.nih.gov/pubmed/1444694?dopt=AbstractPlus\n33. Anon. Metformin. Phase III Drug Profiles. 1994; 4:1-15.\n34. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993; 16:621-629. http://www.ncbi.nlm.nih.gov/pubmed/8462390?dopt=AbstractPlus\n35. Jeppesen J, Chen YDI, Zhou M et al. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care. 1994; 17:1093-99. http://www.ncbi.nlm.nih.gov/pubmed/7821127?dopt=AbstractPlus\n36. Hoffman BB, Lefkowitz RJ. Catecholamines, sympoathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:207-48.\n37. Klip A, Leiter LA. Cellular mechanism of action of metformin.. Diabetes Care. 1990; 13:696-704. http://www.ncbi.nlm.nih.gov/pubmed/2162756?dopt=AbstractPlus\n38. Caille G, Lacassw Y, Raymond M et al. Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method. Biopharmaceutics & Drug Disposition. 1993; 14:257-63.\n39. Widen EI, Eriksson JG, Groop LC. Metformin normalizes nonoxidative glucose metabolism in insulin-resistant. Diabetes. 1992; 41:354-58. http://www.ncbi.nlm.nih.gov/pubmed/1551495?dopt=AbstractPlus\n40. Matthaei S, Reibold JP, Hamann A et al. In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) zucker rat adipocytes. Ednocrinology. 1993; 133:304-11.\n41. Nosadini R, Avogaro A, Trevisan R et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care. 1987; 10:62-67. http://www.ncbi.nlm.nih.gov/pubmed/3552515?dopt=AbstractPlus\n42. Wu MS, Johnston P, Hollenbeck CB et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 1990; 13:1-8. http://www.ncbi.nlm.nih.gov/pubmed/2404714?dopt=AbstractPlus\n43. Vidon N, Chaussade S, Noel M et al. Metformin in the digestive tract. Diabetes Res and Clin Practice. 1988; 4:223-29.\n44. Jackson RA, Hawa MI, Jaspan JB et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes. 1987; 36:632-40. http://www.ncbi.nlm.nih.gov/pubmed/3552795?dopt=AbstractPlus\n45. Hermann LS, Karlsson JE, Sjostrand A. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol. 1991; 41:263-265. http://www.ncbi.nlm.nih.gov/pubmed/1748145?dopt=AbstractPlus\n46. Rains SGH, Wilson GA, Richmond W et al. The effect of glibenclamide and metformin on serum lipoproteins in type II diabetes. Diabetic Medicine. 1988; 5:653-59. http://www.ncbi.nlm.nih.gov/pubmed/2975549?dopt=AbstractPlus\n47. Sarabia V, Lam L, Leiter LA et al. Glucose transport in human skeletal muscle cells in culture. J Clin Invest. 1992; 90:1386-95. http://www.ncbi.nlm.nih.gov/pubmed/1401073?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=443184&blobtype=pdf\n48. Lim P, Khoo OT. Metformin compared to tolbutamide in the treatment of maturity-onset diabetes mellitus. Med J Aust. 1970; 1:271-273. http://www.ncbi.nlm.nih.gov/pubmed/5440868?dopt=AbstractPlus\n49. Sirtori CR, Tremoli E, Sirtori M et al. Treatment of hypertriglyceridemia with metformin. Atherosclerosis. 1977; 26:583-592. http://www.ncbi.nlm.nih.gov/pubmed/193525?dopt=AbstractPlus\n50. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979; 16:195-202. http://www.ncbi.nlm.nih.gov/pubmed/499320?dopt=AbstractPlus\n51. Sirtori CR, Franceschini G, Galli-Kienle M et al. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol and Ther. 1978; 24:683-93.\n52. Hundal H, Ramlal T, Reyes R et al. Cellular mechanism of metformin actioninvolves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology. 1992; 131:1165-73. http://www.ncbi.nlm.nih.gov/pubmed/1505458?dopt=AbstractPlus\n53. Campbell IW, Duncan C, Patton NW et al. The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus. Diabetic Medicine. 1987; 4:337-41. http://www.ncbi.nlm.nih.gov/pubmed/2956047?dopt=AbstractPlus\n54. Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab. 1986; 63:898-905. http://www.ncbi.nlm.nih.gov/pubmed/3745404?dopt=AbstractPlus\n55. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabete et Metabolisme. 1991; 17:168-73. http://www.ncbi.nlm.nih.gov/pubmed/1936471?dopt=AbstractPlus\n56. Chakrabarti R, Hocking ED, Fearnley GR. Fibrinolytic effect of metformin in cornorary-artery disease. Lancet. 1965; 2:256-259. http://www.ncbi.nlm.nih.gov/pubmed/14330058?dopt=AbstractPlus\n57. Chan JCN, Cockram CS, Tomlinson B et al. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care. 1993; 16:1035-38. http://www.ncbi.nlm.nih.gov/pubmed/8359098?dopt=AbstractPlus\n58. Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Int Med. 1991; 229:181-87.\n59. Giugliano D, Quatraro A, Consoli G et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993; 44:107-12. http://www.ncbi.nlm.nih.gov/pubmed/8453955?dopt=AbstractPlus\n60. Hother-Nielsen O, Schmitz O, Andersen PH et al. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol. 1989; 120:257-65. http://www.ncbi.nlm.nih.gov/pubmed/2648723?dopt=AbstractPlus\n61. Nattrass M, Todd PG, Hinks L et al. Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics. Diabetologia. 1977; 13:145-52. http://www.ncbi.nlm.nih.gov/pubmed/404205?dopt=AbstractPlus\n62. Assan R, Heuclin C, Ganeval D et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia. 1977; 13:211-17. http://www.ncbi.nlm.nih.gov/pubmed/406158?dopt=AbstractPlus\n63. Alberti KGMM, Nattrass M. Lactic acidosis. Lancet. 1977; 2:25-9. http://www.ncbi.nlm.nih.gov/pubmed/69109?dopt=AbstractPlus\n64. Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia. 1978; 14:95-100. http://www.ncbi.nlm.nih.gov/pubmed/631461?dopt=AbstractPlus\n65. Lucis OJ. The status of metformin in Canada. Can Med Assoc J. 1983; 128:24-6. http://www.ncbi.nlm.nih.gov/pubmed/6847752?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1874707&blobtype=pdf\n66. Lefkowitz RJ, Hoffman BB, Taylor P. Neuotransmission: the autonomic and somatic motor nervous systems. In: Goodman & Gilman's The pharmacological basis of therapeutics. 9th ed. 1995:105-139.\n67. Vigneri R, Pezzino V, Wong K et al. Comparison of the in vitro effect of biguanides and sulfonylureas on insulin binding to its receptors in target cells. J Clin Endocrinol Metab. 1982; 54:95-100. http://www.ncbi.nlm.nih.gov/pubmed/7033271?dopt=AbstractPlus\n68. Riccio A, Del Prato S, Vigili De Kreutzenberg S et al. Glucose and lipid metabolism in non-insulin-dependent diabetes: effect of metformin. Diab Metab. 1991; 17:180-84.\n69. McIntyre HD, Ma A, Bird DM et al. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust N Z J Med. 1991; 21:714-19. http://www.ncbi.nlm.nih.gov/pubmed/1759920?dopt=AbstractPlus\n70. Tomkin GH, Hadden DR, Weaver JA et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2:685-87. http://www.ncbi.nlm.nih.gov/pubmed/5556053?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1796258&blobtype=pdf\n71. Schernthaner G. Improvement of insulin action is an important part of the antidiabetic effect of metformin. Hormone Metab Res. 1985; 15:116-120.\n72. Hermann LS, Melander A. Biguanides: basic aspects and clinical use. In: Alberti KGMM, DeFronzo RA, Keen H et al, eds. International textbook of diabetes mellitus. New York: John Wiley & Sons; 1992; 773-95.\n73. Swislocki A. Insulin resistance and hypertension. Am J Med Sci. 1990; 300:104-15. http://www.ncbi.nlm.nih.gov/pubmed/2206054?dopt=AbstractPlus\n74. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ. 1986; 293:483. http://www.ncbi.nlm.nih.gov/pubmed/3091170?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1341115&blobtype=pdf\n75. Somogyi A, Stockley C, Keal J et al. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23: 545-51.\n76. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol. 1993; 44:589-91. http://www.ncbi.nlm.nih.gov/pubmed/8405019?dopt=AbstractPlus\n77. Berger W. Incidence of severe side effects during therapy with sulfonylureas and giguanides. Hormone Metab Res. 1985;15: 11-15.\n78. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:541-49. http://www.ncbi.nlm.nih.gov/pubmed/7623902?dopt=AbstractPlus\n79. Cigolini M, Bosello O, Zancanaro C et al. Influence of metformin on metabolic effect of insulin in human adipose tissue in vitro. Diab Metab. 1984; 10:311-15.\n80. Cordingley FT, Crawford GPM. Diabetogenic effects of nifedipine. BMJ. 1984; 289:19.\n81. Stumvoll M, Nurjahan N, Perriello G et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:550-54. http://www.ncbi.nlm.nih.gov/pubmed/7623903?dopt=AbstractPlus\n82. Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. Br Med J. 1973; 3:673-75. http://www.ncbi.nlm.nih.gov/pubmed/4742454?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1587044&blobtype=pdf\n83. Bailey CJ, Flatt PR, Marks V. Drugs inducing hypoglycemia. Pharmacol Ther. 1989; 42:361-84. http://www.ncbi.nlm.nih.gov/pubmed/2672051?dopt=AbstractPlus\n84. Pedersen O, Hother Nielsen, Bak J et al. The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes. Diabet Med. 1989; 6:249-56. http://www.ncbi.nlm.nih.gov/pubmed/2523787?dopt=AbstractPlus\n85. Johnston P, Rough T. Metformin: a newly approved oral hypoglycemic. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus\n86. Pagano G, Tagliaferro V, Caselle MT et al. Metformin reduces insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus\n87. Gin H, Messerchmitt C, Brottier E et al. Metformin improved insulin resistance in type 1, insulin-dependent, diabetic patients. Metab Clin Exp. 1985; 34:923-25. http://www.ncbi.nlm.nih.gov/pubmed/4046836?dopt=AbstractPlus\n88. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. CMAJ. 1992; 147:697-712. http://www.ncbi.nlm.nih.gov/pubmed/1521215?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1336391&blobtype=pdf\n89. Tucker GT, Casey C, Phillips PJ et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981; 12:235-46. http://www.ncbi.nlm.nih.gov/pubmed/7306436?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1401849&blobtype=pdf\n90. Yki-Jarvinen H, Esko N, Eero H et al. Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure. Am J Med. 1988; 84:185-192. http://www.ncbi.nlm.nih.gov/pubmed/3044067?dopt=AbstractPlus\n91. Chan JCN, Cockram CS. Drug-induced disturbances of carbohydrate metabolism. Adv Drug React Toxicol Rev. 1991; 10:1-29.\n92. Piacquadio K, Hollingsworth D, Murphy H. Effects of in-utero oral hypoglycaemic drugs. Lancet. 1991; 338:866-69. http://www.ncbi.nlm.nih.gov/pubmed/1681225?dopt=AbstractPlus\n93. Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res. 1985; 15(Suppl):105-11.\n94. Chow CC, Tsang L, Sorensen J et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995; 18:307-14. http://www.ncbi.nlm.nih.gov/pubmed/7555472?dopt=AbstractPlus\n95. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1995; 18:1510-18. http://www.ncbi.nlm.nih.gov/pubmed/8722084?dopt=AbstractPlus\n96. Lalau J, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995; 18:779-84. http://www.ncbi.nlm.nih.gov/pubmed/7555503?dopt=AbstractPlus\n97. Gregorio F, Ambrosi F, Marchetti P et al. Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations. Acta Diabetol Lat. 1990; 27:139-55. http://www.ncbi.nlm.nih.gov/pubmed/2198745?dopt=AbstractPlus\n98. Lord JM, White SI, Bailey CJ et al. Effect of metformin on insulin receptor binding and glycaemic control in type II diabetes. BMJ. 1983; 286:830-31. http://www.ncbi.nlm.nih.gov/pubmed/6403102?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1547150&blobtype=pdf\n99. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care. 1990; 13:37-41. http://www.ncbi.nlm.nih.gov/pubmed/2209342?dopt=AbstractPlus\n100. Klein W. Sulfonylurea-metformin-combination versus sulfonylurea-inslin-combination in secondary failures of sulfonylurea monotherapy. Diab Metab. 1991; 17(Suppl 1):235-40.\n101. Groop L, Widen E. Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there a place for intermittent insulin therapy? Diab Metab. 1991; 17(Suppl 1):218-23.\n102. Hollenbeck CB, Johnston P, Varasteh BB et al. Effects of metformin on glucose insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diab Metab. 1991; 17:483-90.\n103. Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabet Med. 1987; 4:457-62. http://www.ncbi.nlm.nih.gov/pubmed/2959438?dopt=AbstractPlus\n104. Trischitta V, Italia S, Mazzarino S et al. Comparison of combined therapies in treatment of secondary failure to glyburide. Diabetes Care. 1992; 15:539-42. http://www.ncbi.nlm.nih.gov/pubmed/1499473?dopt=AbstractPlus\n105. Dornan T, Heller S, Peck G et al. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care. 1991; 14:342-44. http://www.ncbi.nlm.nih.gov/pubmed/2060439?dopt=AbstractPlus\n106. Gin H, Orgerie MB, Aubertin J. The influence of guar gum on absorption of metformin from the gut in healthy volunteers. Horm Metab Res. 1989; 21:81-83. http://www.ncbi.nlm.nih.gov/pubmed/2722133?dopt=AbstractPlus\n107. Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics. ACTA Medica Scandinavica. 1979; 206:269-73. http://www.ncbi.nlm.nih.gov/pubmed/506799?dopt=AbstractPlus\n108. Juhan-Vague I, Alessi MC, Badier C et al. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost. 1987; 57:326-28. http://www.ncbi.nlm.nih.gov/pubmed/3310318?dopt=AbstractPlus\n109. Collier A, Watson HHK, Patrick AW et al. Effect of glycaemic control, metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients. Diab Metab. 1989; 15:420-25.\n110. Gustafson A, Bjorntorp P, Fahlen M. Metformin administration in hyperlipidemic states. ACTA Medica Scandinavica. 1971; 190:491-494. http://www.ncbi.nlm.nih.gov/pubmed/5149092?dopt=AbstractPlus\n111. Sambol NC, O'Connor MD, Lin ET et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of metformin HCL (MET) in healthy individuals and individuals with noninsulin-dependent diabetes mellitus (NIDDM). Clin Pharmacol Ther. 1993; 53:211.\n112. Chiasson J, Josse R, Hunt J et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med. 1994; 121:929-935.\n113. Bayer Corp. Precose™ (acarbose) tablets product information. West Haven, CT; 1995 Oct.\n114. Wall R, Linford S, Akhter M. Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment. JAMA. 1963; 183:482-85.\n115. Coretzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J. 1980; 58:795-802. http://www.ncbi.nlm.nih.gov/pubmed/6777880?dopt=AbstractPlus\n116. Coscelli C, Palmari V, Saccardi F et al. Evidence that metformin addition to insulin induces an amelioration of glycaemic profile in type I (insulin-dependent) diabetes mellitus. Curr Ther Res. 1984; 35:1058-64.\n117. Scapa E, Haagensen DE, Thomas P et al. Treatment of metformin-associated lactic acidosis with closed recirculation bicarbonate-buffered hemodialysis. Arch Intern Med. 1984; 144:203-5.\n118. Josephkutty S, Potter JM. Comparison of tolbutamide and metformin in elderly diabetic patients. Diabet Med. 1990; 7:510-14. http://www.ncbi.nlm.nih.gov/pubmed/2142054?dopt=AbstractPlus\n119. McLelland J. Recovery from metformin overdose. Diabet Med. 1985; 2:410-11. http://www.ncbi.nlm.nih.gov/pubmed/2951106?dopt=AbstractPlus\n120. Giugliano D, Torella R, Cacciapuoti F et al. Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol. 1980; 18:395-8. http://www.ncbi.nlm.nih.gov/pubmed/7002569?dopt=AbstractPlus\n121. Schauben J. Calcium channel blockers and insulin secretion. it/Drug Intell Clin Pharm. 1982; 16:881-2. Letter.\n122. Melchior W, Jaber L. Metformin: an antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother. 1996; 30:158-63. http://www.ncbi.nlm.nih.gov/pubmed/8835050?dopt=AbstractPlus\n123. DeFronzo RA, Goodman AM. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269-70.\n124. Bosisio E, Galli-Kienle M, Ciconali M et al. Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes. 1981; 30:644-9. http://www.ncbi.nlm.nih.gov/pubmed/7250534?dopt=AbstractPlus\n125. Arafat T, Kaddoumi A, Shami M et al. Pharmacokinetics and pharamcodynamics of two oral formulations of metformin hydrochloride. Adv Ther. 1994; 11:21-33.\n126. Brookes LG, Sambol NC, Lin ET et al. Effect of dosage form, dose and food on the pharmacokinetics of metformin. Pharm Res. 1991; 8:S320. http://www.ncbi.nlm.nih.gov/pubmed/1905809?dopt=AbstractPlus\n127. Holland B, Kaplan N. Propranolol in the treatment of hypertension. N Engl J Med. 1976; 294:930-6. http://www.ncbi.nlm.nih.gov/pubmed/1256484?dopt=AbstractPlus\n128. Merck Sharp and Dohme. Blocardren (timolol maleate) tabelts prescribing information (dated 1993 Aug). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:1614-7.\n129. Nicklin P, Keates AC, Page T et al. Transfer of metformin across monolayers of human intestinal Caco-2 cells and across rat intestine. Intl J Pharm. 1996; 128:155-62.\n130. Rett K, Wickimayr M, Dietze G et al. Hypoglycemia in hypertensive diabetic patients treated with sulfonylureas, biguanides, and captopril. N Engl J Med. 1988; 319:1609. http://www.ncbi.nlm.nih.gov/pubmed/3059189?dopt=AbstractPlus\n131. Ferriere M, Lachkar H, Richard J et al. Captopril and insulin sensitivity. Ann Intern Med. 1985; 102:134-5. http://www.ncbi.nlm.nih.gov/pubmed/3881067?dopt=AbstractPlus\n132. McMurray J, Fraser DM. Captopril, enalapril, and blood glucose. Lancet. 1986; 1:1035. http://www.ncbi.nlm.nih.gov/pubmed/2871313?dopt=AbstractPlus\n133. Passa Ph, Marre M, Leblanc H. Enalapril, captopril, and blood glucose. Lancet. 1986; 1:1447. http://www.ncbi.nlm.nih.gov/pubmed/2872551?dopt=AbstractPlus\n134. Reviewers' comments (personal observations).\n135. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. (unpublished observations).\n136. GrantPJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996; 19:64-6. http://www.ncbi.nlm.nih.gov/pubmed/8720537?dopt=AbstractPlus\n137. Dachman AH. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545. http://www.ncbi.nlm.nih.gov/pubmed/7480710?dopt=AbstractPlus\n138. Anon. Acarbose for diabetes mellitus. Med Lett Drugs Ther. 1996; 38:9-10. http://www.ncbi.nlm.nih.gov/pubmed/8559114?dopt=AbstractPlus\n139. Jackson EK. Diuretics. In: Hardman JG, Limbird LE,Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill; 1996:685-713.\n140. Molloy AM, Ardill J, Tomkin GH. The effect of metformin treatment on gastric acid secretion and gastrointestinal hormone levels in normal subjects. Diabetologia. 1980; 19:93-6. http://www.ncbi.nlm.nih.gov/pubmed/7418969?dopt=AbstractPlus\n141. Adams JF, Clar JS, Ireland JT et al. Malabsorption of vitamin B12 and intrinsic factor secretion during giguanide therapy. Diabetologia. 1983; 24:16-8. http://www.ncbi.nlm.nih.gov/pubmed/6825978?dopt=AbstractPlus\n142. Tomkin G. Metformin and B12 malabsorption. Ann Intern Med. 1972; 76:668. http://www.ncbi.nlm.nih.gov/pubmed/4640327?dopt=AbstractPlus\n143. White Jr J, Harman J, Campbell K. Drug interactions in diabetic patients. Postgrad Med. 1993; 93:131-9.\n144. Rotter A. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545-6. http://www.ncbi.nlm.nih.gov/pubmed/7480711?dopt=AbstractPlus\n145. DeFronzo RA, Bonadonna RC, Ferannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care. 1992; 15:318-68. http://www.ncbi.nlm.nih.gov/pubmed/1532777?dopt=AbstractPlus\n146. Bailey C, Turner R. Metformin. N Engl J Med. 1996; 334:574-9. http://www.ncbi.nlm.nih.gov/pubmed/8569826?dopt=AbstractPlus\n147. Oates NS, Shah RR, Idle JR et al. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther. 1983;34:827-34.\n148. Shaw S, Jayatilleke E, Bauman W et al. The mechanism of B12 malabsorption and depletion due to metformin and its Reversal with Dietary Calcium. Diabetes. 1994; 43:167A.\n149. Bailey CJ, Puah JA. Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metabol (Paris). 1986; 12:212-8.\n150. Frayn Kn, Adnitt PI. Effects of metformin on glucose uptake by isolated diaphragm from normal and diabetic rats. Biochem Pharmacol. 1972; 21:3153-62. http://www.ncbi.nlm.nih.gov/pubmed/4650637?dopt=AbstractPlus\n151. Lant A. Diuretics clinical pharmacology and therapeutic use (Part II). Drugs. 1985; 29:162-88. http://www.ncbi.nlm.nih.gov/pubmed/3884320?dopt=AbstractPlus\n152. Houston M. The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics. Am Heart J. 1988; 115:640-56. http://www.ncbi.nlm.nih.gov/pubmed/3278578?dopt=AbstractPlus\n153. Joseph J, Schuna A. Management of hypertension in the diabetic patient. Clin Pharm. 1990; 9:864-73. http://www.ncbi.nlm.nih.gov/pubmed/2272152?dopt=AbstractPlus\n154. Antidiabetic drug interactions: thiazide diuretics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:387.\n155. Angiotensin-converting enzyme inhibitor drug interactions: antidiabetics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:127.\n156. Gueriguian J, Green L, Misbin RI et al. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269. http://www.ncbi.nlm.nih.gov/pubmed/8532012?dopt=AbstractPlus\n157. Bailey CJ. Hypoglycaemic, antihyperglycaemic and antidiabetic drugs. Diabetic Med. 1992; 9:482-3. http://www.ncbi.nlm.nih.gov/pubmed/1611838?dopt=AbstractPlus\n158. Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res. 1994; 30:187-228. http://www.ncbi.nlm.nih.gov/pubmed/7862618?dopt=AbstractPlus\n159. Hurel S, Taylor R. Drugs and glucose tolerance. Adverse Drug Reaction Bulletin. 1995; 174:659-62.\n160. Pandit M, Burke J, Gustafson A et al. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993; 118:529-39. http://www.ncbi.nlm.nih.gov/pubmed/8442624?dopt=AbstractPlus\n161. Bailey CJ. Metformin-an update. Gen Pharmacol. 1993; 24:1299-309. http://www.ncbi.nlm.nih.gov/pubmed/8112499?dopt=AbstractPlus\n162. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994; 24:49-57. http://www.ncbi.nlm.nih.gov/pubmed/8165821?dopt=AbstractPlus\n163. Anon. ASHP therapeutic position statement on strict glycemic control in selected patients with insulin-dependent diabetes mellitus. Am J Health-Syst Pharm. 1995; 52:2709-11. http://www.ncbi.nlm.nih.gov/pubmed/8601269?dopt=AbstractPlus\n164. KhanIH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ. 1993; 307:1056-7. http://www.ncbi.nlm.nih.gov/pubmed/8251784?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1679237&blobtype=pdf\n165. Anon. Fatal lactic acidosis with metformin. Aust Adv Drug React Bull. 1995; 14:6-7.\n166. United Kingdom prospective diabetes study group. United Kingdom prospective diabetes study (UKPDS) 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes. 1995; 44:1240-58.\n167. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996; 30:359-71. http://www.ncbi.nlm.nih.gov/pubmed/8743335?dopt=AbstractPlus\n168. Stabler SP. Screening the older population for cobalamin (vitamin B12 deficiency. J Am Geriatrics Soc. 1995; 43:1295-6.\n169. Anon. Urine glucose and ketone determinations. Diabetes Care. 1995; 18:.\n170. Ferguson JE, Dyson DC, Holborok RH et al. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol. 1989; 161:788-95. http://www.ncbi.nlm.nih.gov/pubmed/2782362?dopt=AbstractPlus\n171. Astra. Yutopar (ritodrine hydrochloride) injection prescribing information (dated 1995 Apr). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:570-2.\n172. MacDonald IA, Bennett T, Fellows IW. Catecholamines and the control of metabolism in man. Clinical Science. 1985; 68:613-9. http://www.ncbi.nlm.nih.gov/pubmed/2485261?dopt=AbstractPlus\n173. Kendall MJ. Impact of beta1 selectivity and intrinsic sympathomimetic activity on potential unwanted noncardiovascular effects of beta blockers. Am J Cardiol. 1987; 59:44-7.\n174. Sambol NC, Chiang J, Kin ET et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol. 1995; 35:1094-102. http://www.ncbi.nlm.nih.gov/pubmed/8626883?dopt=AbstractPlus\n175. Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Clin Pharmacol. 1988; 37:4353-8.\n176. Argaud D, Roth H, Wiernsperger N et al. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem. 1993; 213:1341-8. http://www.ncbi.nlm.nih.gov/pubmed/8504825?dopt=AbstractPlus\n177. Alengrin F, Grossi G, Canivet B et al. Inhibitory effects of metformin on insulin and glucagon action in rat hepatocytes involve post-receptor alterations. Diabete Metabol (Paris). 1987; 13:591-7.\n178. Scheen AJ, Letiexhe MR, Lefèbvre PJ. Effects of metformin in obese patients with impaired glucose tolerance. Diabetes/Metabolism Reviews. 1995; 11:S69-80.\n179. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet. 1994; 95-100.\n180. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124(1 Pt 2):104-9.\n181. Ilarde A, Tuck M. Treatment of non-insulin-dependent diabetes mellitus and its complications. Drugs Aging. 1994; 4:470-91. http://www.ncbi.nlm.nih.gov/pubmed/8075474?dopt=AbstractPlus\n182. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-86. http://www.ncbi.nlm.nih.gov/pubmed/8366922?dopt=AbstractPlus\n183. Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):90-6. http://www.ncbi.nlm.nih.gov/pubmed/8554220?dopt=AbstractPlus\n184. Turner R, Cull C, Holman R et al. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):136-45. http://www.ncbi.nlm.nih.gov/pubmed/8554206?dopt=AbstractPlus\n185. Clark CM Jr. Where do we go from here? Ann Intern Med. 1996; 124(1 Part 2):184-6. Editorial.\n186. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus; a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103-17. http://www.ncbi.nlm.nih.gov/pubmed/7587918?dopt=AbstractPlus\n187. Henry RR, Genuth S. Forum One: Current recommendations about intensification of metabolic control in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):175-7. http://www.ncbi.nlm.nih.gov/pubmed/8554214?dopt=AbstractPlus\n188. Laakso M. Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus. The Finnish studies. Ann Intern Med. 1996;124(1 Pt 2):127-30.\n189. Crofford OB. Metformin. N Engl J Med. 1995; 333:588-9. http://www.ncbi.nlm.nih.gov/pubmed/7623910?dopt=AbstractPlus\n190. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993; 329:304-9. http://www.ncbi.nlm.nih.gov/pubmed/8147960?dopt=AbstractPlus\n191. The Upjohn Company. Micronase (glyburide) prescribing information. Kalamazoo, MI; 2002 Mar.\n192. Hoechst-Roussel Pharmaceuticals Inc. DiaBeta (glyburide) prescribing information. Somerville, NJ; 1987 Dec.\n193. Calle-Pascual AL, Garcia-Honduvilla J, Martin-Alvarez PJ et al. Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment. Diabete & Metabolisme (Paris). 1995; 21:256-60.\n194. Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1994; 154:2442-8. http://www.ncbi.nlm.nih.gov/pubmed/7979840?dopt=AbstractPlus\n195. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs. 1993; 46:1025-54. http://www.ncbi.nlm.nih.gov/pubmed/7510610?dopt=AbstractPlus\n196. Zimmerman BR. Preventing long term complications: implicationsfor combination therapy with acarbose. Drugs. 1992; 44:54-9. http://www.ncbi.nlm.nih.gov/pubmed/1280578?dopt=AbstractPlus\n197. Asmal AC, Marble A. Oral hypoglycaemic agents: an update. Drugs. 1984; 28:62-78. http://www.ncbi.nlm.nih.gov/pubmed/6378583?dopt=AbstractPlus\n198. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs. 1981; 22:211-45. http://www.ncbi.nlm.nih.gov/pubmed/7021124?dopt=AbstractPlus\n199. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med. 1983; 75(Suppl 5B):94-9. http://www.ncbi.nlm.nih.gov/pubmed/6369972?dopt=AbstractPlus\n200. Food and Drug Administration. Labeling for oral hypoglycemic drugs of the sulfonylurea class. [Docet No. 75N-0062] Fed Regist. 1984; 49:14303-31.\n201. Scheen AJ, Alves de Magalhaes F, Lefebvre ST et al. Reduction of metformin acute bioavailability by the alpha-glucosidase inhibitor acarbose in normal man. Eur J Clin Invest. 1993; 23(Suppl 1):A43.\n202. Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988; 260:2864-71. http://www.ncbi.nlm.nih.gov/pubmed/3184351?dopt=AbstractPlus\n203. Howanitz PJ, Howantiz JH. Carbohydrates. In: Henry JB, ed. Todd-Sanford-Davidsohn clinical diagnosis and management by laboratory methods. 17th ed. Philadelphia: WB Saunders Company; 1984:165-179.\n204. USP DI: drug information for the health care provider. 20th ed. Englewood, CO: Micromedex, Inc; 2000;1:306.\n205. Bayraktar M, Adalar N, Van Thiel DH. A comparison of acarbose versus metformin as an adjuvant therapy in sulfonylurea-treated NIDDM patients. Diabetes Care. 1996; 19:252-4. http://www.ncbi.nlm.nih.gov/pubmed/8742572?dopt=AbstractPlus\n206. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care. 1996; 19:50-2S.\n207. Sacher RA, McPherson RA, Campos JM. Glucose measurement. In: Sacher RA, McPherson RA, Campos JM, eds. Widman's clinical interpretation of laboratory tests. 10th ed. Philadelphia: FA Davis Company; 1991:323-.\n208. Saffar F, Aiache JM, Andre P. Influence of food on the disposition of the antidiabetic drug metformin in diabetic patients at steady-state. Meth Find Exp Clin Pharmacol. 1995; 17:483-7.\n209. Misbin RI, Green L, Stadel BV et al. Lactic acidosis in patients with diabetes treated with metformin. New Engl J Med. 1998; 338:265-6. http://www.ncbi.nlm.nih.gov/pubmed/9441244?dopt=AbstractPlus\n210. Nestler JE, Jakubowicz DA, Evans WS et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Engl J Med. 1998; 338:1876-80. http://www.ncbi.nlm.nih.gov/pubmed/9637806?dopt=AbstractPlus\n211. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New Wngl J Med. 1996; 335:617-23.\n212. Dunaif A, Scott D, Finegood D et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metabol. 1996; 81:3299-306.\n213. Babich MM, Pike I, Shiffman ML et al. Metformin-induced acute hepatitis. Am J Med. 1998; 104:490-2. http://www.ncbi.nlm.nih.gov/pubmed/9626034?dopt=AbstractPlus\n214. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets patient information. Princeton, NJ; 2001 Jun.\n215. Har SP, Walker JD. Is metformin contra-indicated in diabetic patients with chronic heart failure? Pract Diabetes Intern. 1996; 13:18-20.\n216. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352:854-65. http://www.ncbi.nlm.nih.gov/pubmed/9742977?dopt=AbstractPlus\n217. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust. 1998; 169:511-2.\n218. Nathan DM. Some answers, more controversy, from UKDS. Lancet. 1998; 352:832-3. http://www.ncbi.nlm.nih.gov/pubmed/9742972?dopt=AbstractPlus\n219. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-53. http://www.ncbi.nlm.nih.gov/pubmed/9742976?dopt=AbstractPlus\n220. American Diabetes Association. Position Statement: implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1999; 22(Suppl. 1):S27-S31.\n221. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; September 15, 1998. From American Diabetes Association web site (http://www.diabetes.org).\n222. Genuth P. United Kingdom prospective diabetes study results are in J Fam Pract. 1998; 47:(Suppl.5):S27.\n223. Matthews DR, Cull CA, Stratton RR et al. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over 6 years. Diabet Med. 1998; 15:297-303. http://www.ncbi.nlm.nih.gov/pubmed/9585394?dopt=AbstractPlus\n224. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med. 1998; 15:895-6. http://www.ncbi.nlm.nih.gov/pubmed/9827842?dopt=AbstractPlus\n225. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 1998; 106:369-72. http://www.ncbi.nlm.nih.gov/pubmed/9831300?dopt=AbstractPlus\n226. Morgensen CE. Combined high blood pressure and glucose in type 2 diabetes: double jeopardy. BMJ. 1998; 317:693-4. http://www.ncbi.nlm.nih.gov/pubmed/9732334?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1113869&blobtype=pdf\n227. American Diabetes Association. Consensus statement: treatment of hypertension in diabetes. Diabetes Care. 1993; 16:1394-1401. http://www.ncbi.nlm.nih.gov/pubmed/8269800?dopt=AbstractPlus\n228. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes mellitus: UKPDS 39. BMJ. 1998; 317:713-20. http://www.ncbi.nlm.nih.gov/pubmed/9732338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28660&blobtype=pdf\n229. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703-13. http://www.ncbi.nlm.nih.gov/pubmed/9732337?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28659&blobtype=pdf\n230. Genuth S, Brownless MA, Kuller LH et al. Consensus development conference on insulin resistance: November 5-6 1997. Diabetes Care. 1998; 21:310-4. http://www.ncbi.nlm.nih.gov/pubmed/9540000?dopt=AbstractPlus\n231. Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). JAMA. 1999; 281:2005-12. http://www.ncbi.nlm.nih.gov/pubmed/10359389?dopt=AbstractPlus\n232. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes. 1970; 19(Suppl 2):747-830.\n233. August K, Brooks L (California Department of Health and Human Services). State health director warns consumers about prescription drugs in herbal products. Rockville, MD; 2000 Feb 15. News release No. 09-00. News release from FDA web site (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171209.htm).\n234. Bristol-Myers-Squibb Company. Glucovance(glyburide and metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2010 May.\n235. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. http://www.ncbi.nlm.nih.gov/pubmed/10699131?dopt=AbstractPlus\n236. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000; 23(Suppl 1):S4-19.\n237. Takeda Pharmaceuticals America. Actos (pioglitazone hydrochloride) tablets prescribing information. Deerfield, IL; 2011 Jul.\n238. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24. http://www.ncbi.nlm.nih.gov/pubmed/10333912?dopt=AbstractPlus\n239. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. http://www.ncbi.nlm.nih.gov/pubmed/10454950?dopt=AbstractPlus\n240. Fonseca V,, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000; 283:1695-702. http://www.ncbi.nlm.nih.gov/pubmed/10755495?dopt=AbstractPlus\n241. Aventis Pharmaceuticals Amaryl (glimepiride) tablets 1, 2, and 4 mg prescribing information. Kansas City, MO; 2000 Apr.\n242. Pfizer. Glucotrol XL (glipizide) extended release tablets prescribing information. New York, NY; 1999 Aug.\n243. Mylan Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Morgantown, WV; 2002 Jan.\n244. Bayer Corporation. Precose (acarbose) tablets prescribing information. West Haven, CT; 2003 Mar.\n245. IVAX Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Miami, FL; 2002 Jan.\n246. PurePac Pharmaceutical Company. Metformin hydrochloride tablets prescribing information. Elizabeth, NJ; 2002 Feb.\n247. GlaxoSmithKline. Avandamet(rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2011 May.\n248. Novartis. Starlix (nateglinide) tablets prescribing information. East Hanover, NJ; 2011 Aug.\n249. Novo Nordisk. Prandin(repaglinide) tablets prescribing information. Princeton, NJ; 2009 Jun.\n250. GlaxoSmithKline. Avandia (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2011 May.\n251. Einhorn D, Rendell M, Rosenzweig J et al. Pioglitazone in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther. 2000; 22:1395-409. http://www.ncbi.nlm.nih.gov/pubmed/11192132?dopt=AbstractPlus\n252. Horton ES, Foley J, Clinkingbeard C et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-65. http://www.ncbi.nlm.nih.gov/pubmed/11092289?dopt=AbstractPlus\n253. National Institute for Clinical Excellence, National Health Service. The clinical effectiveness and cost effectiveness of rosiglitazone for type 2 diabetes mellitus: health technology report. London, United Kingdom; 2000 Aug. From the NICE web site: http://www.nice.org.uk\n254. Bristol-Myers Squibb Company. Metaglip (glipizide and metformin hydrochloride) prescribing information. Princeton, NJ; 2009 Feb.\n255. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002; 287:2563-9. http://www.ncbi.nlm.nih.gov/pubmed/12020338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2622728&blobtype=pdf\n256. Bristol Myers Squibb, Princton, NJ: Personal communications.\n257. Ranbaxy Laboratories Inc. Riomet (metformin hydrochloride) oral solution prescribing information. Jacksonville, FL; 2011 Jun.\n258. Andrx Laboratories. Fortamet (metformin hydrochloride) extended-release tablets prescribing information. Weston, FL; 2005 May.\n259. Teva Pharmaceutical USA. Metformin hydrochloride tablets 500 mg, 850 mg, and 1000 mg and metformin hydrochloride extended-release tablets 500 mg prescribing information. Sellersville, PA; 2004 Apr.\n260. Takeda Pharmaceuticals America. Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) tablets prescribing information. Lincolnshire, IL; 2011 Jul.\n261. Depomed. Glumetza (metformin hydrochloride) extended release tablets prescribing information. Menlo Park, CA; 2006 Apr.\n262. Depomed. Technology: diffusional. Available at http://www.depomedinc.com. Accessed 2006 Aug 7.\n263. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care. 2004; 27(Suppl 1):S76-78.\n264. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. http://www.ncbi.nlm.nih.gov/pubmed/16873813?dopt=AbstractPlus\n265. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical paractuce guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2003; 27(Suppl 2):S1-152.\n267. GlaxoSmithKline. Avandamet (rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2007 Aug.\n268. American Diabetes Association. Summary of revisions for the 2009 clinical practice recommendations. Diabetes Care. 2009; 32:S3-S5. http://www.ncbi.nlm.nih.gov/pubmed/19118287?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2613585&blobtype=pdf\n269. Klein S, Allison DB, Heymsfield SB et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care. 2007; 30:1647-52. http://www.ncbi.nlm.nih.gov/pubmed/17360974?dopt=AbstractPlus\n270. Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008; 358:2630-33. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18539918?dopt=AbstractPlus\n271. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321:405-12. http://www.ncbi.nlm.nih.gov/pubmed/10938048?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=27454&blobtype=pdf\n272. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus\n273. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009; 32:187-92. http://www.ncbi.nlm.nih.gov/pubmed/19092168?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2606812&blobtype=pdf\n274. , Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358:2560-72. http://www.ncbi.nlm.nih.gov/pubmed/18539916?dopt=AbstractPlus\n275. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-59. http://www.ncbi.nlm.nih.gov/pubmed/18539917?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4551392&blobtype=pdf\n276. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129-39. http://www.ncbi.nlm.nih.gov/pubmed/19092145?dopt=AbstractPlus\n277. American Diabetes Association. Aspirin therapy in diabetes: position statement. Diabetes Care. 2001; 24(Suppl.1):S62-3. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2663516&blobtype=pdf\n278. Ismail-Beigi F, Moghissi ES. Glycemia management and cardiovascular risk in type 2 diabetes: an evolving perspective. Endocr Pract. 2008 Jul-Aug; 14:639-43.\n279. Weiss IA, Valiquette G, Schwarcz MD. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev. 2009; 17(4):165-75. http://www.ncbi.nlm.nih.gov/pubmed/19525678?dopt=AbstractPlus\n280. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577-89. http://www.ncbi.nlm.nih.gov/pubmed/18784090?dopt=AbstractPlus\n281. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643-53. http://www.ncbi.nlm.nih.gov/pubmed/16371630?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2637991&blobtype=pdf\n282. Skyler JS. Non-insulin-dependent diabetes mellitus: a clinical strategy. Diabetes Care. 1984; 7(Suppl 1):118-29. http://www.ncbi.nlm.nih.gov/pubmed/6376024?dopt=AbstractPlus\n283. Defronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983; 74(Suppl 1A):52-81. http://www.ncbi.nlm.nih.gov/pubmed/6337486?dopt=AbstractPlus\n284. Metformin. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:1155-9.\n285. Hale TW, Kristensen JH, Hackett LP et al. Transfer of metformin into human milk. Diabetologia. 2002; 45(11):1509-14. http://www.ncbi.nlm.nih.gov/pubmed/12436333?dopt=AbstractPlus\n286. Briggs GG, Ambrose PJ, Nageotte MP et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005; 105(6):1437-41. http://www.ncbi.nlm.nih.gov/pubmed/15932841?dopt=AbstractPlus\n287. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2010; Issue 1. Art. No.: CD002967.\n288. Brown JB, Herson MK, Pedula K et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care. 1998; 21:1659-63. http://www.ncbi.nlm.nih.gov/pubmed/9773726?dopt=AbstractPlus\n289. Tso LO, Costello MF, Albuquerque LE et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2009, Issue 2. Art. No.: CD006105.\n290. Costello MF, Shrestha B, Eden J et al. Insulin-sensitizing drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2007, Issue 1. Art. No.: CD005552.\n291. Fedorcsák P, Dale PO, Storeng R et al. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial. Gynecol Endocrinol. 2003; 17(3):207-14.\n292. Practice Committee of the American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2004; 82 Suppl 1):S181-3. http://www.ncbi.nlm.nih.gov/pubmed/15363722?dopt=AbstractPlus\n293. Ehrmann DA. Polycystic ovary syndrome. New Engl J Med. 2005; 352:1223-36. http://www.ncbi.nlm.nih.gov/pubmed/15788499?dopt=AbstractPlus\n294. Tang T, Lord JM, Norman RJ et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro- inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews. 2010, Issue 1. Art. No.: CD003053.\n295. Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular System in polycystic ovary syndrome. Diabetes Care. 2007; 30:471-8. http://www.ncbi.nlm.nih.gov/pubmed/17327307?dopt=AbstractPlus\n296. Doldi N, Persico P, Di Sebastiano F et al. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol Endocrinol. 2006; 22(5):235-8. http://www.ncbi.nlm.nih.gov/pubmed/16785142?dopt=AbstractPlus\n297. Lobo RA. Choice of treatment for women with polycystic ovary syndrome. Fertil Steril. 2006; 86(suppl 1):S22-3. http://www.ncbi.nlm.nih.gov/pubmed/16798280?dopt=AbstractPlus\n298. Teede HJ, Meyer C, Hutchison SK et al. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril. 2010; 93:184-91. http://www.ncbi.nlm.nih.gov/pubmed/19019358?dopt=AbstractPlus\n299. Practice Committee, American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2006; 86(Suppl 4):S221-3. http://www.ncbi.nlm.nih.gov/pubmed/17055827?dopt=AbstractPlus\n300. Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009;79:671-6.\n301. Creanga AA, Bradley HM, McCormick C et al. Use of metformin in polycystic ovary syndrome. Obstet Gynecol. 2008; 111:959-68. http://www.ncbi.nlm.nih.gov/pubmed/18378757?dopt=AbstractPlus\n302. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008; 358:47-54. http://www.ncbi.nlm.nih.gov/pubmed/18172174?dopt=AbstractPlus\n303. Liu JH, Bill AH. Expanding applications for metformin in polycystic ovarian syndrome. J Pediatr. 2006; 148:573-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/16737862?dopt=AbstractPlus\n304. Urman B, Yahin K. Ovulatory disorders and infertility. J Reprod Med. 2006; 51:267-82. http://www.ncbi.nlm.nih.gov/pubmed/16737024?dopt=AbstractPlus\n305. Siebert TI, Kruger, TF, Steyn DW et al. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? Fertil Steril. 2006; 86:1432-7.\n306. Pillai AS, Bang H, Green C. Metformin & glitazones: Do they really help PCOS patients? J Fam Pract. 2007; 56:444-53.\n307. Practice Committee of the American Society for Reproductive Medicine. Use of insulin-sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2008; 90(Suppl 3):S69-73. http://www.ncbi.nlm.nih.gov/pubmed/19007650?dopt=AbstractPlus\n308. Nestler JE. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril. 2008; 90:14-6. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18550055?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2495076&blobtype=pdf\n309. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007; 356:551-66. http://www.ncbi.nlm.nih.gov/pubmed/17287476?dopt=AbstractPlus\n310. Guzick DS. Treating the polycystic ovary syndrome the old-fashioned way. N Engl J Med. 2007; 356:622-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17287483?dopt=AbstractPlus\n311. Palomba S, Orio F Jr, Falbo A et al. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92:3498-3503. http://www.ncbi.nlm.nih.gov/pubmed/17595241?dopt=AbstractPlus\n312. Barbieri RL. Clomiphene versus metformin for ovulation induction in polycystic ovary syndrome: the winner is....J Clin Endocrinol Metab. 2007; 92:3399-3401. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17823274?dopt=AbstractPlus\n313. Novo Nordisk A/S. Prandimet (repaglinide/metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2011 Sept.\n314. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2011 Apr.\n316. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care. 1999; 22:925-7. http://www.ncbi.nlm.nih.gov/pubmed/10372243?dopt=AbstractPlus\n317. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of \"metformin-associated lactic acidosis\". Diabetes Obes Metab. 2001; 3:195-201. http://www.ncbi.nlm.nih.gov/pubmed/11412284?dopt=AbstractPlus\n318. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med. 2003; 163:2594-2602. http://www.ncbi.nlm.nih.gov/pubmed/14638559?dopt=AbstractPlus\n319. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99. http://www.ncbi.nlm.nih.gov/pubmed/17638715?dopt=AbstractPlus\n320. Tahrani AA, Varughese GI, Scarpello JH et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? Br Med J. 2007; 335:508-12.\n321. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004; 27:1791-3. Commentary. http://www.ncbi.nlm.nih.gov/pubmed/15220268?dopt=AbstractPlus\n322. Bodmer M, Jick SS, Meier C et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia. Diabetes Care. 2008; 31:2086-91. http://www.ncbi.nlm.nih.gov/pubmed/18782901?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2571051&blobtype=pdf\n323. US Food and Drug Administration. FDA significantly restricts access to the diabetes drug Avandia. Rockville, MD; 2010 Sep 23. News release from FDA web site. Accessed 2010 Nov 15. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226975\n324. Woodcock J (US Food and Drug Administration). Decision on continued marketing of rosiglitazone (Avandia, Avandamet, Avandaryl). Rockville, MD; Available at FDA website. Accessed 2010 Nov 15. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM226959.pdf\n325. Food and Drug Administration. FDA drug safety communication: Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. Rockville, MD; 2011 May 18. Available from FDA website. Accessed 2011 Jun 20. http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm\n326. Avandia (rosiglitazone maleate), Avandamet (rosiglitazone maleate and metformin hydrochloride), and Avandaryl (rosiglitazone maleate and glimepiride) tablets risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2011 Aug 25. http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm255624.pdf\n327. Food and Drug Administration. FDA advisory committee meeting briefing document for NDA 21071 Avandia (rosiglitazone maleate). Rockville, MD; July 13 and 14, 2010. From FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf\n328. Lipska KJ, Ross JS. Switching from rosiglitazone: thinking outside the class. JAMA. 2011; 305:820-1. http://www.ncbi.nlm.nih.gov/pubmed/21304068?dopt=AbstractPlus\n330. Food and Drug Administration. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Silver Spring, MD; 2016 Apr 8. Available from FDA website. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf\n331. Rachmani R, Slavachevski I, Levi Z et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002; 13:428. http://www.ncbi.nlm.nih.gov/pubmed/12384131?dopt=AbstractPlus\n332. Kamber N, Davis WA, Bruce DG et al. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust. 2008; 188:446-9. http://www.ncbi.nlm.nih.gov/pubmed/18429709?dopt=AbstractPlus\n333. Roussel R, Travert F, Pasquet B et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010; 170:1892-9. http://www.ncbi.nlm.nih.gov/pubmed/21098347?dopt=AbstractPlus\n334. Ekström N, Schiöler L, Svensson AM et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012; 2:. http://www.ncbi.nlm.nih.gov/pubmed/22798258?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3400073&blobtype=pdf\n335. American College of Radiology (ACR) Committee on Drugs and Contrast Media. ACR manual on contrast media: metformin. 2016. Available at ACR website. Accessed 2016 Aug 4. http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/Contrast%20Manual/2016_Contrast_Media.pdf\n336. . In brief: New recommendations for use of metformin in renal impairment. Med Lett Drugs Ther. 2016; 58:51.\n340. Inker LA, Astor BC, Fox CH et al. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD. AM J Kidney Dis. 2014; 63(5):713-35. http://www.ncbi.nlm.nih.gov/pubmed/24647050?dopt=AbstractPlus\n341. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. AM J Kidney Dis. 2012; 60(5):850-86. http://www.ncbi.nlm.nih.gov/pubmed/23067652?dopt=AbstractPlus\n350. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) prescribing information. Princeton, NJ; 2018 May.\n351. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) patient information. Princeton, NJ; 2018 May.\n352. Merck. Janumet XR (sitagliptin/extended-release metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Feb.\n355. Merck. Segluromet (ertugliflozin and metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Oct.\n360. Richy FF, Sabidó-Espin M, Guedes S et al. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care. 2014; 37:2291-5. http://www.ncbi.nlm.nih.gov/pubmed/24879835?dopt=AbstractPlus\n361. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014; 371:2309-19. http://www.ncbi.nlm.nih.gov/pubmed/25494270?dopt=AbstractPlus\n362. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) tablets prescribing information. Wilmington, DE; 2018 Oct.\n363. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) medication guide. Wilmington, DE; 2018 Oct.\n368. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets prescribing information. Wilmington, DE; 2014 Jun.\n369. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets medication guide. Wilmington, DE; 2014 Jun.\n370. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) tablets prescribing information. Titusville, NJ; 2018 Oct.\n371. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) medication guide. Titusville, NJ; 2018 Oct.\n372. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2018 Oct.\n373. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) medication guide. Ridgefield, CT; 2018 Oct.\n374. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) tablets prescribing information. Ridgefield, CT; 2018 Oct.\n375. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) medication guide. Ridgefield, CT; 2018 Oct.\n376. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2017 Aug.\n377. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2017 Aug.\n378. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2019 Jul.\n379. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2019 Jul.\n598. Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endorinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019; 25:69-100. http://www.ncbi.nlm.nih.gov/pubmed/30742570?dopt=AbstractPlus\n602. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S61-S70. http://www.ncbi.nlm.nih.gov/pubmed/30559232?dopt=AbstractPlus\n604. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S90-S102. http://www.ncbi.nlm.nih.gov/pubmed/30559235?dopt=AbstractPlus\n605. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S103-S123. http://www.ncbi.nlm.nih.gov/pubmed/30559236?dopt=AbstractPlus\n609. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S165-S172. http://www.ncbi.nlm.nih.gov/pubmed/30559240?dopt=AbstractPlus\n610. Takeda. Kazano (alogliptin and metformin hydrochloride) tablets, for oral use, prescribing information. Deerfield, IL; 2019 Jun.\n611. Nauck MA, Ellis GC, Fleck PR et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. 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"Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia\nRecruitment Status : Active, not recruiting\nResults First Posted : February 6, 2017\nLast Update Posted : August 18, 2021\nAlliance for Clinical Trials in Oncology\nNational Cancer Institute (NCI)\nNovartis Pharmaceuticals\nThe purpose of this study is to compare the effects, good and/or bad, of a standard chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined with or without midostaurin (also known as PKC412), to find out which is better. This research is being done because it is unknown whether the addition of midostaurin to chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been tested in over 400 patients and is being studied in a number of illnesses, including AML, colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells with the abnormal FLT3 gene.\nLeukemia Drug: cytarabine Drug: daunorubicin Drug: midostaurin Other: placebo Drug: dexamethasone acetate Phase 3\nShow detailed description\nHide detailed description\nIn this study, patients will receive either the experimental agent (midostaurin) or placebo combined with chemotherapy treatment. Patients are stratified according to FLT3 mutation status (internal tandem duplication [ITD] allelic ratio < 0.7 vs ITD allelic ratio ≥ 0.7 vs tandem kinase domain [TKD]). There are three parts to the study treatment: remission induction therapy, remission consolidation therapy and continuation therapy.\nRemission Induction Therapy:\nCytarabine 200 mg/m2/day by continuous intravenous infusion on days 1-7\nDaunorubicin 60 mg/m2/day by intravenous push or short infusion on days 1-3\nMidostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a day by mouth on days 8-21\nA bone marrow aspiration will be performed in all patients on Day 21 to determine the need for a second induction cycle.\nRemission Consolidation (Four Remission Consolidation Cycles):\nHigh dose cytarabine 3000 mg/m2 will be given by intravenous infusion over 3 hours every 12 hours on days 1, 3 and 5. Serial neurologic evaluation will be performed before and following the infusion of high-dose cytarabine.\nDexamethasone 0.1% or other corticosteroid ophthalmic solution 2 drops to each eye once daily to begin 6-12 hours prior to the initiation of the cytarabine infusion and to continue for at least 24 hours after the last cytarabine dose.\nMidostaurin/Placebo Continuation Therapy:\nMidostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) by mouth twice a day for 28 days. Each cycle will be 28 days in length. Continuation therapy with midostaurin/placebo will continue until relapse or for 12 cycles maximum.\nThe primary and secondary objectives of this study are:\nPrimary objective:\nTo determine if the addition of midostaurin to daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and continuation therapy improves overall survival (OS) in both the mutant FLT3-ITD and FLT3-TKD AML patients\nSecondary objectives:\nTo compare the overall survival (OS) in the two groups using an analysis in which patients who receive a stem cell transplant are censored at the time of transplant\nTo compare the complete response (CR) rate between the two treatment groups\nTo compare the event-free survival (EFS) between the two treatment groups\nTo compare the disease free survival (DFS) of the two treatment groups\nTo compare the disease free survival rate one year after completion of the continuation phase of the two groups\nTo assess the toxicity of the experimental combination\nTo describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, white blood cell (WBC) count, morphology, cytogenetics, and molecular and pharmacodynamic features\nTo assess the population pharmacokinetics (popPK) of midostaurin and its two major metabolites (CGP52421 and CGP62221). The potential association(s) between PK exposure and FLT3 status, OS, EFS and clinical response will be explored\nThere is a pharmacokinetic sub-study (CALGB 60706) within CALGB 10603. This embedded companion study must be offered to all patients enrolled on CALGB 10603, although patients may opt not to participate in CALGB 60706.\nAfter study entry, patients are followed periodically for up to 10 years.\nAllocation: Randomized\nIntervention Model: Parallel Assignment\nMasking: Double (Participant, Investigator)\nOfficial Title: A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)\nActual Study Start Date : April 2008\nActual Primary Completion Date : July 2016\nMedlinePlus Genetics related topics: Familial acute myeloid leukemia with mutated CEBPA Cytogenetically normal acute myeloid leukemia Core binding factor acute myeloid leukemia\nMedlinePlus related topics: Acute Myeloid Leukemia Leukemia\nDrug Information available for: Cytarabine Daunorubicin Daunorubicin hydrochloride Midostaurin\nGenetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Acute Graft Versus Host Disease Acute Monoblastic Leukemia Acute Myelomonocytic Leukemia Acute Erythroid Leukemia Di Guglielmo's Syndrome Acute Megakaryoblastic Leukemia Acute Myeloblastic Leukemia Without Maturation Acute Myeloblastic Leukemia With Maturation\nExperimental: Induction and consolidation chemotherapy plus midostaurin\nPatients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and the experimental drug midostaurin. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with the experimental drug midostaurin. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with midostaurin for twelve (12) months.\nDrug: cytarabine\nGiven IV\nDrug: daunorubicin\nDrug: midostaurin\nGiven orally\nDrug: dexamethasone acetate\nocular medication administration\nActive Comparator: Induction and consolidation chemotherapy plus placebo\nPatients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and placebo. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with placebo. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with placebo for twelve (12) months.\nOther: placebo\nOverall Survival (OS) [ Time Frame: Duration of study (Up to 10 years) ]\nOverall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.\nEvent- Free Survival [ Time Frame: Duration of study (Up to 10 years) ]\nEvent free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a CR on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method.\nDue to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint.\nOverall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant [ Time Frame: Duration of study (Up to 10 years) ]\nOverall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method.\nComplete Response Rate [ Time Frame: Induction therapy (up to 60 days) ]\nPercentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60.\nDisease-free Survival (DFS) [ Time Frame: Duration of study (Up to 10 years) ]\nDisease free survival (DFS) is defined as the time from documentation of first CR at any time to the first of relapse or death from any cause in participants who achieved a CR.\nDFS Rate One Year After Completing the Planned Continuation Phase [ Time Frame: 30 months ]\nAges Eligible for Study: 18 Years to 59 Years (Adult)\nDocumentation of Disease:\nUnequivocal diagnosis of AML ( > 20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia). Patients with neurologic symptoms suggestive of CNS leukemia are recommended to have a lumbar puncture. Patients whose CSF is positive for AML blasts are not eligible.\nDocumented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol- designated FLT3 screening laboratory.\nAge Requirement:\nAge ≥ 18 and < 60 years\nPrior Therapy:\nNo prior chemotherapy for leukemia or myelodysplasia with the following exceptions:\nemergency leukapheresis\nemergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days\ncranial RT for CNS leukostasis (one dose only)\ngrowth factor/cytokine support\nAML patients with a history of antecedent myelodysplasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g., azacitidine or decitabine)\nPatients who have developed therapy related AML after prior RT or chemotherapy for another cancer or disorder are not eligible.\nCardiac Function: Patients with symptomatic congestive heart failure are not eligible.\nInitial Laboratory Value: Total bilirubin < 2.5 x ULN (Upper Limit of Normal)\nPregnancy and Nursing Status:\nNon-pregnant and non-nursing due to the unknown teratogenic potential of midostaurin in humans, pregnant or nursing patients may not be enrolled.\nWomen of childbearing potential must have a negative serum or urine pregnancy test within a sensitivity of at least 50 mIU/mL within 16 days prior to registration.\nWomen of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or commit to TWO acceptable methods of birth control:\none highly effective method (eg, IUD, hormonal (non-oral contraceptive), tubal ligation, or partner's vasectomy) and\none additional effective method (e.g., latex condom, diaphragm or cervical cap)\nThe two acceptable methods of birth control must be used AT THE SAME TIME, before beginning midostaurin/placebo therapy and continuing for 12 weeks after completion of all therapy.\nNote that oral contraceptives are not considered a high effective method because of the possibility of a drug interaction with midostaurin.\nWomen of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has not had menses at any time in the preceding 24 consecutive months.\nMen must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking midostaurin/placebo and for 12 weeks after therapy is stopped, even if they have undergone a successful vasectomy.\nShow 176 study locations Hide 176 study locations\nUnited States, Alabama\nUAB Comprehensive Cancer Center\nBirmingham, Alabama, United States, 35294\nUnited States, Arkansas\nArkansas Cancer Research Center at University of Arkansas for Medical Sciences\nLittle Rock, Arkansas, United States, 72205\nUniversity of California Davis Cancer Center\nSacramento, California, United States, 95817\nUnited States, Colorado\nAurora Presbyterian Hospital\nAurora, Colorado, United States, 80012\nBoulder Community Hospital\nBoulder, Colorado, United States, 80301-9019\nPenrose Cancer Center at Penrose Hospital\nColorado Springs, Colorado, United States, 80933\nSt. Anthony Central Hospital\nDenver, Colorado, United States, 80204\nPorter Adventist Hospital\nPresbyterian - St. Luke's Medical Center\nSt. Joseph Hospital\nRose Medical Center\nCCOP - Colorado Cancer Research Program\nDenver, Colorado, United States, 80224-2522\nSwedish Medical Center\nEnglewood, Colorado, United States, 80110\nNorth Colorado Medical Center\nGreeley, Colorado, United States, 80631\nSky Ridge Medical Center\nLone Tree, Colorado, United States, 80124\nHope Cancer Care Center at Longmont United Hospital\nLongmont, Colorado, United States, 80501\nMcKee Medical Center\nLoveland, Colorado, United States, 80539\nNorth Suburban Medical Center\nThornton, Colorado, United States, 80229\nExempla Lutheran Medical Center\nWheat Ridge, Colorado, United States, 80033\nUnited States, Connecticut\nHelen and Harry Gray Cancer Center at Hartford Hospital\nHartford, Connecticut, United States, 06102-5037\nUnited States, Delaware\nTunnell Cancer Center at Beebe Medical Center\nLewes, Delaware, United States, 19958\nCCOP - Christiana Care Health Services\nNewark, Delaware, United States, 19713\nUnited States, Florida\nUniversity of Florida Shands Cancer Center\nGainesville, Florida, United States, 32610-0232\nMemorial Cancer Institute at Memorial Regional Hospital\nHollywood, Florida, United States, 33021\nBaptist Cancer Institute - Jacksonville\nJacksonville, Florida, United States, 32207\nFlorida Hospital Cancer Institute at Florida Hospital Orlando\nOrlando, Florida, United States, 32803-1273\nH. Lee Moffitt Cancer Center and Research Institute at University of South Florida\nTampa, Florida, United States, 33612-9497\nUnited States, Georgia\nMBCCOP - Medical College of Georgia Cancer Center\nAugusta, Georgia, United States, 30912\nCharles B. Eberhart Cancer Center at DeKalb Medical Center\nDecatur, Georgia, United States, 30033\nMedical Center of Central Georgia\nMacon, Georgia, United States, 31208\nNancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler\nSavannah, Georgia, United States, 31405\nUnited States, Hawaii\nCancer Research Center of Hawaii\nHonolulu, Hawaii, United States, 96813\nQueen's Cancer Institute at Queen's Medical Center\nUnited States, Illinois\nIllinois CancerCare - Bloomington\nBloomington, Illinois, United States, 61701\nRobert H. Lurie Comprehensive Cancer Center at Northwestern University\nChicago, Illinois, United States, 60611-3013\nUniversity of Chicago Cancer Research Center\nDecatur Memorial Hospital Cancer Care Institute\nDecatur, Illinois, United States, 62526\nCardinal Bernardin Cancer Center at Loyola University Medical Center\nMaywood, Illinois, United States, 60153\nBroMenn Regional Medical Center\nNormal, Illinois, United States, 61761\nOncology Hematology Associates of Central Illinois, PC - Peoria\nPeoria, Illinois, United States, 61615\nMethodist Medical Center of Illinois\nUnited States, Indiana\nFort Wayne Medical Oncology and Hematology\nFort Wayne, Indiana, United States, 46845\nUnited States, Iowa\nMcFarland Clinic, PC\nAmes, Iowa, United States, 50010\nHolden Comprehensive Cancer Center at University of Iowa\nIowa City, Iowa, United States, 52242-1002\nSiouxland Hematology-Oncology Associates, LLP\nSioux City, Iowa, United States, 51101\nMercy Medical Center - Sioux City\nSt. Luke's Regional Medical Center\nUnited States, Kentucky\nLucille P. Markey Cancer Center at University of Kentucky\nLexington, Kentucky, United States, 40536-0093\nUnited States, Louisiana\nTulane Cancer Center Office of Clinical Research\nAlexandria, Louisiana, United States, 71315-3198\nFeist-Weiller Cancer Center at Louisiana State University Health Sciences\nShreveport, Louisiana, United States, 71130-3932\nGreenebaum Cancer Center at University of Maryland Medical Center\nUnited States, Massachusetts\nBoston, Massachusetts, United States, 02114\nDana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute\nBoston University Cancer Research Center\nBaystate Regional Cancer Program at D'Amour Center for Cancer Care\nSpringfield, Massachusetts, United States, 01199\nUnited States, Michigan\nBattle Creek Health System Cancer Care Center\nBattle Creek, Michigan, United States, 49017\nMecosta County Medical Center\nBig Rapids, Michigan, United States, 49307\nButterworth Hospital at Spectrum Health\nGrand Rapids, Michigan, United States, 49503\nCCOP - Grand Rapids\nLacks Cancer Center at Saint Mary's Health Care\nBorgess Medical Center\nKalamazoo, Michigan, United States, 49001\nWest Michigan Cancer Center\nKalamazoo, Michigan, United States, 49007-3731\nBronson Methodist Hospital\nProvidence Cancer Institute at Providence Hospital - Southfield Campus\nSouthfield, Michigan, United States, 48075\nMunson Medical Center\nTraverse City, Michigan, United States, 49684\nMetro Health Hospital\nWyoming, Michigan, United States, 49519\nUnited States, Minnesota\nFairview Ridges Hospital\nBurnsville, Minnesota, United States, 55337\nMercy and Unity Cancer Center at Mercy Hospital\nCoon Rapids, Minnesota, United States, 55433\nFairview Southdale Hospital\nEdina, Minnesota, United States, 55435\nMercy and Unity Cancer Center at Unity Hospital\nFridley, Minnesota, United States, 55432\nHealthEast Cancer Care at St. John's Hospital\nMaplewood, Minnesota, United States, 55109\nMinnesota Oncology Hematology, PA - Maplewood\nVirginia Piper Cancer Institute at Abbott - Northwestern Hospital\nMinneapolis, Minnesota, United States, 55407\nHennepin County Medical Center - Minneapolis\nMasonic Cancer Center at University of Minnesota\nHubert H. Humphrey Cancer Center at North Memorial Outpatient Center\nRobbinsdale, Minnesota, United States, 55422-2900\nMayo Clinic Cancer Center\nRochester, Minnesota, United States, 55905\nCCOP - Metro-Minnesota\nSaint Louis Park, Minnesota, United States, 55416\nPark Nicollet Cancer Center\nRegions Hospital Cancer Care Center\nSaint Paul, Minnesota, United States, 55101\nUnited Hospital\nRidgeview Medical Center\nWaconia, Minnesota, United States, 55387\nMinnesota Oncology Hematology, PA - Woodbury\nWoodbury, Minnesota, United States, 55125\nUnited States, Mississippi\nUniversity of Mississippi Cancer Clinic\nJackson, Mississippi, United States, 39216\nUnited States, Missouri\nEllis Fischel Cancer Center at University of Missouri - Columbia\nColumbia, Missouri, United States, 65203\nSiteman Cancer Center at Barnes-Jewish Hospital - Saint Louis\nSaint Louis, Missouri, United States, 63110\nUnited States, Nebraska\nUNMC Eppley Cancer Center at the University of Nebraska Medical Center\nOmaha, Nebraska, United States, 68198-6805\nUnited States, Nevada\nUniversity Medical Center of Southern Nevada\nLas Vegas, Nevada, United States, 89102\nCCOP - Nevada Cancer Research Foundation\nSunrise Hospital and Medical Center\nUnited States, New Hampshire\nNorris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center\nLebanon, New Hampshire, United States, 03756-0002\nUnited States, New Mexico\nUniversity of New Mexico Cancer Center\nAlbuquerque, New Mexico, United States, 87131-5636\nUnited States, New York\nBuffalo, New York, United States, 14263-0001\nMonter Cancer Center of the North Shore-LIJ Health System\nLake Success, New York, United States, 11042\nCCOP - North Shore University Hospital\nManhasset, New York, United States, 11030\nDon Monti Comprehensive Cancer Center at North Shore University Hospital\nTucker Center for Cancer Care at Orange Regional Medical Center\nMiddletown, New York, United States, 10940-4199\nWinthrop University Hospital\nMineola, New York, United States, 11501\nNew Hyde Park, New York, United States, 11040\nNew York Weill Cornell Cancer Center at Cornell University\nNew York, New York, United States, 10021\nMount Sinai Medical Center\nJames P. Wilmot Cancer Center at University of Rochester Medical Center\nRochester, New York, United States, 14642\nSUNY Upstate Medical University Hospital\nSyracuse, New York, United States, 13210\nUnited States, North Carolina\nLineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill\nChapel Hill, North Carolina, United States, 27599-7295\nBlumenthal Cancer Center at Carolinas Medical Center\nCharlotte, North Carolina, United States, 28232-2861\nDuke Comprehensive Cancer Center\nDurham, North Carolina, United States, 27710\nLeo W. Jenkins Cancer Center at ECU Medical School\nGreenville, North Carolina, United States, 27834\nKinston Medical Specialists\nKinston, North Carolina, United States, 28501\nWake Forest University Comprehensive Cancer Center\nWinston-Salem, North Carolina, United States, 27157-1096\nSumma Center for Cancer Care at Akron City Hospital\nAkron, Ohio, United States, 44309-2090\nBarberton Citizens Hospital\nBarberton, Ohio, United States, 44203\nCharles M. Barrett Cancer Center at University Hospital\nCincinnati, Ohio, United States, 45267\nArthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center\nColumbus, Ohio, United States, 43210-1240\nSt. Rita's Medical Center\nLima, Ohio, United States, 45801\nUnited States, Oklahoma\nCleo Craig Cancer Research Clinic\nLawton, Oklahoma, United States, 73505\nOklahoma University Cancer Institute\nOklahoma City, Oklahoma, United States, 73104\nUnited States, Pennsylvania\nGeisinger Cancer Institute at Geisinger Health\nDanville, Pennsylvania, United States, 17822-0001\nGeisinger Hazleton Cancer Center\nHazleton, Pennsylvania, United States, 18201\nPenn State Hershey Cancer Institute at Milton S. Hershey Medical Center\nHershey, Pennsylvania, United States, 17033-0850\nWestern Pennsylvania Cancer Institute at Western Pennsylvania Hospital\nPittsburgh, Pennsylvania, United States, 15224-1791\nUPMC Cancer Centers\nPittsburgh, Pennsylvania, United States, 15232\nGeisinger Medical Group - Scenery Park\nState College, Pennsylvania, United States, 16801\nFrank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center\nWilkes-Barre, Pennsylvania, United States, 18711\nUnited States, South Carolina\nHollings Cancer Center at Medical University of South Carolina\nCharleston, South Carolina, United States, 29425\nCancer Centers of the Carolinas - Easley\nEasley, South Carolina, United States, 29640\nCancer Centers of the Carolinas - Faris Road\nGreenville, South Carolina, United States, 29605\nCancer Centers of the Carolinas - Grove Commons\nGreenville Hospital Cancer Center\nCCOP - Greenville\nSelf Regional Cancer Center at Self Regional Medical Center\nGreenwood, South Carolina, United States, 29646\nCancer Centers of the Carolinas - Greer Medical Oncology\nGreer, South Carolina, United States, 29650\nCancer Centers of the Carolinas - Seneca\nSeneca, South Carolina, United States, 29672\nCancer Centers of the Carolinas - Spartanburg\nSpartanburg, South Carolina, United States, 29307\nUnited States, South Dakota\nAvera Cancer Institute\nSioux Falls, South Dakota, United States, 57105\nSanford Cancer Center at Sanford USD Medical Center\nSioux Falls, South Dakota, United States, 57117-5039\nUnited States, Tennessee\nUniversity of Tennessee Cancer Institute - Memphis\nMemphis, Tennessee, United States, 38104\nTennessee Oncology, PLLC at Sarah Cannon Cancer Center\nNashville, Tennessee, United States, 37203\nVanderbilt-Ingram Cancer Center\nNashville, Tennessee, United States, 37232-6838\nUnited States, Texas\nBaylor University Medical Center - Houston\nHouston, Texas, United States, 77030\nBen Taub General Hospital\nVeterans Affairs Medical Center - Houston\nUnited States, Vermont\nMountainview Medical\nBerlin, Vermont, United States, 05602\nFletcher Allen Health Care - University Health Center Campus\nBurlington, Vermont, United States, 05401\nUnited States, Virginia\nVirginia Commonwealth University Massey Cancer Center\nRichmond, Virginia, United States, 23298-0037\nUnited States, West Virginia\nWest Virginia University Health Sciences Center - Charleston\nCharleston, West Virginia, United States, 25304\nMary Babb Randolph Cancer Center at West Virginia University Hospitals\nMorgantown, West Virginia, United States, 26506\nUnited States, Wisconsin\nMarshfield Clinic - Chippewa Center\nChippewa Falls, Wisconsin, United States, 54729\nCenter for Cancer Treatment & Prevention at Sacred Heart Hospital\nEau Claire, Wisconsin, United States, 54701\nMarshfield Clinic Cancer Care at Regional Cancer Center\nGreen Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center\nGreen Bay, Wisconsin, United States, 54301-3526\nGreen Bay Oncology, Limited at St. Mary's Hospital\nGreen Bay, Wisconsin, United States, 54303\nSt. Mary's Hospital Medical Center - Green Bay\nSt. Vincent Hospital Regional Cancer Center\nUniversity of Wisconsin Paul P. Carbone Comprehensive Cancer Center\nMadison, Wisconsin, United States, 53792-6164\nHoly Family Memorial Medical Center Cancer Care Center\nManitowoc, Wisconsin, United States, 54221-1450\nBay Area Cancer Care Center at Bay Area Medical Center\nMarinette, Wisconsin, United States, 54143\nMarshfield Clinic - Marshfield Center\nMarshfield, Wisconsin, United States, 54449\nSaint Joseph's Hospital\nMarshfield Clinic - Lakeland Center\nMinocqua, Wisconsin, United States, 54548\nD.N. Greenwald Center\nMukwonago, Wisconsin, United States, 53149\nRegional Cancer Center at Oconomowoc Memorial Hospital\nOconomowoc, Wisconsin, United States, 53066\nMinistry Medical Group at Saint Mary's Hospital\nRhinelander, Wisconsin, United States, 54501\nMarshfield Clinic - Indianhead Center\nRice Lake, Wisconsin, United States, 54868\nMarshfield Clinic at Saint Michael's Hospital\nStevens Point, Wisconsin, United States, 54481\nWaukesha Memorial Hospital Regional Cancer Center\nWaukesha, Wisconsin, United States, 53188\nMarshfield Clinic - Weston Center\nWeston, Wisconsin, United States, 54476\nMinistry Saint Clare's Hospital\nMarshfield Clinic - Wisconsin Rapids Center\nWisconsin Rapids, Wisconsin, United States, 54494\nCanada, Alberta\nTom Baker Cancer Centre - Calgary\nCalgary, Alberta, Canada, T2N 4N2\nCanada, Manitoba\nCancerCare Manitoba\nWinnipeg, Manitoba, Canada, R3E 0V9\nCanada, Nova Scotia\nNova Scotia Cancer Centre\nHalifax, Nova Scotia, Canada, B3H 1V8\nCanada, Ontario\nPrincess Margaret Hospital\nToronto, Ontario, Canada, M5G 2M9\nCanada, Quebec\nMaisonneuve-Rosemont Hospital\nMontreal, Quebec, Canada, H1T 2M4\nMcGill Cancer Centre at McGill University\nMontreal, Quebec, Canada, H2W 1S6\nStudy Chair: Richard M. Stone, MD Dana-Farber Cancer Institute\nPublications of Results:\nStone RM, Dohner H, Ehninger G, et al.: CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. [Abstract] J Clin Oncol 29 (Suppl 15): A-TPS199, 2011.\nPublications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):\nVoso MT, Larson RA, Jones D, Marcucci G, Prior T, Krauter J, Heuser M, Lavorgna S, Nomdedeu J, Geyer SM, Walker A, Wei AH, Sierra J, Sanz MA, Brandwein JM, de Witte TM, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Amadori S, Cheng Y, Chen Y, Pallaud C, Du L, Piciocchi A, Ehninger G, Byrd J, Thiede C, Dohner K, Stone RM, Dohner H, Bloomfield CD, Lo-Coco F. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. 2020 Oct 13;4(19):4945-4954. doi: 10.1182/bloodadvances.2020002904.\nWalker CJ, Kohlschmidt J, Eisfeld AK, Mrozek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.\nYin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, Mandrekar SJ. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019 Jun 11;3(11):1714-1721. doi: 10.1182/bloodadvances.2018026112.\nStein E, Xie J, Duchesneau E, Bhattacharyya S, Vudumula U, Ndife B, Bonifacio G, Guerin A, Li N, Joseph G. Cost Effectiveness of Midostaurin in the Treatment of Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in the United States. Pharmacoeconomics. 2019 Feb;37(2):239-253. doi: 10.1007/s40273-018-0732-4.\nStone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23.\nStone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, Cortes J, Kantarjian HM, DeAngelo DJ, Huntsman-Labed A, Dutreix C, del Corral A, Giles F. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012 Sep;26(9):2061-8. doi: 10.1038/leu.2012.115. Epub 2012 Apr 27.\nResponsible Party: Alliance for Clinical Trials in Oncology\nOther Study ID Numbers: CALGB-10603\nCALGB-10603\nEUDRACT-2006-006852-37\nCDR0000590404 ( Registry Identifier: Phyisician Data Query )\nResults First Posted: February 6, 2017\nLast Update Posted: August 18, 2021\nLast Verified: August 2021\nKeywords provided by Alliance for Clinical Trials in Oncology:\nadult acute basophilic leukemia\nadult acute eosinophilic leukemia\nadult acute lymphoblastic leukemia\nadult acute megakaryoblastic leukemia (M7)\nadult acute minimally differentiated myeloid leukemia (M0)\nadult acute monoblastic leukemia (M5a)\nadult acute monocytic leukemia (M5b)\nadult acute myeloblastic leukemia with maturation (M2)\nadult acute myeloblastic leukemia without maturation (M1)\nadult acute myeloid leukemia with 11q23 (MLL) abnormalities\nadult acute myeloid leukemia with inv(16)(p13;q22)\nadult acute myeloid leukemia with t(16;16)(p13;q22)\nadult acute myeloid leukemia with t(8;21)(q22;q22)\nadult acute myelomonocytic leukemia (M4)\nadult erythroleukemia (M6a)\nadult pure erythroid leukemia (M6b)\nuntreated adult acute myeloid leukemia\nLeukemia, Myeloid\nLeukemia, Myeloid, Acute\nNeoplasms by Histologic Type\nDexamethasone acetate\nBB 1101\nAnti-Inflammatory Agents\nAntiemetics\nAutonomic Agents\nPeripheral Nervous System Agents\nPhysiological Effects of Drugs\nGastrointestinal Agents\nGlucocorticoids\nHormones, Hormone Substitutes, and Hormone Antagonists\nAntineoplastic Agents, Hormonal\nAntineoplastic Agents\nAntimetabolites\nMolecular Mechanisms of Pharmacological Action\nAntiviral Agents\nAnti-Infective Agents\nImmunosuppressive Agents\nImmunologic Factors\nAntibiotics, Antineoplastic"

"Acute myeloid leukaemia induction/consolidation (Lowenberg) SUPERSEDED\nID: 3351 v.2\nEssential Medicine List EML\nAll antineoplastic drugs and essential supportive drugs in this protocol are included on the World Health Organisation (WHO) Model List of Essential Medicines (21st List June 2019).\nSelect link for more information and access to the full WHO Model List of Essential Medicines.\nThis protocol has been superseded as it is not considered best practice for this patient population. AML Induction 7-3 (cytarabine and DAUNOrubicin) is the preferred regimen.\nPatients with leukaemia should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.\nThere are a number of AML induction 7-3 protocols available on eviQ each of which have subtle differences in doses of the chemotherapy agents. Please check the doses to ensure you are viewing the correct protocol with your intended dosing schedule.\nThis protocol is not exportable and does not have a calculator.\nThe original paper was published with a dosage error which stated cytarabine be administered once daily in cycle two. This was amended in 2010 to the correct dose of twice daily cytarabine. Please see Erratum to N Engl J Med. 2009 Sep 24;361(13):1235-48 for details.\nTreatment schedule\nIndications and patient population\nDose modifications\nAdministration c1\nTreatment schedule Treatment schedule\nDAUNOrubicin 90 mg/m2 IV 1 to 3\nCytarabine (Ara-C) 200 mg/m2 CIV 1 to 7\nCytarabine (Ara-C) 1,000 mg/m2 TWICE a day IV infusion 1 to 6\nSecond cycle to commence upon haematological recovery as per clinician's discretion\nCycles:\n2 (i.e. 1 x cycle 1 and 1 x cycle 2)\nPatients then went onto another form of post consolidation therapy which included allogeneic transplant or other alternatives. If this protocol is to be used, the clinician will need a plan of how to proceed in patients in complete remission after cycles 1 and 2 above.\nDaunorubicin was administered over 3 hours in the Lowenberg et al trial.r However in this protocol daunorubicin IV is administered over 5 to 15 minutes as per clinical practice.\nDrug status:\nCytarabine is on the PBS general schedule\nDaunorubicin is TGA registered but not PBS listed for this indication\n~ $7,120 (cycle 1); ~$ 2,330 (cycle 2) \"How this cost is calculated\"\nThe cost displayed on the protocol is intended as rudimentary guide only for the Australian context.\nThe cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.\nDrug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.\nWhere there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.\nThe protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.\nOne off loading doses are not included in protocol cost calculations.\nThe cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.\nThe supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.\nAntiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.\nDAUNOrubicin 90 mg/m2 (IV) over 5 to 15 minutes\nCytarabine (Ara-C) 200 mg/m2 (CIV) in sodium chloride 0.9% over 24 hours as a continuous infusion\nCytarabine (Ara-C) 1,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (12 doses in total).\nTreatment schedule - Overview\nTreatment schedule - Detail\nAcute myeloid leukaemia (AML), in newly diagnosed patients 60 years of age or older\n(Note: in the study on which this protocol is based,r the greatest clinical benefit of daunorubicin dose intensification was seen in those aged between 60 and 65)\nVenous access\nCentral venous access device (CVAD) is required to administer this treatment.\nRead more about central venous access device line selection\nAntiemetics for multi-day protocols\nAntiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required.\nEnsure that patients also have sufficient antiemetics for breakthrough emesis:\nMetoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR\nProchlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.\nRead more about preventing antineoplastic induced nausea and vomiting\nCumulative lifetime dose of daunorubicin\nThe total cumulative lifetime dose of daunorubicin is 550 mg/m2.\nReduce the total cumulative lifetime dose to 400 to 450 mg/m2 if elderly, prior mediastinal radiation, hypertensive cardiomegaly, concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. dacarbazine, dactinomycin, etoposide, mitomycin, melphalan, vincristine and bleomycin).\nBaseline clinical assessment, echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation. Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of anthracycline threshold is reached or if patient displays symptoms of cardiac impairment.\nRead more about cardiac toxicity associated with anthracyclines\nOcular toxicities\nAdminister corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose.\nRead more about ocular toxicities associated with high dose cytarabine\nCytarabine syndrome\nTreatment with cytarabine may cause a \"cytarabine syndrome\" characterised by flu-like symptoms, skin rash and occasionally chest pain.\nCytarabine induced neurotoxicity\nThis may occur in patients treated with high dose cytarabine. Assess cerebellar function prior to each cytarabine dose.\nRead more about neurotoxicity associated with high dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart\nTumour lysis risk\nAssess patient for risk of developing tumour lysis syndrome.\nRead more about prevention and management of tumour lysis syndrome.\nPneumocystis jiroveci pneumonia (PJP) prophylaxis\nRead more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients\nAntiviral prophylaxis\nRead more about antiviral prophylaxis drugs and doses\nAntifungal prophylaxis\nRead more about antifungal prophylaxis drugs and doses.\nGrowth factor support\nG-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.\nAccess the PBS website\nFBC, EUC and LFTs at baseline and prior to each treatment.\nHepatitis B screening and prophylaxis\nRoutine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.\nRead more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy\nLive vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.\nRefer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.\nEffects of cancer treatment on fertility\nCancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.\nRead more about the effect of cancer treatment on fertility\nEvidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient's situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient​ preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.\nNote: all dose reductions are calculated as a percentage of the starting dose.\nHaematological toxicity\nDose reductions for haematological toxicity not usually recommended. Discuss with Haematologist. Consider adding G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) from Day 8\nRenal impairment\nNo specific dose modifications recommended for cytarabine in renal impairment, but please note an increased risk of neurotoxicity has been associated with high dose cytarabine with creatinine clearance less than 60 mL/min\nHepatic impairment\nHepatic dysfunction\nMild Reduce daunorubicin by 25%\nModerate Reduce daunorubicin by 50%\nSevere Omit daunorubicin. Consider alternative regimen.\nElevations in liver function tests occur with both standard and high dose cytarabine. Significant liver function abnormalities may require discontinuation or a dose reduction\nReferences & Disclaimer\nNo specific clinically significant drug-drug interactions\nDaunorubicin\nClinical management\nCardiotoxic drugs (eg. calcium channel blockers, propranolol) Increased risk of daunorubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity\nWarfarin Antineoplastic agents may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.\nDirect oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran\nInteraction with both CYP3A4 and P-gp inhibitors /inducers.\nDOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).\nApixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers.\nRivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors.\nDabigatran: avoid combination with strong P‑gp inducers and inhibitors.\nIf concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.\nDigoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.\nAntiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.\nAlso monitor closely for efficacy of the antineoplastic therapy.\nAntiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.\nIf combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.\nSerotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.\nIf combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).\nFor more information link to TGA Medicines Safety Update\nVaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.\nFor more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook\nAdministration Cycle 1\nDays 1 - 3\nDays 1 to 3\nSafe handling and waste management\nSafe administration\nGeneral patient assessment prior to each treatment.\nAny toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.\nPrime IV line(s).\nAccess CVC.\nbaseline weight\nbaseline urinalysis\nstrict fluid balance input and output\nHydration if prescribed\nPre treatment medication\nVerify antiemetics taken or administer as prescribed.\nChemotherapy - Time out\nAdminister daunorubicin (vesicant)\nover 5 to 15 minutes\nvia a minibag OR\nby IV bolus via a side port of a freely flowing IV infusion\nensure vein is patent and monitor for signs of extravasation throughout administration\nflush with ~150 mL of sodium chloride 0.9%\npotential for flare reaction during administration of daunorubicin (facial flushing and red streaking along the vein). Stop infusion and exclude extravasation before continuing at a slower rate of infusion.\nAlthough rare, cardiac arrhythmias may occur during or immediately after daunorubicin administration. If sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration immediately and obtain urgent medical officer review.\nadminister via continuous IV infusion over 7 days\nhang a new bag every 24 hours\ndo not interrupt the infusion of cytarabine.\nObserve for symptoms of cytarabine syndrome:\nfever, myalgia, bone pain, and/or occasionally rash, chest pain, or conjunctivitis which can occur 6 to 12 hours following drug administration. Symptoms usually resolve within 24 hours after cytarabine is discontinued.\ncorticosteroids may be used for treatment and prophylaxis.\nContinue safe handling precautions until 7 days after completion of drug(s)\ndaily weight\ndaily urinalysis\nDeaccess CVC.\nDischarge information\nAntiemetics\nAntiemetics as prescribed.\nArrangements for administration if prescribed.\nProphylaxis medications\nProphylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.\nEnsure patient receives patient information sheet.\nHydration if prescribed.\nCommence corticosteroid eye drops prior to the first dose of cytarabine.\nPrior to administration:\nVerify that cytarabine neurological assessment has been performed prior to administration of cytarabine:\nif the patient scores 0 then administer cytarabine as charted\nif the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.\nAdminister cytarabine:\nvia IV infusion over 3 hours\nflush with ~50 mL of sodium chloride 0.9%.\nAdminister second dose of cytarabine 12 hours after first dose.\nContinue corticosteroid eye drops for 72 hours after the completion of cytarabine.\nCorticosteroid eye drops\nContinue corticosteroid eye drops for at least 72 hours after completion of final cytarabine dose.\nThe side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.\nImmediate (onset hours to days)\nFlare reaction\nAnthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.\nCytarabine (Ara-C) syndrome\nFlu-like symptoms including fever, myalgia and malaise can occur 6 to 12 hours after cytarabine administration. Symptoms generally resolve within 24 hours of completing therapy.\nReversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine. Corticosteroid eye drops must be administered concurrently with treatment.\nRead more about ocular toxicities associated with cytarabine\nHigh dose cytarabine has been associated with acute cerebellar syndrome and diffuse cerebral dysfunction.\nRead more about neurotoxicity associated with high dose cytarabine\nRead more about prevention of treatment induced nausea and vomiting\nRed-orange discolouration of urine\nPink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.\nTaste and smell alteration\nRead more about taste and smell changes\nExtravasation, tissue or vein injury\nThe unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.\nRead more about extravasation management\nEarly (onset days to weeks)\nAbnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively.\nRead more about neutropenia\nA reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.\nRead more about thrombocytopenia\nOral mucositis\nErythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).\nRead more about oral mucositis\nRadiation recall\nErythematous or inflammatory skin reaction resembling severe sunburn at sites previously treated with radiotherapy can occur with certain antineoplastic drugs. Symptoms include vesiculation, desquamation and ulceration of the skin.\nRead more about radiation recall\nLoss of appetite accompanied by decreased food intake.\nRead more about anorexia\nRead more about treatment induced diarrhoea\nRead more about fatigue\nIncreased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.\nPalmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)\nBilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.\nRead more about hand-foot syndrome associated with chemotherapy\nAntineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction.\nRead more about skin rash\nLate (onset weeks to months)\nAbnormally low levels of red blood cells (RBCs) or haemoglobin in the blood.\nRead more about anaemia\nCognitive changes (chemo fog)\nChanges in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.\nRead more about cognitive changes (chemo fog)\nHair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.\nRead more about alopecia\nDelayed (onset months to years)\nAnthracyclines are the most frequently implicated antineoplastic agents associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses.\nThe evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial involving 813 patients.r\nPatients in whom AML or high-risk refractory anaemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square metre by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square metre (411 patients) or at an escalated dose of 90 mg per square metre (402 patients). The primary end point was event-free survival.r\nEligible patients were randomly assigned to receive daunorubicin at a dose of 45 mg per square metre (conventional-dose group) (411 patients) or at a dose of 90 mg per square metre (escalated-dose group) (402 patients) — both administered intravenously over the course of 3 hours on days 1 to 3 of the first cycle of induction treatment plus cytarabine at a dose of 200 mg per square metre, administered by continuous infusion for 7 days. In the second cycle of treatment, both groups received cytarabine at a dose of 1000 mg per square metre twice daily, given intravenously over the course of 6 hours on days 1 through 6.r\nIn patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects.r\nIn this study, it is apparent that the subgroup of patients who were 60 to 65 years of age benefited the most from intensified doses of daunorubicin. In this subgroup, the rate of complete remission among patients who received the escalated dose, as compared with those who received the conventional dose, was 73% versus 51%; this subgroup, as compared with all other cytogenetic subgroups, also had the highest rates of overall survival.r\nHowever, a 2015 randomised UK NCRI trial, the AML17 trialr, reported no overall benefit with the use of daunorubicin at 90 mg/m2 compared to 60 mg/m2 when used in conjunction with cytarabine for AML induction. However, it should be noted that 60 day mortality was increased in the 90 mg/m2 group (HR 1.98 [1.30-3.02]; P= 0.001).\nFurthermore, a 2018 EHA abstract compared 90 mg/m2 versus 60 mg/m2 daunorubicin in a standard 7 + 3 induction regimen and found that a dose escalation of 60 to 90 mg/m2 does not result in a significant increase in response rates.r\nEfficacyr\nFrom October 27, 2000, through June 9, 2006, a total of 813 eligible patients who could be evaluated were randomly assigned to a treatment group — 411 to the conventional-dose group and 402 to the escalated-dose group. The median follow-up period for patients who were still alive at the date of last contact (148 patients) was 40 months.\nThe complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%).\n© NEJM 2009\nExploratory post hoc analyses showed that patients who were 60 to 65 years of age had the greatest benefit from an escalated dose of daunorubicin with respect to the complete remission rate (51% in the conventional-dose group vs. 73% in the escalated-dose group), the 2-year rate of event-free survival (14% vs. 29%), and the 2-year rate of overall survival (23% vs. 38%). Tests for an interaction between age and treatment were significant with respect to complete remission, event-free survival, and overall survival. Tests for an interaction between cytogenetic risk category and treatment were not significant except with respect to disease-free survival, but in the subgroup with abnormalities in core-binding factors, the escalated dose was associated with an increased rate of complete remission and with reduced hazard ratios for disease progression or death. None of the tests for interaction with respect to the other factors were significant.\nToxicityr\nThere were no significant differences between the two groups in 30-day mortality (12% in the conventional-dose group and 11% in the escalated-dose group), the number of nights spent in the hospital, and the time to recovery of neutrophil or platelet counts. There were also no significant differences with respect to the rate of death during induction or the incidence of serious adverse events after the first two cycles overall. In the escalated-dose group, as compared with the conventional-dose group, there were more infections of grade 2 to 4, slightly more platelet transfusions were given, and the time to the beginning of the second cycle was, on average, 3 days longer. The difference in the time to the second cycle probably reflects the higher rate of complete remission after the first cycle in the escalated-dose group; among patients with no response, the second cycle was frequently started as soon as possible because haematologic recovery was not expected. There was no significant difference in the rate of grade 2 to 4 (i.e., moderate, severe, or life-threatening) side effects between the two groups (74% in the conventional-dose group and 80% in the escalated-dose group, P = 0.08).\nProtocol presented at the eviQ Haematology Reference Committee meeting.\nProtocol V.1 published on eviQ. Review in 1 year.\nWarning box added above the treatment schedule explaining the correction in dosage error from the original published paper.\nProtocol reviewed by the haematology reference committee and decision made to supersede this regimen as it is not considered best practice for this patient population. Version number change to V.2.\nClinical information updated with PBS expanded indications for G-CSF.\nReview due:\nSuperseded:\nhttps://www.eviq.org.au/p/3351"

"Sponsor's Protocol Code Number: H8A-MC-LZAN\nNational Competent Authority: France - ANSM\nA.1 Member State Concerned France - ANSM\nEffect of Passive Immunization on the Progression of Alzheimer's Disease: LY2062430 versus Placebo\nA.4.1 Sponsor's protocol code number H8A-MC-LZAN\nB.1.1 Name of Sponsor Eli Lilly and Company\nD.3.1 Product name LY2062430\nD.3.2 Product code LY2062430\nD.3.9.2 Current sponsor code LY2062430\nD.3.1 Product name [18F]AV-45\nD.3.2 Product code [18F]AV-45\nD.3.4 Pharmaceutical form Solution for injection\nD.3.7 Routes of administration for this IMP Intravenous bolus use (Noncurrent)\nD.3.9.2 Current sponsor code [18F] AV-45\nD.3.10.1 Concentration unit MBq megabecquerel(s)\nD.8.3 Pharmaceutical form of the placebo Concentrate for solution for infusion\nE.1.2 Term Alzheimer's disease\nThe primary objective of this study is to test the hypothesis that intravenous infusion of LY2062430 will slow the decline of AD as compared with placebo, as assessed at 80 weeks after initiation of treatment using a mixed-model repeated-measures (MMRM) analysis of 2 coprimary outcomes, the 11 item Alzheimer's Disease Assessment Scale—Cognitive subscore (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL). The specific hypothesis is that the change at the end of the treatment phase for LY2062430 will be significantly less than that for placebo.\nTo assess global clinical benefit of treatment as demonstrated through CDR-SB and NPI\nTo provide supporting evidence that LY2062430 attenuates the underlying pathologic process in AD by vMRI to assess the rate of decline in brain volumes\nTo compare the safety of LY2062430 and placebo\nTo characterize population pharmacokinetics\nTo test the hypothesis that LY2062430 will slow the rate of decline associated with AD compared with placebo using ADAS-Cog11, ADCS-ADL, ADAS-Cog12, ADAS-Cog14 and MMSE\nTo assess clinical benefit of treatment with LY2062430 as demonstrated through RUD-Lite, EQ-5D Proxy, and QoL-AD scale\nTo assess differential rate of functional decline with LY2062430 compared with placebo using a subset of items from the ADCS-ADL for instrumental ADLs\nTo provide further supporting evidence that LY2062430 attenuates the underlying pathologic process in AD as measured by several additional biomarkers that will be collected via optional study addenda\nTitle: H8A-MC-LZAN (1) (Sample Banking) Effect of Passive Immunization on the Progression of Alzheimer's Disease: LY2062430 versus Placebo.\nDate: 07 October 2008 Version: 1\nObjective: Eli Lilly and Company has established a program, Combined Specimen Banking (CSB), to bank samples from patients enrolled in studies sponsored by Eli Lilly and Company. The Banked Samples are collected and banked for research to identify the (1) genes, (2) gene products, (3) biochemical markers, or (4) any combination thereof associated with diseases, response to clinical trial medication, or both or other medication taken during the trial.\nTitle: H8A-MC-LZAN (2) (Lumbar Punctures) Effect of Passive Immunization on the Progression of Alzheimer's Disease: LY2062430 versus Placebo\nObjectives: Lumbar punctures (LPs) will be used to collect cerebrospinal fluid (CSF) for assays of CSF glucose, protein, cell count with differential, and albumin; LY2062430, amyloid β peptides (Aβ), and tau proteins and CSF storage. A secondary objective of the study is to show that concentrations of free (unbound to antibody) Aβ1-42 in CSF may be increased in LY2062430-treated patients compared with placebo-treated patients.\nTitle: H8A-MC-LZAN (3) (Amyloid Imaging) Effect of Passive Immunization on the Progression of Alzheimer's Disease: LY2062430 versus Placebo\nDate: 22December 2008 version 1\nThis technique will be used in this study to meet 2 secondary study objectives: first, to test the hypothesis that amyloid burden will be reduced in patients treated with LY2062430 (versus placebo) and second, that only patients demonstrating sufficient amyloid burden at baseline will respond to treatment as determined by clinical measures.\n1.Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD (McKhann et al. 1984; Protocol Attachment LZAN.3) as determined by a neurologist or geriatrician.\n2.Has a Modified Hachinski Ischemia Scale (MHIS; Hachinski et al. 1975; Protocol Attachment LZAN.3) score of ≤4.\n3.Has a Folstein MMSE score of 16 through 26 at Visit 1 (Folstein et al. 1975; Protocol Attachment LZAN.3).\n4.Has a Geriatric Depression Scale (GDS) score of ≤6 (on the staff-administered short form).\n5.Has had an MRI or computerized tomography (CT) scan performed within the past 2 years has confirmed no findings inconsistent with a diagnosis of AD. Results of this MRI or CT are to be on file at the site. If a patient has not had a prestudy MRI/CT scan in the past 2 years or attempts to obtain offsite imaging results are unsuccessful, then a screening non-contrast head CT is to be performed; due diligence to obtain offsite results should be documented in the patient's file before obtaining a screening non-contrast head CT scan.\n6.Is at least 55 years old, and if a female of childbearing potential, tests negative for pregnancy at Visit 1 and is using a medically accepted means of contraception.\n7.If receiving concurrent treatment with an AChEI or memantine, has been on the medication for at least 4 months with a stable dose for at least 2 months before screening. Dosing must remain stable throughout the study.\n1. Does not have a reliable caregiver who is in frequent contact with the patient (defined as at least 10 hours per week), will accompany the patient to the office and/or be available by telephone at designated times, and will monitor administration of prescribed medications.\n2. Meets National Institute of Neurological Disorders and Stroke/ Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia.\n3. Does not have good venous access, such that intravenous drug delivery or multiple blood draws would be precluded.\n4. Has current serious or unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses of safety and efficacy in this study; or has a life expectancy of <2 years.\n5. Has had multiple episodes of head trauma, or a history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis) or head trauma resulting in protracted loss of consciousness.\n6. Has a history within the last 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostrate specific antigen (PSA) posttreatment.\n7. Has allergies to humanized monoclonal antibodies.\n8. Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).\n9. Has a history of chronic alcohol or drug abuse/dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) within the past 5 years.\n10. Is clinically judged by the investigator to be at serious risk for suicide.\n11. Has a recent (within 6 months before screening) or current laboratory result (if available) indicating a clinically significant laboratory abnormality as determined by the investigator.\n12. Has ECG abnormalities obtained at Visit 1 that, in the opinion of the investigator, are clinically significant with regard to the patient's participation in the study, including corrected QT (QTc) prolongation (Bazett's corrected QT interval [QTcB] males >458 msec or females >474 msec).\n13. At Visit 1, has alanine transaminase (ALT/SGPT) values ≥2 times the upper limit of normal (ULN) of the performing laboratory, aspartate transaminase (AST/SGOT) values ≥3 times the ULN, or total bilirubin values ≥2 times the ULN.\n14. Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.\n15. Has received AChEIs or memantine for less than 4 months or has less than 2 months of stable therapy on these treatments by Visit 2. (Note: If a patient has recently stopped AChEIs or memantine, he or she must have discontinued treatment at least 2 months before Visit 2.)\n16. Has received medications that affect the central nervous system (except treatments for AD) for less than 4 weeks; that is, doses of chronic medications that affect CNS should be stable for at least 4 weeks before Visit 2.\n17. Has had IgG therapy (sometimes called gamma globulin therapy) within the last year. Has previously completed or withdrawn from this study or previous participation in any other study investigating active immunization against Aβ.\n18. Requires treatment with other monoclonal antibodies.\n19. Is investigative site personnel directly affiliated with this study or immediate family or is a Lilly employee. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.\n20. Is currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.\n21. Lacks, in the investigator's opinion, adequate premorbid literacy to complete the required psychometric tests.\nEach of the 2 coprimary endpoints, ADAS-Cog11 and the ADCS-ADL, will be analyzed separately using an MMRM analysis. The change from baseline score at each visit postbaseline during the treatment period will be the dependent variable. The model for the fixed effects will include 8 terms: baseline score, investigator, treatment, MMSE stratification factor at baseline (mild or moderate), visit, treatment-by-visit interaction, concomitant AChEI or memantine use at baseline (yes/no), and age at baseline. Visit will be considered a categorical variable with values equal to the visit numbers at which the scales were assessed. The null hypothesis is that the contrast between the LY2062430 group versus placebo at the last visit equals zero. A rejection of the null hypothesis in favor of the alternative, showing that LY2062430 is superior to placebo, will demonstrate a treatment effect\nE.7.3 Therapeutic confirmatory (Phase III) Yes\nstudy partner/caregiver\nF.4.2.2 In the whole clinical trial 1000"

"Phl p 7.0101 is a minor, non-glycosylated, allergen of timothy grass pollen, recognizing serum IgE antibodies of grass pollen-sensitized individuals. It is a Ca2+-binding protein with high sequence homology to pollen proteins found in a number of other plants, therefore likely to cross-react with those. DIARECT™ antigens are for further manufacturing or research use only.\nRecombinant. Expressed in E. coli bacterial cells.\nSDS-PAGE (purity > 80%); Western blot with patient sample.\nOur team has the expertise and commitment to provide best-in-class solutions to meet your IVD needs.\nSurmodics: Medical Device Coatings, Products, and IVD Technologies for the Healthcare Industry.\n© 2019 Surmodics, Inc. All Rights Reserved.\n\" ) ); $( \"#antigens-page #subcategories\" ).prepend( $( \"\n\" ) ); $( \"#antigens-learn-page #subcategories\" ).prepend( $( \"\n\" ) ); $( \"#microarray-slides-surfaces-page #subcategories\" ).prepend( $( \"\n\" ) ); $( \"#microarray-slides-surfaces-learn-page #subcategories\" ).prepend( $( \"\n\" ) ); $( \"#dried-protein-stability-blocking-learn-page #products\" ).prepend( $( \"\n\" ) ); $( \"#dried-protein-stability-blocking-products-page #products\" ).prepend( $( \"\n\" ) ); $( \"#tmb-microwell-substrates-learn-page #products\" ).prepend( $( \"\n\" ) ); $( \"#tmb-microwell-substrates-page #products\" ).prepend( $( \"\n\" ) ); $( \".product-page #related-product-sets\" ).prepend( $( \"\n\" ) ); $( \".product-page #page-body\" ).prepend( $( \"\n\" ) ); $( \"#page-header-nav-inner > ul\" ).prepend( $( \"\n\" ) ); $( \".product-page #product-tabs\").insertAfter(\".product-page #product-main\"); $( \".product-page #product-page-html\").insertAfter(\".product-page #product-main\"); //$( \".product-page .product-description\").insertAfter(\".product-page #product-main\"); //$( \".product-page #full-description\").insertBefore(\".product-page #product-main\"); //$( \".product-page .product-description\" ).prepend( $( \"\n\" ) ); //$( \".product-page #full-description\" ).prepend( $( \""

"To be able to use Biometec Shop in full range, we recommend activating Javascript in your browser.\nBiometec Shop\nMy account Service/Help\nOrdering information's and pricing\nTerms and Conditions (AGB)\n€0.00*\nDisplay positions\nOther Monoclonal Antibodies\nBiometec Shop / Other Monoclonal Antibodies / NIFUN monoclonal antibody (M01), clone 3B8-1C4\nNIFUN monoclonal antibody (M01), clone 3B8-1C4\nOrder number: H00023479-M01\nAmount: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100\nProduct information \"NIFUN monoclonal antibody (M01), clone 3B8-1C4\"\nMouse monoclonal antibody raised against a full length recombinant NIFUN.\nIsotype: IgG1 kappa\nGeneid: 23479\nGene name: ISCU\nGene alias: 2310020H20Rik|HML|ISU2|MGC74517|NIFU|NIFUN|hnifU\nGene description: iron-sulfur cluster scaffold homolog (E. coli)\nImmunogen: NIFUN (AAH11906, 26 a.a. ~ 167 a.a) full-length recombinant protein with GST tag. MW of the GST tag alone is 26 KDa.\nProtein accession: AAH11906\nStorage buffer: In 1x PBS, pH 7.2\nStorage instruction: Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing.\nSpecies reactivity / Cross reactivity: Human\nApplication key: S-ELISA,ELISA,WB-Re,WB-Ce,IF\nDatasheet: DS_H00023479-M01.pdf\nQuality controle images:\nWestern Blot detection against Immunogen (41.36 KDa) .\nImmunofluorescence of monoclonal antibody to NIFUN on HeLa cell. [antibody concentration 10 ug/ml]\nNIFUN monoclonal antibody (M01), clone 3B8-1C4 Western Blot analysis of NIFUN expression in HL-60 ( Cat # L014V1 ).\nPrivacy (in German)"

"Buy the highest Quality Peptides from Research Peptides. All bacteriostatic water and 10 syringes supplied free with each order.\nTo join our mailing list to receive news and our specials click here ! To place an order or make a stock enquiry visit our online order form.\n​ ACTH 1-39(Adrenocorticotropic hormone ) 2mg per vialR300-00 ex. VAT Clinical Test Expectation - Human Subjects :Stimulate cortisol release NOT SUITABLE FOR USE ON ANIMALS OR LIVESTOCK Adipotide 5mg per vialR500-00 ex. VAT Clinical Test Expectation - Human Subjects :Faster muscle mass growth, superior fat-burning power Aicar(AICA ribonucleotide) 5mg per vialR300-00 ex. VAT Clinical Test Expectation - Human Subjects :Burn fat, Endurance (sustain output) Alarelin(Alarelin Acetate) 5mg per vialR200-00 ex. VAT Clinical Test Expectation - Human Subjects :\"Induces Ovulation\" AOD 9604(Anti-Obesity Drug-9604) 2mg per vialR300-00 ex. VAT Clinical Test Expectation - Human Subjects :\"Anti Obesity Drug\"\nTriptorelin (GnRH - 57773-63-4) 2mg per vialR300-00 ex. VAT Clinical Test Expectation - Human Subjects :Powerful PCT.Treatment of hormone-responsive cancers such as prostate cancer or breast cancer in women."

"Main Drugs Index\nEuropean Human Drugs\nHerbal Drugs\nDrug Manufactures Index\nGenome Dictionary\nBiomethodology\nGeographic Main\nDrug Reference\nDRUGS INDEX | MANUFACTURERS INDEX | ANATOMY | GEOGRAPHY | USA STATISTICS | CHINA STATISTICS | RELIGION | JOBS\nATryn, Antithrombin (Recombinant) (GTC Biotherapeutics)\nTranslate Español 简体中国 Français Deutsch Русские हिन् العربية Português\nDosage/Administration\nNonclinical Toxicology\nStorage/Handling\nPatient Councseling\n- Drugs index\n- Manufacturers\nThese highlights do not include all the information needed to use Ranexa safely and effectively. See full prescribing information for Ranexa.\nATryn, Antithrombin (Recombinant)\nLyophilized powder for reconstitution\n----------------------------- INDICATIONS AND USAGE ---------------------------\nATryn is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.\nIt is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients.\n--------------------------- DOSAGE AND ADMINISTRATION -----------------------\nFor intravenous use only after reconstitution\nThe dosage of ATryn is individualized for each patient. Treatment goal is to restore and maintain functional antithrombin (AT) activity levels between 80% - 120% (0.8 - 1.2 IU/mL) of normal.\nAdminister loading dose as a 15-minute intravenous infusion immediately followed by continuous infusion of the maintenance dose.\nAT activity monitoring is required for proper treatment. Check AT activity once or twice per day with dose adjustments made according to table below.\nContinue administration of ATryn until adequate follow-on anticoagulation has been established.\nStore at 2-8�C (36-46�F). Discard any unused portion.\n-------------------------- DOSAGE FORMS AND STRENGTHS -----------------------\nATryn is a sterile lyophilized powder for reconstitution. Each single dose vial of ATryn contains the potency as stated on the label, which is approximately 1750 IU.\n-------------------------------- CONTRAINDICATIONS ------------------------------\nKnown hypersensitivity to goat and goat milk proteins.\n---------------------------- WARNINGS AND PRECAUTIONS ------------------------\nAnaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with the product should be discontinued, and emergency treatment should be administered.\nThe anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, regularly perform coagulation tests suitable for the anticoagulant used, at close intervals, especially in the first hours following the start or withdrawal of ATryn and monitor patients for bleeding or thrombosis.\n--------------------------------- ADVERSE REACTIONS ----------------------------\nMost common adverse reactions reported in clinical trials at a frequency of >= 5% were hemorrhage and infusion site reaction. (6)\nTo report SUSPECTED ADVERSE REACTIONS, contact Ovation Pharmaceuticals at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\n---------------------------- DURG INTERACTIONS ------------------------\nATryn enhances anticoagulant effect of heparin and low molecular weight heparin. (7)\nThe half-life of ATryn may be altered by concomitant treatment with anticoagulants that use antithrombin to exert their anticoagulant effect.\n----------------------- USE IN SPECIFIC POPULATIONS ------------------\nPregnancy Category C: Studies in pregnant women have not shown that ATryn increases the risk of fetal abnormalities if administered during the third trimester of pregnancy. No data is available for use of ATryn in earlier stages of pregnancy. (8.1)\nLabor and Delivery: ATryn is used in the treatment of peri-partum women with hereditary antithrombin deficiency. (8.2)\nNursing Mothers: ATryn administered by infusion will be present in breast milk at estimated concentrations 1/50 to 1/100 that of concentration in blood. Use only if clearly needed.\n2.1 Preparation for Administration\n2.2 Recommended Dose and Schedule\n5.2 Coagulation Monitoring Tests\n13.1 13 NONCLINICAL TOXICOLOGY\n14 CLINICAL STUDIES 13.1\n* Sections or subsections omitted from the full prescribing information are not listed.\nATryn� is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients1.\nBring vials to room temperature no more than 3 hours prior to reconstitution.\nReconstitute with 10 mL Sterile Water for Injection [(WFI) not supplied with ATryn] immediately prior to use. Do not shake.\nDo not use solution containing visible particulates or if it is discolored or cloudy.\nDraw solution from one or more vials into a sterile disposable syringe for intravenous administration or add solution to an infusion bag containing 0.9% sterile sodium chloride for injection (e.g., dilute solution to obtain a concentration of 100 IU/mL).\nAdminister using an infusion set with a 0.22 micron pore-size, in-line filter.\nAdminister contents of infusion syringes or diluted solution within 8 to 12 hours of preparation when stored at room temperature (68-77�F (20-25�C)).\nDiscard unused product in accordance with local requirements.\nThe dosage of ATryn is to be individualized based on the patient�s pre-treatment functional AT activity level (expressed in percent of normal) and body weight (expressed in kilograms) and using therapeutic drug monitoring (Table 1).\nThe goal of treatment is to restore and maintain functional antithrombin (AT) activity levels between 80% - 120% of normal (0.8 - 1.2 IU/mL).\nTreatment should be initiated prior to delivery or approximately 24 hours prior to surgery to ensure that the plasma antithrombin level is in the target range at that time.\nDifferent dosing formulae are used for the treatment of surgical and pregnant patients. Pregnant women who need a surgical procedure other than Cesarean section should be treated according to the dosing formulae for pregnant patients.\nAdminister loading dose as a 15-minute intravenous infusion, immediately followed by a continuous infusion of the maintenance dose.\nAT activity monitoring and dose adjustments should be made according to Table 2.\nContinue treatment until adequate follow-on anticoagulation is established.\nTable 1: Dosing Formula for Surgical Patients and Pregnant Women\nAT Activity Monitoring and Dose Adjustment\nAT activity monitoring is required for proper treatment. Check AT activity once or twice per day with dose adjustments made according to Table 2.\nTable 2: AT Activity Monitoring and Dose Adjustment\nAs surgery or delivery may rapidly decrease the AT activity levels, check the AT level just after surgery or delivery. If AT activity level is below 80%, an additional bolus dose may be administered to rapidly restore decreased AT activity level. In such instances, the loading dose formulae in Table 1 should be used, utilizing in the calculation the last available AT activity result. Thereafter, restart the maintenance dose at the same rate of infusion as before the bolus.\nATryn is a sterile lyophilized formulation. Each vial of ATryn contains the potency stated on the label, which is approximately 1750 IU.\nATryn is contraindicated in patients with known hypersensitivity to goat and goat milk proteins.\nAllergic-type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur during administration, treatment must be discontinued immediately and emergency treatment should be administered.\nThe anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, monitor the patients for the occurrence of bleeding or thrombosis in such situation.\nThe serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). The most common adverse events reported in\nClinical Trials Experience\nBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions that occurred in clinical trials with hereditary AT deficient patients are shown in Table 3 by System Organ Class.\nTable 3: Adverse Reactions in Hereditary AT Deficient Patients (one event per patient, 2% of total population, n=47)\nIntra-abdominal Hemorrhage\nGeneral Disorders and Administration Site Disorders\nApplication Site Pruritus\nFeeling Hot\nNon-cardiac Chest Pain\nHemarthrosis\nImmunogenicity\nFor ATryn, a potential safety issue is the development of an immunological reaction to the recombinant protein or any of the potential contaminating proteins. Assays were developed and used to detect antibodies directed against antithrombin (Recombinant), goat AT, or goat-milk proteins. No confirmed specific immunological reaction was seen in any of the patients tested, nor were there any clinical adverse events that might indicate such a response.\nA post-marketing patient registry has been established to collect additional data on the immunogenic potential of ATryn in patients treated with ATryn on more than one occasion. Physicians are encouraged to participate in the registry by collecting pre- and post-treatment serum samples from patients according to instructions provided by Ovation Pharmaceuticals, Inc. and submitting them to Ovation for analysis for the development of antibodies to antithrombin (Recombinant). Serum samples should be collected within one week before initiation of treatment and on days 1, 7 and 28 days from initiation of treatment. Physicians wanting to participate in this program are encouraged to contact Ovation Pharmaceuticals, Inc. at 1-800-455-1141. Ovation will provide detailed instructions for the collection, processing and shipping of samples, as well as all tubes and labels that are necessary for the collection and processing of samples.\nThe anticoagulant effect of heparin and low molecular weight heparin (LMWH) is enhanced by antithrombin. The half-life of antithrombin may be altered by concomitant treatment with these anticoagulants due to an altered antithrombin turnover. Thus, concurrent administration of antithrombin with heparin, low molecular weight heparin, or other anticoagulants that use antithrombin to exert their anticoagulant effect must be monitored clinically and biologically. To avoid excessive anticoagulation, regular coagulation tests (aPTT, and where appropriate, anti-Factor Xa activity) are to be performed at close intervals, with adjustment in dosage of the anticoagulant as necessary.\nPregnancy Category C: In rats, a dose of 210 mg/kg/day ATryn (5-6 times the human dose for pregnant women) administered during most of the pregnancy and entire lactation showed a slight but statistically significant increase in pup mortality in day one through day four when compared to concurrent control (90% compared to 94% viability index for 210 mg/kg/day versus control). This slight statistical difference does not reflect a true treatment-related effect. This same dose was shown to be safe in a second rat study when administered around parturition and during lactation where the no adverse effect level for dam and pups was 210 mg/kg/day.\nThere are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.\nStudies in pregnant women have not shown that ATryn increases the risk of fetal abnormalities if administered during the third trimester of pregnancy. In clinical trials in hereditary AT deficient patients, 22 pregnant women have been treated with ATryn around parturition.\nNo adverse reactions were reported in 22 neonates born from pregnant women treated with ATryn during clinical trials.\nATryn is indicated for the treatment of pregnant women during the peri-partum period. Pregnant patients who need a surgical procedure other than Cesarean section are to be treated according to the dosing formulae for pregnant patients.\nATryn will be present in breast milk at levels estimated to be 1/50 to 1/100 of its concentration in the blood. This level is the same as that estimated to be present in breast milk of normal lactating women which is not known to be harmful to breastfed neonates. However, caution should be exercised when ATryn is administered to a nursing woman. Use only if clearly needed.\nIn 2 reproductive toxicology studies performed in rats, antithrombin (Recombinant) was administered to pregnant dams at doses up to 210 mg/kg/day, resulting in supraphysiologic plasma levels of antithrombin. Pups were allowed to breastfeed and were monitored for changes in prothrombin (PT) or aPTT, as well as pup viability, body weight at birth, growth, and development. In these studies, there were no adverse effects in offspring who consumed milk from dams treated with ATryn.\nClinical studies of ATryn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.\nATryn for Injection is a nanofiltered, sterile, terminally heat treated, lyophilized dosage form. Antithrombin (Recombinant), active ingredient of ATryn, is a recombinant human antithrombin. It is a 432 amino acid glycoprotein with a molecular weight of approximately 57,215 Daltons. The molecular formula is: C2191H3457N583O656S18. Antithrombin (Recombinant) is produced by recombinant DNA technology using genetically engineered goats into which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, which directs the expression of the antithrombin into the milk. The goats in which antithrombin (Recombinant) is produced are USDA certified scrapie-free, and controlled for specific pathogens.\nThe amino acid sequence of Antithrombin (Recombinant) is identical to that of human plasma-derived antithrombin. Antithrombin (Recombinant) and plasma-derived antithrombin both contain six cysteine residues forming three disulphide bridges and 3-4 N-linked carbohydrate moieties. The glycosylation profile of Antithrombin (Recombinant) is different from plasma-derived antithrombin, which results in an increased heparin affinity. When assayed in the presence of excess of heparin the potency of the recombinant product is not different from that of plasma-derived product.\nEach vial of ATryn is tested for potency stated on the product label using a reference standard calibrated against the World Health Organization international standard for antithrombin concentrate. In addition to Antithrombin (Recombinant), each vial of the product contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is approximately 7.0. Following reconstitution, the solution may be further diluted into 0.9% sodium chloride for injection.\nATryn does not contain any preservatives nor is it formulated with human plasma proteins. Antithrombin (Recombinant) is affinity purified using a heparin immobilized resin and contains no detectable heparin (<0.0002 IU heparin per IU antithrombin) in the final product.\nThe purification and drug product manufacturing processes have been validated to demonstrate its capacity for removal and/or inactivation of viruses4. Results of removal and/or inactivation for each of the steps are shown in Table 4.\nTable 4: Viral Clearance Results (log10 reductions)\nAntithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and Factor Xa5, the serine proteases that play pivotal roles in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.\nHereditary AT deficiency causes an increased risk of venous thromboembolism (VTE). During high-risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 506,7. In hereditary antithrombin deficient patients ATryn restores (normalizes) plasma AT activity levels during peri-operative and peri-partum periods.\nIn an open-label, single dose pharmacokinetic study, male and female patients (>=18 years of age) with hereditary AT deficiency, received either 50 (n = 9, all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously. These patients were not in high-risk situations. The baseline corrected pharmacokinetic parameters for antithrombin (Recombinant) are summarized in Table 5.\nTable 5: Baseline Corrected Mean Pharmacokinetic Parameters (%CV)\nIncremental recovery [mean (%CV)] was 2.24 (20.2) and 1.94 (14.8) %/IU/kg body weight for 50 and 100 IU/kg, respectively.\nPopulation pharmacokinetic analysis of hereditary deficient patients in a high risk situation revealed that the clearance and volume of distribution in pregnant patients were (1.38 L/h and 14.3 L respectively) which are higher than non-pregnant patients (0.67 L/h and 7.7 L respectively). Therefore, distinct dosing formulae for surgical and pregnant patients should be used (see 2.2, Recommended Dose and Schedule).\nAs compared to plasma derived antithrombin, ATryn has a shorter half-life and more rapid clearance (approximately nine and seven times, respectively).\nPharmacokinetics may be influenced by concomitant heparin administration, as well as surgical procedures, delivery, or bleeding. AT activity monitoring (see 2.2 Recommended Dose and Schedule) should be performed to properly treat such patients.\nCarcinogenesis: No carcinogenicity data for ATryn are available in animals or humans.\nMutagenesis and Genotoxicity: ATryn was not mutagenic when tested in the Ames bacterial test and in in vitro cytogenetic assays nor was it shown to be genotoxic when tested in an in vivo test to assess chromosomal aberration.\nImpairment of Fertility: No studies have been conducted to evaluate the effects of ATryn on fertility in humans.\nPharmacokinetic and toxicokinetic (1 single, 2 repeated dose) studies of antithrombin (Recombinant) were performed in mice, rats, dogs and monkeys. In toxicokinetic studies in monkeys the area under the curve was 3-4 times greater than in the rat at all doses used.\nThe toxicological profile of antithrombin (Recombinant) administered by the intravenous route as bolus injections and infusions has been evaluated in both single- and repeat-dose studies performed in rats, dogs, and monkeys across a range of doses from 2.1 to 360 mg/kg. The highest doses in the single dose toxicity studies in rats and dogs were 360 mg/kg and 210 mg/kg, respectively. Toxicities observed were limited to transient injection site swelling observed in rats and dogs at the highest doses tested, and increased AST at highest dose in the dog study, both resolved during recovery period.\nThe highest dose in the 28-day repeated-dose toxicity study in rats was 360 mg/kg/day. The toxicity at this dose was limited to transient limb swelling and local injection site bruising and swelling. The highest dose in the 14-day repeated-dose toxicity study in monkeys was 300 mg/kg/day or approximately 7-8 times human dose. Toxicities observed in female monkeys at this dose included internal bleeding, hematological changes and liver toxicity, with one out of three female animals showing multifocal hepatic necrosis. Both sexes showed increased AST and ALK on day 15, with both parameters returning to normal by day 22. There was no adverse effect in monkeys dosed with 120 mg/kg/day.\nThe efficacy of ATryn to prevent the occurrence of venous thromboembolic events was assessed by comparing the incidence of the occurrence of such events in 31 ATryn treated hereditary AT deficient patients with the incidence in 35 human plasma-derived AT treated hereditary AT deficient patients. Data on ATryn-treated patients were derived from two prospective, single-arm, open-label studies. Data on plasma AT treated patients were collected from a prospectively designed concurrently conducted retrospective chart review. Patients in both studies had confirmed hereditary AT deficiency (AT activity <=60% of normal) and a personal history of thromboembolic events. Patients had to be treated in the peri-operative and peri-partum period. ATryn was administered as a continuous infusion for at least 3 days, starting one day prior to the surgery or delivery. Plasma AT was administered for at least two days as single bolus infusions. Due to the retrospective nature of the study, dosing was done with the locally available AT concentrate according to the local practice.\nThe occurrence of a venous thromboembolic event was confirmed if signs and symptoms for such events were confirmed by a specific diagnostic assessment, or when treatment for an event was initiated based on diagnostic imaging, without the presence of signs and symptoms. The efficacy was assessed during treatment with AT and up to 7 days after stopping AT treatment.\nIn the ATryn-treated group there was one confirmed diagnosis of an acute deep vein thrombosis (DVT). The incidence of any thromboembolic event from the start of treatment to 7 days after last dosing is summarized by treatment group in Table 6 as are the Clopper-Pearson exact 95% CI for the proportion of patients with a thromboembolic event and the exact 95% lower confidence bound for the difference between treatments.\nTable 6: Overall Incidence of Any Confirmed Thromboembolic Event\nThe lower 95% confidence bound of difference between treatment groups was -0.167, a value that is greater than the pre-specified lower confidence bound of -0.20. This demonstrates that ATryn was non-inferior to plasma AT in terms of the prevention of peri-operative or peri-partum thromboembolic events. Supportive data come from a study in the same population with 5 hereditary AT deficient patients treated on 6 occasions in a compassionate use program and provides additional reassurance of the efficacy of ATryn. None of these patients reported a thromboembolic event.\n(1) Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39.\n(2) Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion 2003 March;43(3):390-4.\n(3) Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 1998 June 15;91(12):4561-71.\n(4) Echelard Y, Meade H, Ziomek C. The first biopharmaceutical from transgenic animals: ATryn. Modern Biopharmaceuticals 2005;995-1016. Page 11 of 13\n(5) Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40.\n(6) Buchanan GS, Rodgers GM, Ware Branch. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003 June;17(3):397-411.\n(7) Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.\nApproximately 1750 IU/vial in a sterile white to off-white lyophilized powder for reconstitution. Each carton contains one single dose vial of ATryn.\nThe actual potency of ATryn is stated on the vial label and carton.\nSTORAGE AND HANDLING\nStore ATryn refrigerated at between 2-8�C (36-46�F).\nDo not use product beyond the expiration date printed on the package. Discard unused portions.\nPATIENT COUNSELING INFORMATION\nInform patients that allergic-type hypersensitivity reactions are possible and instruct them to inform their physicians about any past or present known hypersensitivity to goats or goat milk proteins prior to treatment with ATryn. Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis and to notify their health care provider immediately if these events develop.\nInform patients about the risk of bleeding when ATryn is administered with other anticoagulants and instruct them to notify their physicians of any bleeding events while on treatment with ATryn.\nGTC Biotherapeutics, Inc.\nPalo Alto, CA 94304 USA\nU.S. License No. 1794\nOvation Pharmaceuticals, Inc.\nDeerfield, IL 60015, U.S.A.\nATryn is a registered U.S. � Trademark of Ovation Pharmaceuticals, Inc.\nIssued: February 2009 - - - LBL-7074\n- To bookmark this page (add it to your favorites), please click the image to the left.\n- If you wish to link to this page, you can do so by referring to the URL address below this line.\nhttps://theodora.com/drugs/atryn_antithrombin_recombinant_gtc_biotherapeutics.html\nThis page was last modified 30-JUN-07"

"Trial record 20 of 1393 for: bilirubin AND alanine\nWEUKBRE5555: IMI PROTECT(Work Package 2): Liver Injury & Antibiotics\nFirst Posted : April 30, 2012\nLast Update Posted : December 10, 2014\nThe studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 (WP2) and Workgroup 1. The primary aim of these studies is to develop, test and disseminate methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE) studies applicable to different safety issues and using different data sources. To achieve this, results from PE studies on 5 key adverse events (AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the studies in this protocol and not on the clinical consequences of the association under investigation. The standards to develop will contribute to decreasing the discrepancies in results from different studies in the future and increase the usefulness and reliability of these studies for benefit-risk assessment in the EU.\nWe propose to assess the association between antibiotics use and idiopathic acute liver injury with different study designs (descriptive, cohort, nested case-control and case crossover) across different primary care databases and to compare the results between databases, across designs to evaluate the impact of design/database/population differences on the outcome of the studied association.\nSpecific aims (in each database):\nTo describe characteristics, clinical features, and risk factors for acute liver injury in patients exposed and unexposed to antibiotics.\nTo estimate the overall risk of acute liver injury associated with antibiotics exposure (users and non-users) in each database\nTo estimate the risk of acute liver injury associated with various antibiotics classes\nTo estimate the risk of acute liver injury associated with specific individual antibiotics\nTo assess the effect of dose and duration of use for specific individual antibiotics.\nTo compare the results of a case-control study with the results of a retrospective cohort study and self-controlled case series study in the different databases\nThe proposed studies will be collected in populations from the following databases: The General Practice Research Database [GPRD] (UK), Health Improvement Network [THIN] (UK), BIFAP [Base de datos Informatizada para estudios Farmacoepidemiologicos en Atencion Primaria] (Spain)- the Bavarian Claims Database (Germany), Mondriaan (Netherlands), and the National Databases of Denmark.\nInfections, Bacterial Drug: Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009\nAcute liver injury is one of the most important safety concerns, being the leading cause for drug withdrawal from the market on safety grounds. For most suspected hepatotoxic drugs the only existing information comes from spontaneous reports, lacking appropriate risk quantification through formal epidemiological studies. A few population-based studies examining the risk of acute and clinically relevant liver injury among users of various drugs have been published, reporting an elevated risk of liver injury in users of antibiotics. As acute liver injury is often idiosyncratic and because its diagnostic criteria used in epidemiological studies have been variable, the reported range of incidences of acute liver injury caused by antibiotics is broad. In the United Kingdom (UK), case-control studies investigating the effect of antibiotics on acute liver injury have generated odds ratios ranging from 94.8 for the combination of amoxicillin/clavulanic acid to 6.2 for tetracyclines. Age, sex, alcohol intake, concomitant medication and comorbidities have been proposed as risk factors for antibiotic induced liver injury and may have influenced the quantification of risk estimates. In the present protocol, we propose to further quantify the risk of acute liver injury associated with antibiotics in the general population using different study designs and in different primary care databases, and to compare the results to evaluate the impact of design and population differences on the outcome of the study association.\nAcute liver injury or hepatotoxicity in this study implies chemical, drug driven liver damage which can be classified based on clinical presentation and laboratory features ranging from asymptomatic mild biochemical abnormalities to acute liver failure. The most common classification used for drug induced liver injury (DILI) is according to laboratory abnormalities (hepatocellular, cholestatic or mixed) and according to mechanism of toxicity (direct, immune-mediated, idiosyncratic, or mitochondrial toxicity). Being idiosyncratic in most cases, reactions often cannot be reproduced experimentally in laboratory animals. The relationship between the dose and the occurrence or severity of the reaction is not constant, and the latent period between drug exposure and sensitivity reaction is rather variable. The infrequency of DILI, though with significant impact, and complicated case ascertainment in pharmacoepidemiological studies has led to wide ranges of reported incidence rates. A recent study, using data from the GPRD database, reported crude incidence rates of liver injury caused by any type of drug ranging from 1 to 18 per 100,000 prescriptions. The Drug-Induced Liver Injury Network (DILIN), a US based collaboration between academic and health institutions to study the aetiology and prevention of DILI, found antibiotics to be the largest class of agents to cause drug-induced liver injury. UK based estimates of incidence rates of antibiotic induced liver injury range from 2.5 to 8.6 per 100,000 users.\nAntibiotics are a type of antimicrobial used to treat infections and are amongst the twenty most prescribed drugs in England, with approximately 38.7 million prescriptions dispensed in 2009. The most frequently prescribed type of antibiotics is penicillins, a group of bactericidal antibiotics that interfere with bacterial cell wall synthesis. Other bactericidal antibiotics include cephalosporins and aminoglycosides. Antibiotics with bacteriostatic mechanisms of action, inhibiting the growth or proliferation of bacterial cells, include tetracyclines, macrolides, sulphonamides and quinolones. Most types of antibiotics have been associated with drug-induced liver injury.\nLiver injury accounts for 10% of all adverse reactions to drugs and is the most frequent reason for withdrawal of medications from the market. This study would provide a valuable contribution to our current knowledge as drug induced liver injury is the most common cause of acute liver failure and antibiotics are the largest drug class of agents, with the highest exposure prevalence, to cause acute liver injury.\nStudy Type : Observational\nOfficial Title: WEUKBRE5555: IMI PROTECT (Work Package 2): The Risk of Acute Liver Injury Associated With the Use of Antibiotics\nStudy Start Date : November 2011\nActual Primary Completion Date : July 2014\nActual Study Completion Date : July 2014\nMedlinePlus related topics: Antibiotics\nPatients with a definite case of acute liver injury\nThe information recorded in the patients' medical record met all the criteria to be classified as idiopathic acute liver injury and the patient presents with at least with one of the following conditions (A+B or A+C):\nA - A diagnosis of liver injury (codes listed in tables 1a, 1b, 1c) with a referral to a specialist or hospital.\nTogether with B - An increase of more than two times the upper limit of the normal range in alanine aminotransferase (ALT) or C - A combined increase in aspartate aminotransferase (AST), alkaline phosphatase (AP) and total bilirubin provided one of them is twice the upper limit of the respective normal range.\nDrug: Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009\nAntibiotics will be analysed overall, by class (tetracyclines, penicillins and betalactamics, cephalosporins, macrolides, aminoglycosides, quinolones and other antibiotics (sulphonamides & others combinations)) and individually. The antibiotics administered to patients include: cefuroxime axetil, cefuroxime sodium, ceftazidime sodium, amoxicillin, amoxicillin/ clavulanate, ampicillin, ampicillin/cloxacillin, flucloxacillin, ticarcillin, and ticarcillin/ clavulanate.\nPatients with a probable case of acute liver injury\nThe information recorded in the patients' medical file was compatible with idiopathic acute liver injury, but not fulfilling all conditions and criteria to be defined as definite case. For example, patients identified with a READ or ICPC code for acute liver injury with a hospitalization or visit to a specialist but without complete laboratory criteria or patients identified with a READ or ICPC code for acute liver injury without a referral to a hospital/specialist, and with or without complete laboratory data.\nNon-cases\nAny potential or probable case that was excluded in one of the previous steps and those with insufficient data to determine their case status. Patients presenting normal liver function tests (LFTs), alcohol related problems, gallbladder disease, pancreatic disease, or other liver diseases with clear aetiology such as viral, alcoholic or autoimmune, or presence of other well defined pathology known to cause acute liver injury will be considered non-cases.\nIdiopathic acute liver injury [ Time Frame: Up to six years following drug exposure ]\nIdiopathic acute liver injury, defined at least with one of the following conditions (A+B or A+C): A - A diagnosis of liver injury (codes listed in tables 1a, 1b, 1c) with a referral to a specialist or hospital. Together with B - An increase of more than two times the upper limit of the normal range in alanine aminotransferase (ALT) or C - A combined increase in aspartate aminotransferase (AST), alkaline phosphatase (AP) and total bilirubin provided one of them is twice the upper limit of the respective normal range.\nSampling Method: Non-Probability Sample\nThe primary source population will be comprised of patients of all ages with an active or died registration status during the study period of January 1, 2004 to December 31, 2009. Patients must have attained one year of enrolment with the general practioner (GP) and one year of computerized prescription history.\nFrom the aforementioned source population, two study cohorts will be selected.\nThe first cohort will include all patients who received at least one antibiotic prescription during the study period. For this cohort, the date of first prescription of an antibiotic after meeting the eligibility criteria (entry date) defines the start of follow-up (start date), for the exposed cohort.\nThe second cohort will be selected from the same source population among patients who have not received an antibiotic prescription during the study period and in the year before the entry date (date when the patient meet the eligibility criteria and enter in the study).\nIndividuals with an active or died registration status d during the study period of January 1, 2004 to December 31, 2009\nIndividuals enrolled at least one year with the with the GP and having one year of computerized prescription history\nIndividuals with Read codes for idiopathic acute liver injury/disease, ICD-10 codes for Acute Liver injury, or CIAP codes for Idiopathic Acute Liver injury prior to start date\nIndividuals with one of the following diagnoses prior to the start date: cancer, alcoholism, alcohol related problems, gallbladder disease, pancreatic disease, and other chronic liver diseases.\nStudy Director: GSK Clinical Trials GlaxoSmithKline\nResponsible Party: GlaxoSmithKline\nOther Study ID Numbers: 115738\nWEUKBRE5559 ( Other Identifier: GSK )\nFirst Posted: April 30, 2012 Key Record Dates\nLast Update Posted: December 10, 2014\nLast Verified: December 2014\nKeywords provided by GlaxoSmithKline:\nAcute liver injury\nLiver Extracts\nHematinics"

"Label: XATMEP- methotrexate solution\nBoxed Warnings\nNDC Code(s): 52652-2001-1, 52652-2001-6\nPackager: Azurity Pharmaceuticals, Inc.\nMarketing Status: New Drug Application\nHIGHLIGHTS OF PRESCRIBING INFORMATION\nThese highlights do not include all the information needed to use XATMEP® safely and effectively. See full prescribing information for XATMEP.\nXATMEP (methotrexate) oral solution\nInitial U.S. Approval: 1953\nWARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY\nSee full prescribing information for complete boxed warning.\nMethotrexate can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression (5.1), infection (5.2), renal (5.3), gastrointestinal (5.4), hepatic (5.5), pulmonary (5.6), hypersensitivity and dermatologic (5.7).\nMethotrexate can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with XATMEP (5.9, 8.1, 8.3).\nXATMEP is a folate analog metabolic inhibitor indicated for the:\nTreatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen (1.1).\nManagement of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy (1.2).\nUse another formulation of methotrexate for patients requiring dosing via routes of administration other than oral (2.1).\nMeasure with an accurate measuring device (2.1).\nALL: 20 mg/m2 one time weekly (2.2).\npJIA: Starting dose of 10 mg/m2 one time weekly (2.3).\nDOSAGE FORMS AND STRENGTHS\nOral solution: 2.5 mg/mL (3).\nPregnancy (patients with pJIA) (4).\nSevere hypersensitivity to methotrexate (4).\nSecondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue methotrexate before starting treatment for lymphoma (5.8).\nImmunizations may be ineffective (5.10).\nEffects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).\nMost common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection (6).\nTo report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\nOral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly (7.1).\nNitrous Oxide: May increase the risk of toxicity (7.1).\nNSAIDs, Aspirin, and Steroids: May elevate and prolong serum methotrexate levels and increase gastrointestinal toxicity. Monitor patients accordingly (7.1).\nUSE IN SPECIFIC POPULATIONS\nLactation: Advise women not to breastfeed (8.2).\nSee 17 for PATIENT COUNSELING INFORMATION.\nRevised: 9/2020\nFULL PRESCRIBING INFORMATION: CONTENTS*\n1 INDICATIONS AND USAGE\n1.1 Acute Lymphoblastic Leukemia\n1.2 Polyarticular Juvenile Idiopathic Arthritis\n2 DOSAGE AND ADMINISTRATION\n2.1 Important Administration Information\n2.4 Evaluations Prior to Starting Methotrexate\n2.5 Handling Information\n3 DOSAGE FORMS AND STRENGTHS\n4 CONTRAINDICATIONS\n5 WARNINGS AND PRECAUTIONS\n5.1 Bone Marrow Suppression\n5.2 Serious Infections\n5.3 Renal Toxicity and Increased Toxicity with Renal Impairment\n5.4 Gastrointestinal Toxicity\n5.5 Hepatic Toxicity\n5.6 Pulmonary Toxicity\n5.7 Hypersensitivity and Dermatologic Reactions\n5.8 Secondary Malignancies\n5.9 Embryo-Fetal Toxicity\n5.10 Ineffective Immunization and Risks Associated with Live Vaccines\n5.11 Effects on Reproduction\n5.12 Increased Toxicity Due to Third-Space Accumulation\n5.13 Soft Tissue and Bone Toxicity with Radiation Therapy\n5.14 Laboratory Tests\n5.15 Risk of Improper Dosing\n6 ADVERSE REACTIONS\n6.1 Clinical Trials Experience\n6.2 Postmarketing Experience\n7 DRUG INTERACTIONS\n7.1 Effect of Other Drugs on XATMEP\n7.2 Effect of XATMEP on Other Drugs\n8 USE IN SPECIFIC POPULATIONS\n8.1 Pregnancy\n8.2 Lactation\n8.3 Females and Males of Reproductive Potential\n8.4 Pediatric Use\n8.6 Renal Impairment\n8.7 Hepatic Impairment\n10 OVERDOSAGE\n11 DESCRIPTION\n12 CLINICAL PHARMACOLOGY\n12.1 Mechanism of Action\n12.2 Pharmacodynamics\n12.3 Pharmacokinetics\n13 NONCLINICAL TOXICOLOGY\n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility\n14 CLINICAL STUDIES\n16 HOW SUPPLIED/STORAGE AND HANDLING\n17 PATIENT COUNSELING INFORMATION\nSections or subsections omitted from the full prescribing information are not listed.\nBOXED WARNING (What is this?)\nMethotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate.\nBone marrow suppression [see Warnings and Precautions (5.1)]\nSerious infections [see Warnings and Precautions (5.2)]\nRenal toxicity and increased toxicity with renal impairment [see Warnings and Precautions (5.3)]\nGastrointestinal toxicity [see Warnings and Precautions (5.4)]\nHepatic toxicity [see Warnings and Precautions (5.5)]\nPulmonary toxicity [see Warnings and Precautions (5.6)]\nHypersensitivity and dermatologic reactions [see Warnings and Precautions (5.7)]\nMethotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with XATMEP [see Contraindications (4), Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3)].\nXATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.\nXATMEP is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).\nXATMEP is intended for oral use only. Use another formulation of methotrexate for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Warnings and Precautions (5.15), Overdosage (10)].\nIt is important that XATMEP be measured with an accurate measuring device [see Warnings and Precautions (5.15), Patient Counseling Information (17)]. A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.\nThe recommended starting dose of XATMEP, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2 given one time weekly. After initiating XATMEP, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.\nThe recommended starting dose of XATMEP is 10 mg/m2 given one time weekly.\nDosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week in pediatric patients, doses greater than 20 mg/m2/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered by an alternative route using another formulation.\nTherapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.\nCertain side effects such as mouth sores may be reduced by folate supplementation with methotrexate in pJIA.\nAssess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with XATMEP [see Warnings and Precautions (5.1, 5.3, 5.5, 5.7, 5.14)]. Exclude pregnancy in females of reproductive potential before starting XATMEP [see Contraindications (4), Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3)].\nXATMEP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1\nXATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter.\nXATMEP is contraindicated in the following:\nPregnancy in patients with non-malignant diseases. XATMEP can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].\nPatients with severe hypersensitivity to methotrexate [see Warnings and Precautions (5.7), Adverse Reactions (6.1, 6.2)].\nXATMEP suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.\nObtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue XATMEP as needed.\nPatients treated with XATMEP are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections.\nMonitor patients for the signs and symptoms of infection during and after treatment with XATMEP and treat promptly. Consider dose modification or discontinuation of XATMEP in patients who develop serious infections [see Warnings and Precautions (5.1)].\nXATMEP can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.\nConsider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function [see glucarpidase Prescribing Information].\nXATMEP can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.\nInterrupt or discontinue XATMEP and institute appropriate supportive care as needed.\nUnexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of XATMEP (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)].\nXATMEP can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of XATMEP in patients with chronic liver disease.\nAssess liver function prior to initiating XATMEP and monitor liver function tests during treatment. Interrupt or discontinue XATMEP as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.\nOther risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age.\nMethotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue XATMEP as appropriate.\nSevere, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with methotrexate. Discontinue XATMEP if severe dermatologic reactions occur.\nAnaphylaxis can occur with methotrexate. If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue methotrexate and institute appropriate therapy. Methotrexate is contraindicated for use in patients with a history of severe hypersensitivity.\nRadiation dermatitis and sunburn may be \"recalled\" by the use of methotrexate.\nSecondary malignancies can occur at all dose levels of methotrexate.\nThere have been instances of lymphoproliferative disease associated with low-dose oral methotrexate which have regressed completely following withdrawal of methotrexate without institution of antineoplastic therapy. Discontinue XATMEP first and institute appropriate treatment if the lymphoma does not regress.\nBased on published reports and methotrexate's mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, methotrexate is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final methotrexate dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].\nImmunization may be ineffective when given during XATMEP therapy.\nImmunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.\nBased on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients [see Use in Specific Populations (8.3)].\nMethotrexate can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to methotrexate administration [see Clinical Pharmacology (12.3)].\nConcomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate.\nClosely monitor patients undergoing XATMEP therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1, 5.3, 5.5)].\nIncrease monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration).\nTransient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation [see Warnings and Precautions (5.5)].\nPulmonary Function Tests\nPulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available [see Warnings and Precautions (5.6)].\nBoth the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosage and Administration (2.1), Overdosage (10)].\nAdvise patients to measure XATMEP with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions [see Overdosage (10)]. Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [see Dosage and Administration (2.1), Patient Counseling Information (17)].\nThe following adverse reactions are discussed in more detail in other sections of the labeling.\nSecondary Malignancies [see Warnings and Precautions (5.8)]\nIneffective Immunization and Risks Associated with Live Vaccines [see Warnings and Precautions (5.10)]\nInfertility [see Warnings and Precautions (5.11)]\nIncreased Toxicity Due to Third‑Space Accumulation [see Warnings and Precautions (5.12)]\nSoft Tissue and Bone Toxicity with Radiation Therapy [see Warnings and Precautions (5.13)]\nBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.\nThe most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase methotrexate toxicity.\nPolyarticular Juvenile Idiopathic Arthritis\nThe approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.\nAdditional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system.\nBlood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia\nCardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension\nEye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia\nGastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis\nHepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations\nImmune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions\nInfections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex\nMetabolism: Hyperglycemia and tumor lysis syndrome\nMusculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis\nNervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.\nFollowing low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.\nRenal Disorders: Azotemia, hematuria, proteinuria, cystitis\nReproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia\nRespiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis\nSkin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.\nOral Antibiotics\nPenicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Monitor patients accordingly [see Warnings and Precautions (5.1, 5.4)].\nTrimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving methotrexate. Monitor patients accordingly [see Warnings and Precautions (5.1)].\nHepatotoxins\nThe potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving XATMEP with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.\nProbenecid may reduce renal elimination of methotrexate. Consider alternative drugs.\nThe use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increase toxicity. Avoid the simultaneous use of nitrous oxide and methotrexate.\nNonsteroidal Anti-Inflammatory Drugs (NSAIDs), Aspirin, and Steroids\nConcomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.\nCaution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including XATMEP. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.\nDespite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis, including patients with polyarticular juvenile idiopathic arthritis (pJIA), have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in pJIA (10 mg/m2/week as starting dose) are somewhat lower than those used in acute lymphoblastic leukemia and that larger doses could lead to unexpected toxicity. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate.\nMethotrexate may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with XATMEP.\nRisk Summary\nBased on published reports and methotrexate's mechanism of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1)]. In pregnant women with non-malignant disease, XATMEP is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.\nThe estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.\nHuman Data\nPublished data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.\nA prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.\nLimited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during XATMEP therapy.\nTest for pregnancy prior to initiating therapy with XATMEP.\nXATMEP can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].\nAdvise females of reproductive potential to use effective contraception during and for 6 months after the final methotrexate dose.\nMethotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final methotrexate dose.\nBased on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that XATMEP can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.\nBased on published reports of male infertility after therapy with methotrexate, advise males of reproductive potential that XATMEP can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.\nSafety and effectiveness of XATMEP in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) [see Clinical Studies (14)].\nMethotrexate elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue XATMEP administration [see Warnings and Precautions (5.3)].\nThe effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity [see Warnings and Precautions (5.5)]. Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.\nFatal overdosage has occurred with methotrexate. Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.\nLeucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure.\nGlucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase Prescribing Information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.\nIn cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.\nXATMEP contains methotrexate, a folate analog metabolic inhibitor.\nChemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:\nXATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL). Inactive ingredients include purified water, sodium citrate, citric acid, methylparaben sodium, propylparaben sodium, and sucralose. It may also contain sodium hydroxide or hydrochloric acid for pH adjustment.\nMethotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.\nThe mechanism of action in pJIA is unknown; it may affect immune function.\nTwo reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mono-nuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects.\nIn pediatric patients with ALL, oral absorption of methotrexate appears to be dose dependent; the absorption of doses greater than 40 mg/m2 is significantly less than that of lower doses. The extent of oral absorption ranges from 23% to 95%, and the time to peak concentration (Tmax) ranges from 0.7 hours to 4 hours after an oral dose of 15 mg/m2.\nIn pediatric patients with pJIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours following oral administration of methotrexate at a dose of 6.4 mg/m2/week to 11.2 mg/m2/week.\nEffect of Food\nThe administration of XATMEP with food did not affect the area under the curve (AUC), but decreased the maximal concentrations (Cmax) by 50% and delayed the absorption.\nAfter intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight).\nMethotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved.\nMethotrexate in serum is approximately 50% protein bound.\nMethotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally.\nIn adults, the half-life of methotrexate following administration of low dose methotrexate (less than 30 mg/m2) ranges from 3 hours to 10 hours.\nIn pediatric patients receiving methotrexate for ALL (6.3 mg/m2 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 hours to 5.8 hours.\nIn pediatric patients receiving methotrexate for JIA (3.75 mg/m2 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.9 hours to 2.3 hours.\nMethotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7‑hydroxymethotrexate may occur at doses commonly prescribed. The aqueous solubility of 7‑hydroxymethotrexate is 3- to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.\nRenal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.\nRenal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in patients at doses between 7.5 mg and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels.\nMethotrexate clearance decreases at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. When a patient has delayed drug elimination due to compromised renal function, a third-space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.\nMethotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain.\nClinical trials in patients with polyarticular juvenile idiopathic arthritis were performed using other formulations of methotrexate.\nIn a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile idiopathic arthritis (JIA) (mean age, 10.1 years; age range 2.5 to 18 years, mean duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given one time weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician's global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JIA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/week methotrexate. The overwhelming majority of the remaining patients had systemic-course JIA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial.\n\"Hazardous Drugs\" OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html\nXATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL). It is packaged in a high-density polyethylene (HDPE) bottle with a child-resistant cap and tamper-evident seal.\nXATMEP is available in bottles of 60 mL (NDC 52652-2001-6) and 120 mL (NDC 52652-2001-1).\nStore XATMEP refrigerated (2°C to 8°C/36°F to 46°F) tightly closed in the original container prior to dispensing.\nOnce dispensed, patients may store XATMEP either refrigerated (2°C to 8°C/36°F to 46°F) or at room temperature (20°C to 25°C/68°F to 77°F) with excursions permitted to 15°C to 30°C/59°F to 86°F [see USP Controlled Room Temperature]. If stored at room temperature, discard after 60 days. Avoid freezing and excessive heat.\nImportance of Proper Dosing and Administration\nAdvise patients that the recommended dose should be taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosage and Administration (2.1), Warnings and Precautions (5.15)].\nAdvise patients and caregivers to measure XATMEP with an accurate milliliter measuring device. A household teaspoon is not an accurate measuring device. Advise patients and caregivers to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose.\nBone Marrow Suppression and Serious Infections\nAdvise patients to contact their healthcare provider for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions (5.1, 5.2)].\nRenal Toxicity\nAdvise patients that methotrexate can cause renal toxicity [see Warnings and Precautions (5.3)].\nGastrointestinal Toxicity\nAdvise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis [see Warnings and Precautions (5.4)].\nHepatic Toxicity\nAdvise patients concerning the risk of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions (5.5)].\nPulmonary Toxicity\nAdvise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions (5.6)].\nAdvise patients concerning the risk for severe hypersensitivity reactions due to XATMEP treatment. These can be fatal and may include severe dermatologic reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, and erythema multiforme. Advise patients to contact their healthcare provider for signs of a new or worsening rash [see Warnings and Precautions (5.7)].\nSecondary Malignancies\nAdvise patients that there is a risk of secondary malignancies during or following treatment with XATMEP [see Warnings and Precautions (5.8)].\nEmbryo-Fetal Toxicity\nAdvise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.9), Use in Specific Populations (8.1)].\nAdvise females of reproductive potential to use effective contraception during XATMEP therapy and for 6 months after the final dose [see Use in Specific Populations (8.3)].\nAdvise males of reproductive potential to use effective contraception during XATMEP therapy and for 3 months after the final dose [see Use in Specific Populations (8.3)].\nIneffective Immunization and Risks Associated with Live Vaccines\nAdvise patients to avoid receiving vaccines during treatment with XATMEP because they may not be effective and live virus vaccines may cause infection [see Warnings and Precautions (5.10)].\nAdvise patients of reproductive potential that XATMEP may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions (5.11), Use in Specific Populations (8.3)].\nAdvise females not to breastfeed during therapy with XATMEP [see Use in Specific Populations (8.2)].\nProper Storage and Disposal\nAdvise patients to store XATMEP either refrigerated (2°C to 8°C/36°F to 46°F) or at room temperature (20°C to 25°C/68°F to 77°F) with excursions permitted to 15°C to 30°C/59°F to 86°F. If stored at room temperature, discard after 60 days. Inform patients and caregivers of the need for proper storage and disposal of dispensing bottles and dosing devices [see References (15)].\nManufactured for:\nAzurity Pharmaceuticals, Inc.\nWilmington, MA 01887 USA\nU.S. Patent: 9,259,427; 9,855,215\nThis product's label may have been updated. For current full prescribing information, please visit www.xatmep.com\nPI100072.03 Rev. 9/2020\nPRINCIPAL DISPLAY PANEL - 120 mL Bottle Label\n120 mL Bottle Label\nNDC 52652-2001-1\nXatmep®\n(methotrexate)\nOral Solution\nFor Oral Use Only\nCAUTION: Cytotoxic agent\nazurity\nEach 1 mL contains 2.5 mg\nmethotrexate (equivalent to\n2.74 mg methotrexate sodium).\nUsual Dose:\nSee prescribing information.\nKEEP THIS AND ALL MEDICATIONS\nOUT OF THE REACH OF CHILDREN\nStore refrigerated\n2° - 8°C (36° - 46°F)\nPatients may store Xatmep\neither refrigerated or at\n(20° - 25°C/68° - 77°F).\nIf stored at room temperature,\ndiscard after 60 days.\nDiscard on\n_____/_____/_____\nXATMEP\nmethotrexate solution\nProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52652-2001\nRoute of Administration ORAL\nMETHOTREXATE (UNII: YL5FZ2Y5U1) (METHOTREXATE - UNII:YL5FZ2Y5U1) METHOTREXATE 2.5 mg in 1 mL\nSODIUM CITRATE, UNSPECIFIED FORM (UNII: 1Q73Q2JULR)\nCITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)\nMETHYLPARABEN SODIUM (UNII: CR6K9C2NHK)\nPROPYLPARABEN SODIUM (UNII: 625NNB0G9N)\nSUCRALOSE (UNII: 96K6UQ3ZD4)\nSODIUM HYDROXIDE (UNII: 55X04QC32I)\nHYDROCHLORIC ACID (UNII: QTT17582CB)\nNDC:52652-2001-1 120 mL in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2017\nNDC:52652-2001-6 60 mL in 1 BOTTLE; Type 0: Not a Combination Product 08/13/2018\nNDA NDA208400 05/01/2017\nLabeler - Azurity Pharmaceuticals, Inc. (117528301)\nBoxed Warnings, Report Adverse Events, FDA Safety Recalls, Presence in Breast Milk\nXATMEP- methotrexate solution\n1 1921592 methotrexate 2.5 MG/ML Oral Solution PSN\n2 1921592 methotrexate 2.5 MG/ML Oral Solution SCD\n3 1921592 methotrexate 2.5 MG/ML (methotrexate sodium 2.74 MG/ML) Oral Solution SY\n4 1921598 Xatmep 2.5 MG/ML Oral Solution PSN\n5 1921598 methotrexate 2.5 MG/ML Oral Solution [Xatmep] SBD\n6 1921598 methotrexate 2.5 MG/ML (methotrexate sodium 2.74 MG/ML) Oral Solution [Xatmep] SY\n7 1921598 Xatmep 2.5 MG/ML Oral Solution SY\nhttps://dailymed.nlm.nih.gov/dailymed/labelrss.cfm?setid=aec9984e-34c5-481b-b6bf-9bb5caf1daf8\n1 52652-2001-1"

"Plasma concentration maximum of LPV, ABC and 3TC with the 4-in-1 formulation.\nConcentration time maximum for LPV, ABC and 3TC with the 4-in-1 formulation.\nClearance function for LPV, ABC and 3TC with the 4-in-1 formulation.\nGeometric mean ratio (GMR) of steady state LPV, ABC and 3TC versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen.\nArea under curve plasma concentration versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen.\nGeometric mean ratio (GMR) of steady state LPV, ABC and 3TC in the 4-in-1 formulation versus the reference treatment regimen.\nPeak plasma concentration in the 4-in-1 formulation versus the reference treatment regimen.\nSafety: A description of the proportion of children experiencing an Adverse event or Serious Adverse event binomial distribution compared between the two formulations.\nComparison of proportion of children with viral load less than 1000 copies/ml at baseline and at end of the study.\nA phase I/II, open label, randomized crossover pharmacokinetic, safety and acceptability study of the Abacavir/Lamivudine/ Lopinavir/Ritonavir (30/15/ 40/10mg ;4-in-1) Fixed-Dose Combination vs. Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg tablets) in HIV infected Children.\nThe study is intended to support the adoption of the 4-in-1 by healthcare providers and will provide data that may support its registration in certain countries. The study will be carried out in HIV-infected children in Uganda weighing 3 to 25 kg (inclusive) and unable to swallow tablets and will provide supportive clinical data on the pharmacokinetics, safety, tolerability and acceptability of the 4-in-1.\nThe primary objective is to estimate the population average exposure to LPV, ABC and 3TC provided by the 4-in-1 formulation in HIV-infected children dosed per WHO weight bands.\nTo evaluate and compare the safety and tolerability of the 4-in-1 formulation versus a reference treatment regimen.\nTo compare the bioavailability of LPV, ABC and 3TC in the 4-in-1 formulation versus a reference treatment regimen.\nTo assess the factors that contribute to acceptability of the new 4-in-1 formulation.\nThis is a fixed dose combination. Each capsule contains Lopinavir (40mg), Ritonavir (10mg), Abacavir (30mg) and Lamivudine (15mg) in granules formulation.\nAbacavir/Lamivudine/ Lopinavir/Ritonavir (30/15/ 40/10mg ;4-in-1) Fixed-Dose Combination in granules formulation administered twice daily for at least 3 weeks, Followed by Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) administered twice daily for at least 3 weeks.\nLopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) administered twice daily for at least 3 weeks.\nFollowed by Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) administered twice daily for at least 3 weeks.\nParent or guardian able and willing to provide written informed consent.\nFor lowest weight band (≥3 and ≤ 5.9kgs) ONLY: under treatment for at least 3 weeks but not more than 12 weeks.\nPlanned or concurrent use of NNRTIs, integrase inhibitors, entry inhibitors, or Protease Inhibitors (PIs) other than LPV/r.\nTreatment failure with proven resistances to PIs.\nPulmonary Tuberculosis and any clinically significant disease or finding during screening that, in the investigator's opinion, would compromise participation in this study."

"VINORELBINE- vinorelbine injection, solution\nHospira, Inc.\nHIGHLIGHTS OF PRESCRIBING INFORMATION\nThese highlights do not include all the information needed to use VINORELBINE INJECTION safely and effectively. See full prescribing information for VINORELBINE INJECTION.\nVINORELBINE INJECTION, USP, injection, for intravenous use\nInitial U.S. Approval: 1994\nWARNING: MYELOSUPPRESSION\nSee full prescribing information for complete boxed warning.\nSevere myelosuppression resulting in serious infection, septic shock, and death may occur (5.1).\nDecrease the dose or withhold Vinorelbine in accord with recommended dose modifications (2.2).\nINDICATIONS AND USAGE\nVinorelbine Injection, USP, is a vinca alkaloid indicated:\nIn combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). (1)\nAs a single agent for first-line treatment of patients with metastatic NSCLC. (1)\nDOSAGE AND ADMINISTRATION\nIn combination with cisplatin: 25 to 30 mg/m2 as a single intravenous injection weekly. (2.1)\nSingle agent: 30 mg/m2 as a single intravenous injection weekly. (2.1)\nAdjust the dose in patients with decreased neutrophil counts or elevated serum total bilirubin. (2.2)\nInjection: single-dose vials of 10 mg/mL and 50 mg/5 mL (3)\nHepatic toxicity: monitor liver function during treatment. (5.2)\nSevere constipation and bowel obstruction including necrosis and perforation can occur. Institute a prophylactic bowel regimen to mitigate potential constipation. Monitor for abdominal pain and severe constipation. (5.3)\nExtravasation can result in severe tissue injury, necrosis and/or thrombophlebitis. Immediately stop Vinorelbine and institute recommended management procedures. (5.4)\nNeurologic toxicity: severe sensory and motor neuropathies can occur. Monitor patients for new or worsening signs and symptoms of neuropathy. (5.5)\nPulmonary toxicity and respiratory failure can occur with use of Vinorelbine. Monitor patient's respiratory disorders: dyspnea and bronchospasm Interrupt Vinorelbine in patients who develop unexplained dyspnea. (5.6)\nEmbryo-fetal toxicity: can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus. (5.7, 8.1)\nMost common adverse reactions (incidence ≥ 20%) are neutropenia, anemia, liver enzyme elevation, nausea, vomiting, asthenia, constipation, injection site reaction, and peripheral neuropathy. (6.1)\nTo report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\nInhibitors of CYP3A4: increased severity of adverse reactions. (7.1)\nUSE IN SPECIFIC POPULATIONS\nNursing Mothers: discontinue drug or nursing taking into consideration importance of drug to mother. (8.3)\nSee 17 for PATIENT COUNSELING INFORMATION.\nRevised: 7/2018\nFULL PRESCRIBING INFORMATION: CONTENTS*\n1 INDICATIONS AND USAGE\n2 DOSAGE AND ADMINISTRATION\n2.1 Recommended Dose\n2.2 Dose Modifications\n2.3 Preparation and Administration\n2.4 Procedures for Proper Handling and Disposal\n3 DOSAGE FORMS AND STRENGTHS\n4 CONTRAINDICATIONS\n5 WARNINGS AND PRECAUTIONS\n5.1 Myelosuppression\n5.2 Hepatic Toxicity\n5.3 Severe Constipation and Bowel Obstruction\n5.4 Extravasation and Tissue Injury\n5.5 Neurologic Toxicity\n5.6 Pulmonary Toxicity and Respiratory Failure\n5.7 Embryo-Fetal Toxicity\n6 ADVERSE REACTIONS\n6.1 Clinical Trials Experience\n6.2 Postmarketing Experience\n7 DRUG INTERACTIONS\n7.1 CYP3A Inhibitors\n8 USE IN SPECIFIC POPULATIONS\n8.1 Pregnancy\n8.3 Nursing Mothers\n8.4 Pediatric Use\n8.5 Geriatric Use\n8.6 Hepatic Impairment\n8.7 Females and Males of Reproductive Potential\n10 OVERDOSAGE\n11 DESCRIPTION\n12 CLINICAL PHARMACOLOGY\n12.1 Mechanism of Action\n12.3 Pharmacokinetics\n13 NONCLINICAL TOXICOLOGY\n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility\n14 CLINICAL STUDIES\n14.1 Combination Use with Cisplatin\n14.2 Single Agent\n16 HOW SUPPLIED/STORAGE AND HANDLING\n17 PATIENT COUNSELING INFORMATION\nSections or subsections omitted from the full prescribing information are not listed.\nFULL PRESCRIBING INFORMATION\nSevere myelosuppression resulting in serious infection, septic shock, hospitalization and death may occur [see Warnings and Precautions (5.1)].\nDecrease the dose or withhold Vinorelbine in accord with recommended dose modifications [see Dosage and Administration (2.2)].\nVinorelbine Injection, USP is indicated:\nIn combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)\nAs a single agent, for the treatment of patients with metastatic NSCLC\nIn Combination with Cisplatin 100 mg/m2\nThe recommended dose of Vinorelbine is 25 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes on Days 1, 8, 15, and 21 of a 28 day cycle in combination with cisplatin 100 mg/m2 on Day 1 only of each 28 day cycle.\nThe recommended dose of Vinorelbine is 30 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m2 on Days 1 and 29, then every 6 weeks.\nSingle-Agent\nThe recommended dose of Vinorelbine is 30 mg/m2 administered intravenously over 6 to 10 minutes once a week.\nHematologic Toxicity\n[see Warnings and Precautions (5.1)]\nHold or decrease the dose of Vinorelbine in patients with decreased neutrophil counts using the following schema.\nNeutrophils on Day of Treatment\n(Cells/mm3)\nPercentage of Starting Dose of Vinorelbine\n≥ 1,500\n1,000 to 1,499\n< 1,000\nDo not administer Vinorelbine. Repeat neutrophil\ncount in one week. If three consecutive weekly doses\nare held because Neutrophil count is\n< 1,000 cells/mm3, discontinue Vinorelbine\nNote: For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine should be:\n> 1,500\ncount in one week.\nHepatic Impairment/Toxicity\n[see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]\nReduce Vinorelbine dose in patients with elevated serum total bilirubin concentration according to the following schema:\nSerum total bilirubin concentration (mg/dl)\nConcurrent Hematologic Toxicity and Hepatic Impairment\nIn patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of Vinorelbine determined from the above schemas.\nNeurologic Toxicity\nDiscontinue Vinorelbine for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.\nPreparation of Vinorelbine Injection\nVinorelbine Injection must be diluted in either a syringe or intravenous bag using one of the recommended solutions.\nDilute to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:\n5% Dextrose Injection, USP\n0.9% Sodium Chloride Injection, USP\nIntravenous Bag\n0.45% Sodium Chloride Injection, USP\n5% Dextrose and 0.45% Sodium Chloride Injection, USP\nRinger's Injection, USP\nLactated Ringer's Injection, USP\nDiluted Vinorelbine Injection may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F).\nAdminister diluted Vinorelbine over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.\nVinorelbine must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine is injected.\nParenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine should not be administered.\nManagement of Suspected Extravasation\nIf Vinorelbine leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)].\nHandle and dispose Vinorelbine consistent with recommendations for the handling and disposal of hazardous drugs.1\nExercise caution in handling and preparing the solution of Vinorelbine. The use of gloves is recommended. If the solution of Vinorelbine contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.\nAvoid contamination of the eye with Vinorelbine. If exposure occurs, flush the eyes with water immediately and thoroughly.\nVinorelbine Injection, USP is a clear, colorless to pale yellow solution in single-dose vials:\n10 mg/mL Single-Dose Vial\n50 mg/5 mL Single-Dose Vial\nMyelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with Vinorelbine as a single agent and in combination with cisplatin [see Adverse Reactions (6.1 and 6.2)]. Neutropenia is the major dose-limiting toxicity with Vinorelbine. Grade 3-4 neutropenia occurred in 53% of patients treated with Vinorelbine at 30 mg/m2 per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with Vinorelbine administered at 30 mg/m2 per week, neutropenia resulted in hospitalizations for pyrexia and/or sepsis in 8% of patients. Death due to sepsis occurred in 1% of patients. Neutropenia nadirs occur between 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days.\nMonitor complete blood counts prior to each dose of Vinorelbine. Do not administer Vinorelbine to patients with neutrophil counts <1,000 cells/mm3. Adjustments in the dosage of Vinorelbine should be based on neutrophil counts obtained on the day of treatment [see Dosage and Administration (2.2)].\nDrug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving Vinorelbine alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of Vinorelbine and periodically during treatment. Reduce the dose of Vinorelbine for patients who develop elevations in total bilirubin > 2 times upper limit of normal [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].\nSevere and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur with Vinorelbine administration. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners.\nExtravasation of Vinorelbine can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of Vinorelbine and institute recommended management procedures [see Dosage and Administration (2.3) and Adverse Reaction (6.1)].\nSensory and motor neuropathies, including severe neuropathies, occur in patients receiving Vinorelbine. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving Vinorelbine. Discontinue Vinorelbine for NCI CTCAE Grade 2 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reaction (6.1)].\nPulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurs with use of Vinorelbine. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range 3 to 8 days) [see Adverse Reactions (6.1)].\nInterrupt Vinorelbine in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue Vinorelbine for confirmed interstitial pneumonitis or ARDS.\nVinorelbine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy with Vinorelbine [see Use in Specific Populations (8.1, 8.7)].\nThe following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the label:\nMyelosuppression [see Warnings and Precautions (5.1)]\nPulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.6)]\nConstipation and Bowel Obstruction [see Warnings and Precautions (5.3)]\nExtravasation Tissue Injury [see Warnings and Precautions (5.4)]\nNeurologic Toxicity [see Warnings and Precautions (5.5)]\nHepatic Toxicity [see Warnings and Precautions (5.2)]\nBecause clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.\nThe data below reflect exposure to Vinorelbine as a single agent administered at a dose of 30 mg/m2 on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of Vinorelbine. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% Caucasian, 48% had adenocarcinoma histology. The data also reflect exposure to Vinorelbine in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of Vinorelbine. Vinorelbine is not indicated for the treatment of breast cancer.\nSelected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions (≥ 20%) of single agent Vinorelbine were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with Vinorelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued Vinorelbine due to adverse reactions. The most frequent adverse reactions leading to Vinorelbine discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever.\nTable 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving Vinorelbine *†:\nGrade based on modified criteria from the National Cancer Institute version 1.\nPatients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.\nAll patients (n=365)\nNSCLC (n= 143)\nLaboratory Hematologic\n< 2,000 cells/mm3\n< 500 cells/mm3\nLeukopenia\n< 100,000 cells/mm3\n< 11 g/dl\n< 8 g/dl\nHospitalizations due to neutropenic complications\nTable 2: Non-hematologic Adverse Reactions Experienced in > 5% of Patients Receiving Vinorelbine*†:\nIncidence of paresthesia plus hypesthesia.\nGrades 3+4\nLaboratory Hepatic\nAST increased (n=346)\nbilirubin increased\nInjection site reaction\nInjection site pain\nNeuropathy peripheral‡\n≤1%\nMyelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent Vinorelbine. Neutropenia is the major dose-limiting toxicity.\nNeurotoxicity: neurotoxicity was most commonly manifested as constipation, paresthesia, hypersthesia, and hyporeflexia. Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single-agent Vinorelbine.\nInjection site reactions: Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients.\nCardiovascular toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in less than 0.1% of patients.\nPulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.\nOther: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.\nIn Combination with Cisplatin\nTable 3 presents the incidence of selected adverse reactions, occurring in ≥ 10% of Vinorelbine treated patients reported in a randomized trial comparing the combination of Vinorelbine 25 mg/m2 administered every week of each 28-day cycle and cisplatin 100 mg/m2 administered on Day 1 of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1).\nPatients randomized to Vinorelbine plus cisplatin received a median of 3 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. Thirty-Five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. The incidence of Grade 3 and 4 neutropenia was significantly higher in the Vinorelbine plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the Vinorelbine plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of Vinorelbine, and 3 from febrile neutropenia.\nTable 3: Adverse Reactions Experienced by ≥ 10% of Patients on Vinorelbine plus Cisplatin versus Single-Agent Cisplatin*\nGraded according to the standard SWOG criteria version 1.\nCategorical toxicity grade not specified\nVinorelbine 25 mg/m2 plus\nCisplatin 100 mg/m2 (n=212)\nHematologic\nFebrile neutropenia†\nBlood creatinine increased\nMalaise/Fatigue/Lethargy\nDecreased appetite\nWeight decreased\nFever without infection\nParaesthesia\nTaste alterations\nPeripheral numbness\nMyalgia/Arthralgia\nPhlebitis/Thrombosis/Embolism\nRespiratory tract infection\nTable 4 presents the incidence of selected adverse reactions, occurring in ≥ 10% of Vinorelbine treated patients reported in a randomized trial of Vinorelbine plus cisplatin, vindesine plus cisplatin and Vinorelbine alone in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either Vinorelbine 30 mg/m2 every week plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or Vinorelbine 30 mg/m2 every week (N=204).\nPatients randomized to Vinorelbine plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and Vinorelbine received 13 weeks. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to Vinorelbine plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively. Grade 3 and 4 neutropenia was significantly greater in the Vinorelbine plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and Vinorelbine alone (53%). Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 3-4, 7%) of the patients receiving Vinorelbine plus cisplatin, 58% (Grades 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3-4, 8.5%) of the patients receiving Vinorelbine alone.\nTable 4: Adverse Reactions Experienced by ≥ 10 % of Patients from a Comparative Trial of Vinorelbine Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent Vinorelbine*\n* Grade based on criteria from the World Health Organization (WHO).\n† n=194 to 207; all patients receiving Vinorelbine/cisplatin with laboratory and non-laboratory data.\n‡ n=173 to 192; all patients receiving vindesine/cisplatin with laboratory and non-laboratory data.\n§ n=165 to 201; all patients receiving Vinorelbine with laboratory and non-laboratory data.\n¦ Categorical toxicity grade not specified.\n¶ Neurotoxicity includes peripheral neuropathy and constipation.\nVinorelbine/Cisplatin†\nVindesine/Cisplatin‡\nVinorelbine§\nBlood creatinine\nincreased¦\nNeurotoxicity¶\nOtotoxicity\nThe following adverse reactions have been identified during post-approval use of Vinorelbine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\nInfections and infestations: pneumonia\nImmune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema\nNervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache\nEar and labyrinth disorders: vestibular disorder, hearing impaired\nCardiac disorders: tachycardia\nRespiratory disorders: pulmonary edema\nVascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation\nGastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis\nSkin disorders: generalized cutaneous reactions (rash), palmar-plantar erythrodysesthesia syndrome\nMusculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia\nGeneral disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin\nInjury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis\nLaboratory abnormalities: electrolyte imbalance including hyponatremia\nOther: tumor pain, back pain, abdominal pain\nExercise caution in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. Concurrent administration of Vinorelbine with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of adverse reactions.\nPregnancy Category D\nRisk Summary\nVinorelbine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.\nAnimal Data\nIn a mouse embryofetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m2 or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic. Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m2 (approximately 0.18 times the recommended human dose based on body surface area) or greater. At doses that did not cause maternal toxicity in either species, vinorelbine administration resulted in reduced fetal weight and delayed ossification.\nIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from vinorelbine, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.\nThe safety and effectiveness of Vinorelbine in pediatric patients have not been established. Results from a single-arm study of Vinorelbine administered at the dose of 33.75 mg/m2 (for 35 patients) or at the dose of 30 mg/m2 (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks). Forty-six patients age 1 to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients), and central nervous system (CNS) tumors (N=21 patients) were enrolled. The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade 3 or 4 non-hematological toxicity adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma. No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4).\nOf the 769 number of patients who received Vinorelbine alone and Vinorelbine in combination with Cisplatin in studies 1, 2 and 3, 247 patients were 65 years of age or older. No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients [see Clinical Pharmacology (12.3)].\nThe influence of hepatic impairment on the pharmacokinetics of Vinorelbine has not been evaluated, but the liver plays an important role in the metabolism of Vinorelbine. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving Vinorelbine alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of Vinorelbine for patients with bilirubin elevation [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].\nVinorelbine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use highly effective contraception during therapy with Vinorelbine.\nVinorelbine may damage spermatozoa [see Nonclinical Toxicology (13.1)]. Males with female sexual partners of reproductive potential should use highly effective contraception during and for 3 months after therapy with Vinorelbine.\nBased on animal findings, Vinorelbine may cause decreased fertility in males [see Nonclinical Toxicology (13.1)].\nThere is no known antidote for overdoses of Vinorelbine. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m2) have been reported. The toxicities described were consistent with those listed in the ADVERSE REACTIONS section including paralytic ileus, stomatitis, and esophagitis. Bone marrow aplasia, sepsis, and paresis have also been reported. Fatalities have occurred following overdose of Vinorelbine. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician.\nVinorelbine Injection, USP contains vinorelbine tartrate, USP, salt of a semi-synthetic vinca alkaloid. The molecular formula for vinorelbine tartrate, USP is C45H54N4O8∙2C4H6O6.\nIt has a molecular weight of 1079.11.\nThe structural formula is as follows:\nVinorelbine tartrate, USP, is a white to light yellow amorphous powder. It is easily soluble in water, very soluble in methanol, and practically insoluble in hexane. Vinorelbine Injection, USP is a sterile nonpyrogenic aqueous solution. Each milliliter of solution contains 13.85 mg vinorelbine tartrate USP equivalent to 10 mg vinorelbine in Water for Injection, USP. The pH of Vinorelbine Injection, USP is approximately 3.5.\nVinorelbine is a vinca alkaloid that interferes with microtubule assembly. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at a concentration of 2 μM inducing a blockade of cells at metaphase, but produced depolymerization of axonal microtubules at a concentration 40 μM, suggesting a modest selectivity of vinorelbine for mitotic microtubules.\nThe pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 administered as 15- to 20-minute constant-rate infusions. Vinorelbine concentrations in plasma decay in a triphasic manner. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg.\nSteady-state volume of distribution (VSS) values range from 25.4 to 40.1 L/kg. Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in human plasma over a concentration range of 234 to 1169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.\nVinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily.\nAfter intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In a different study, 10.9% ± 0.7% of a 30-mg/m2 intravenous dose was excreted as parent drug in urine.\nElderly: Age has no effect on the pharmacokinetics (CL, VSS and t1/2) of vinorelbine.\nThe pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.\nThe carcinogenic potential of Vinorelbine has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.\nVinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m2 (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.\nThe safety and efficacy of Vinorelbine in combination with cisplatin was evaluated in two randomized, multicenter trials.\nCisplatin 100 mg/m2\nStudy 1 was a randomized, multicenter, open-label trial of Vinorelbine plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. A total of 432 patients were randomized 1:1 to receive either Vinorelbine 25 mg/m2 on Day 1 then every week of each 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each 28-day cycle (N=214) or cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=218).\nPatient demographics and disease characteristics were similar between arms. Of the overall study population, the median age was 64 (range 33-84), 66% were male, 80% were Caucasian, 92% had stage IV disease and 8% stage IIIB, 53% had adenocarcinoma, 21% squamous cell, 14% large cell histology. The major efficacy outcome measure was overall survival. The efficacy results are presented in Table 7 and Figure 1.\nTable 7. Efficacy Results (Study 1)\nVinorelbine plus Cisplatin\nCisplatin Alone\nOverall Survival\nMedian Survival in months\n7.8 (6.9, 9.6)\nUnstratified log-rank p-value\nOverall Response rate (ORR)\nEvaluable patients\nORR (95% CI)\n19% (14%, 25%)\n8% (5%, 13%)\nChi-square test p-value\nStudy 2 was a randomized, 3-arm, open-label, multicenter trial of Vinorelbine plus cisplatin, vindesine plus cisplatin and Vinorelbine alone for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy. The study was conducted in Europe. A total of 612 patients were randomized 1:1:1 to receive Vinorelbine 30 mg/m2 every week of a 6- week cycle plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=206); and vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=200) or Vinorelbine 30 mg/m2 every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between Vinorelbine plus cisplatin and vindesine plus cisplatin. The other efficacy outcome measure was to compare overall survival in the better of the two combination regimens to that of Vinorelbine alone.\nPatient demographics were in general similar between arms: the median age of the overall population was 60 years (range 30 to 75), 90% were male, 78% had WHO performance status of 0 or 1. Tumor characteristics were in general similar with the exception of histologic subtype of NSCLC. Adenocarcinoma was the histologic subtype in 32% of patients in the Vinorelbine plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the Vinorelbine alone arm. Ten percent of the patients had stage IIIA disease, 28% stage IIIB and 50% stage IV. Twelve percent of the patients had received prior surgery or radiotherapy.\nThe efficacy results of Study 2 are presented in Table 8.\n1n/a = not applicable\nVinorelbine Alone (N=206)\nVinorelbine plus cisplatin (N=206)\nVindesine plus cisplatin (N=200)\nMedian survival in\nmonths (99.5% CI)\n7.2 (5.4 to 9.1)\n9.2 (7.4 to 11.1)\nUnstratified log-rank\nn/a1\nOverall Response (ORR)\nEvaluable Patients ORR\n19% (14%, 25% )\nChi-square test\nThe safety and efficacy of Vinorelbine as a single agent was evaluated in one randomized multi-center trial.\nStudy 3 was a randomized, open-label clinical trial of Vinorelbine or 5-Fluorouracil (5-FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy A total of 211 patients were randomized 2:1 to receive Vinorelbine 30 mg/m2 weekly of an 8-week cycle (N=143) or 5-FU 425 mg/m2 bolus intravenously plus LV 20 mg/m2 bolus intravenously daily for 5 days of a 4-weeks cycle (N=68).\nPatient demographics and disease characteristics were in general similar between arms. In the overall population, the median age was 61 years (range 32 -83), 74% were male, 88% were Caucasian, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status ≥ 90 in the Vinorelbine arm compared to 38% in the 5-FU and LV arm.\nThe primary efficacy outcome of the study was overall survival. The median survival time was 30 weeks versus 22 weeks for patients receiving Vinorelbine versus 5-FU/LV, respectively (P=0.06). Partial objective responses were observed in 11.1% (95% CI=6.2%, 17.9%) and 3.5% (95% CI=0.4%, 11.9%) of patients who received Vinorelbine and 5-FU/LV, respectively.\nOSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html\nVinorelbine Injection, USP is a clear, colorless to pale yellow aqueous solution available in single-dose, clear glass vials with elastomeric stoppers and green caps, individually packaged in a carton in the following vial sizes:\n10 mg/mL Single-Dose Vial, Carton of 1 (NDC 61703-341-06).\n50 mg/5 mL Single-Dose Vial, Carton of 1 (NDC 61703-341-09).\nStore the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE. Unopened vials of Vinorelbine Injection, USP are stable at 25°C (77°F) for up to 72 hours.\nVinorelbine Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1\nInform patients of the following:\nMyelosuppression\nAdvise patients to contact a healthcare provider for new onset fever, or symptoms of infection [see Warnings and Precautions (5.1)].\nConstipation and bowel obstruction\nAdvise patients to follow a diet rich in fibers, drink fluids to stay well hydrated and use stool softeners to avoid constipation. Contact a health care provider for severe constipation, new onset abdominal pain, nausea and vomiting [see Warnings and Precautions (5.3)].\nAdvise patients to contact a health care provider for new onset or worsening of numbness, tingling, decrease sensation or muscle weakness [see Warnings and Precautions (5.5)].\nPulmonary Toxicity\nAdvise patients to contact a healthcare provider for new onset or worsening of shortness of breath, cough, wheezing or other new pulmonary symptoms [see Warnings and Precautions (5.6)].\nFemales and Males of Reproductive Potential\nVinorelbine can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Vinorelbine, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].\nVinorelbine may damage sperm. Advise males to use highly effective contraception during and for 3 months after therapy [see Use in Specific Population (8.7) and Nonclinical Toxicology (13.1)].\nVinorelbine may cause decreased fertility in males [see Nonclinical Toxicology (13.1)].\nLAB-1343-1.0\nDistributed by Hospira, Inc., Lake Forest, IL 60045 USA\nPRINCIPAL DISPLAY PANEL - 10 mg/mL Vial Label\nRx only\nNDC 61703-341-06\nVinorelbine Injection, USP\nFOR INTRAVENOUS USE\nMUST BE DILUTED\nDiscard Unused Portion\nCytotoxic Agent\nSingle Dose Vial\nPRINCIPAL DISPLAY PANEL - 10 mg/mL Vial Carton\n1 x 1 mL Vial\nInjection, USP\nequivalent to vinorelbine\nCaution: Cytotoxic Agent\nPRINCIPAL DISPLAY PANEL - 50 mg/5 mL Vial Label\n5 mL Vial\n50 mg/5 mL\n(10 mg/mL)\nPRINCIPAL DISPLAY PANEL - 50 mg/5 mL Vial Carton\nvinorelbine injection, solution\nProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61703-341\nRoute of Administration INTRAVENOUS\nVINORELBINE TARTRATE (UNII: 253GQW851Q) (VINORELBINE - UNII:Q6C979R91Y) VINORELBINE 10 mg in 1 mL\nNDC:61703-341-06 1 in 1 CARTON 04/09/2007 10/31/2017\n1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product\nANDA ANDA076827 04/02/2007 05/31/2019\nLabeler - Hospira, Inc. (141588017)\nDocument Id: 7133a031-8cfa-4c67-8c09-12711a45184a\nSet id: 06eeaab8-a00d-4b41-b46b-40163f09ecb8\nEffective Time: 20180806"

"From WikiProjectMed\n/ɒsəlˈtæmɪvɪər/\nethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate\nAU: B1[1]\nRoutes of\nBy mouth (hard capsules or liquid)\nDefined daily dose\n0.15 gram[2]\nLicense data\nEU EMA: by INN\nUS DailyMed: Oseltamivir\nUS FDA: Oseltamivir\nAU: S4 (Prescription only)\nUK: POM (Prescription only)\nUS: ℞-only\n>80%[3]\n42% (parent drug), 3% (active metabolite)[3]\nHepatic, to oseltamivir carboxylate[3]\nElimination half-life\n1–3 hours, 6–10 hours (active metabolite)[3]\nUrine (>90% as oseltamivir carboxylate), faeces[3]\nChemical and physical data\nC16H28N2O4\nMolar mass\n312.410 g·mol−1\nCCC(CC)OC1C=C(CC(C1NC(=O)C)N)C(=O)OCC\nInChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1 Y\nKey:VSZGPKBBMSAYNT-RRFJBIMHSA-N Y\nN Y (what is this?) (verify)\nOseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B (flu).[4] Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection.[5] They recommend it to prevent infection in those at high risk, but not the general population.[5] The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection.[5][6][7] It is taken by mouth, either as a pill or liquid.[4]\nRecommendations regarding oseltamivir are controversial as are criticisms of the recommendations.[5][8][9][10] A 2014 Cochrane Review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza.[10] Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[11][12] They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations.[11][12] However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels.[13]\nCommon side effects include vomiting, diarrhea, headache, and trouble sleeping.[4] Other side effects may include psychiatric symptoms and seizures.[4][14][15] In the United States it is recommended for influenza infection during pregnancy.[1] It has been taken by a small number of pregnant women without signs of problems.[1] Dose adjustment may be needed in those with kidney problems.[4]\nOseltamivir was approved for medical use in the US in 1999.[4] It was the first neuraminidase inhibitor available by mouth.[16] It is on the World Health Organization's List of Essential Medicines but was downgraded to \"complementary\" status in 2017.[17][18] A generic version was approved in the US in 2016.[19][20] As of 2014[update], the wholesale cost in the developing world was about US$4.27 per day.[21] The wholesale cost for a course of treatment in the United States is about US$54.00 as of 2019[update].[22] In 2017, it was the 159th most commonly prescribed medication in the United States, with more than three million prescriptions.[23][24]\n1 Medical use\n1.1 High-risk people\n1.2 Otherwise healthy people\n1.3 Prevention\n1.4 Dosage\n2 Side effects\n3 Mechanism of action\n4.1 H1N1 flu or \"Swine flu\"\n4.2 Seasonal flu\n4.3 H3N2\n4.4 Influenza B\n4.5 H5N1 Avian influenza \"Bird flu\"\n4.6 H7N9 Avian influenza\n5 Pharmacokinetics\n7 Veterinary use\n8 Research\nAn oseltamivir capsule\nOseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses.[4][25] It is on the World Health Organization's List of Essential Medicines.[26] The WHO supports its use for severe illness due to confirmed or suspected influenza virus infection in critically ill people who have been hospitalized.[26] Oseltamivir's risk-benefit ratio is controversial.[9][10] In 2017, it was moved from the core to the complementary list based on its lower cost-effectiveness.[27] The Expert Committee did not recommend the deletion of oseltamivir from the EML and EMLc, recognizing that it is the only medicine included on the Model Lists for critically ill patients with influenza and for influenza pandemic preparedness.[17] However, the Committee noted that, since the inclusion of oseltamivir on the Model List in 2009, new evidence in seasonal and pandemic influenza has lowered earlier estimates of the magnitude of effect of oseltamivir on relevant clinical outcomes.[17] The Committee recommended that the listing of oseltamivir be amended, moving the medicine from the core to the Complementary List, and that its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients.[17] The Expert Committee noted that WHO guidelines for pharmacological management of pandemic and seasonal influenza would be updated in 2017: unless new information is provided to support the use of oseltamivir in seasonal and pandemic outbreaks, the next Expert Committee might consider oseltamivir for deletion.[17]\nHigh-risk people\nThe US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), Public Health England and the American Academy of Pediatrics (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications.[5][6][28][29][30] This includes those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and Indigenous peoples of the Americas among others.[28] The Infectious Disease Society of America takes the same position as the CDC.[8]\nA systematic review of systematic reviews in PLoS One did not find evidence for benefits in people who are at risk, noting that \"the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality\",[11] as did a 2014 Cochrane Review.[31] The Cochrane Review further recommended: \"On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza.\"[31] That is not utilizing NIs for prevention or treatment \"Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks.\"[31]\nThe CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and Roche (the originator) reject the conclusions of the Cochrane Review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza.[5][6][8][29][30] The EMA did not change its labeling of the drug in response to the Cochrane study.[32]\nA 2014 review in the New England Journal of Medicine recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of community-acquired pneumonia receive oseltamivir until the absence of influenza infection is established by PCR testing.[33]\nA 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of otitis media. The same review found that oseltamivir did not significantly increase the risk of adverse events.[34] A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of \"nausea, vomiting, [and] psychiatric events in adults and vomiting in children.\"[35] The decrease in duration of sickness was about 18 hours.[36]\nOtherwise healthy people\nIn those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours.[28] A German clinical practice guideline recommends against its use.[37]\nTwo 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks.[11][12] When the analysis was restricted to people with confirmed infection, the same 2014 Cochrane Review (see above) found unclear evidence of change in the risk of complications such as pneumonia,[31] while three other reviews found a decreased risk.[12][38][39] Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day.[40] Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting.[15]\nThe 2014 Cochrane Collaboration review concluded that oseltamivir did not affect the need for hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms.[31][41]\nThe US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), the Public Health England (PHE), the Infectious Disease Society of America (IDSA), the American Academy of Pediatrics (AAP), and Roche (the originator) rejected the recommendations of the 2014 Cochrane Review to urgently change treatment guidelines and drug labels.[5][6][8][29][30][32]\nAs of 2017[update], the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development.[28] They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated.[28] They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed.[28]\nAs of 2011[update], reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease.[31][42] A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1 to 12% (a relative decrease of 64 to 92%).[11] It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated high risk persons.[11]\nThe defined daily dose is 0.15 gram (by mouth)[2]\nA package of capsules\nCommon adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of people) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the number needed to harm was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious arrhythmias.[31]\nPostmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, abnormal heart rhythms, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome.[43][44]\nThe US and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance.[45][46] The frequency of these appears to be low and a causative role for oseltamivir has not been established.[46][47] The 2014 Cochrane Review found a dose-response effect on psychiatric events. In trials of prevention in adults one person was harmed for every 94 treated.[31] Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events.[45]\nIt is pregnancy category C in the United States and category B in Australia, meaning that it has been taken by a small number of women without signs of problems and in animal studies it looks safe.[25][48] Dose adjustment may be needed in those with kidney problems.[4]\nOseltamivir is a neuraminidase inhibitor, a competitive inhibitor of influenza's neuraminidase enzyme. The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell. Thus oseltamivir prevents new viral particles from being released.[25]\nA/H5N1 subtype\nPandemrix\nLive attenuated\nSeasonal flu vaccine brands\nLaninamivir\nPeramivir\nRimantadine\nUmifenovir\n1918 Spanish flu\n1957 Asian flu\n1968–1969 Hong Kong flu\n2009 swine flu\n2006 H5N1 India\n2007 Australian equine\n2007 Bernard Matthews H5N1\n2008 West Bengal\n2015 United States H5N2 outbreak\nInfluenza evolution\nInfluenza research\nInfluenza-like illness\nVaccine reformulations\nThe vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[49] A 2011 meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher rates among influenza A patients, especially the H1N1 subtype. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia.[49] In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir)-resistant virus, even after oseltamivir treatment was stopped.[5]\nH1N1 flu or \"Swine flu\"\nAs of December 15, 2010[update], the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide showed resistance to oseltamivir.[50]\nThe CDC found sporadic oseltamivir-resistant 2009 H1N1 virus infections had been identified, including with rare episodes of limited transmission, but the public health impact had been limited. Those sporadic cases of resistance were found in immunosuppressed patients during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis.[51]\nDuring 2011, a new influenza A(H1N1)2009 variant with mildly reduced oseltamivir (and zanamivir) sensitivity was detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia.[52]\nWhile there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013[update], widespread transmission of oseltamivir-resistant pH1N1 has not occurred.[53]\nDuring the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.[54] In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance.[55]\nFrom 2009 to 2014, oseltamivir resistance was very low in seasonal flu. In the 2010–11 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US.[56] In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible.[57][58] In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir.[59]\nThree studies have found resistance in 0%, 3.3%, and 18% of subjects.[49] In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations.[60]\nInfluenza B\nIn 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%.[61] According to the CDC, As of 2019[update], transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare.[62]\nH5N1 Avian influenza \"Bird flu\"\nAs of 2013[update], H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt.[63]\nH7N9 Avian influenza\nAs of 2013[update], two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation.[64]\nIts oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver.[3] It has a volume of distribution of 23–26 litres.[3] Its half-life is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours.[3] More than 90% of the oral dose is eliminated in the urine as the active metabolite.[3]\nPlate from François-Pierre Chaumeton's 1833 \"Flore Medicale\"\nOseltamivir was discovered by scientists at Gilead Sciences using shikimic acid as a starting point for synthesis; shikimic acid was originally available only as an extract of Chinese star anise; but by 2006, 30% of the supply was manufactured recombinantly in E. coli.[65][66] Gilead exclusively licensed their relevant patents to Roche in 1996.[67] The drug's patent has not been protected in Thailand, the Philippines, Indonesia, and several other countries.[67]\nIn 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults[68] based on two double-blinded, randomized, placebo-controlled clinical trials.[69] In June 2002, the European Medicines Agency (EMA) approved oseltamivir phosphate for prophylaxis and treatment of influenza. In 2003, a pooled analysis of ten randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults.[70]\nOseltamivir (as Tamiflu) was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005.[medical citation needed] In response to the epidemic, various governments – including those of the United Kingdom, Canada, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic[71] and there were worldwide shortages of the drug, driven by the high demand for stockpiling.[65] In November 2005, US President George W. Bush requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Donald Rumsfeld, who was a past chairman of Gilead Sciences, recused himself from all government decisions regarding the drug.[72]\nIn 2006, a Cochrane Review (since withdrawn) raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness.[73]\nIn December 2008, the Indian drug company Cipla won a case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the World Health Organization (WHO) certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.[74]\nMarketing display used at festivals features a person living in a hermetically sealed environment\nIn 2009, a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009, the WHO declared the A/H1N1 influenza a pandemic.[75] The National Institute for Health and Care Excellence (NICE), the CDC, the WHO, and the ECDC maintained their recommendation to use oseltamivir.[7][76]\nFrom 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide.[77] In 2011, a freedom of information request to the European Medicines Agency (EMA) provided Cochrane with reports from 16 Roche oseltamivir trials. In 2012, the Cochrane team published an interim review based on those reports. In 2013, Roche released 74 full clinical study reports of oseltamivir trials after GSK released the data on zanamivir studies.[78] In 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents.[31][77] In 2016, Roche's oseltamivir patents began to expire.[67]\nVeterinary use\nThere have been[when?] reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirus infection.[79] The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production.[80]\nAs of 8 April 2020, no evidence supports effectiveness in treating COVID-19.[81]\nAmantadine and rimantadine – M2 inhibitors, for influenza treatment\nBaloxavir marboxil, an endonuclease inhibitor, for influenza treatment\n↑ 1.0 1.1 1.2 1.3 \"Oseltamivir (Tamiflu) Use During Pregnancy\". Drugs.com. Archived from the original on 9 September 2017. Retrieved 16 January 2017.\n↑ 2.0 2.1 \"WHOCC - ATC/DDD Index\". www.whocc.no. Retrieved 12 September 2020.\n↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Davies BE (April 2010). \"Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations\". The Journal of Antimicrobial Chemotherapy. 65 Suppl 2: ii5–ii10. doi:10.1093/jac/dkq015. PMC 2835511. PMID 20215135.\n↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 \"Oseltamivir Phosphate Monograph for Professionals\". The American Society of Health-System Pharmacists. Archived from the original on 13 May 2016. Retrieved 8 January 2017.\n↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 \"CDC Recommendations for Influenza Antiviral Medications Remain Unchanged\". U.S. Centers for Disease Control and Prevention (CDC). 10 April 2014. Archived from the original on 18 January 2017. Retrieved 16 January 2017.\n↑ 6.0 6.1 6.2 6.3 European Centre for Disease Prevention and Control (2 June 2014). \"New and updated evaluations of neuraminidase inhibitors for preventing and treating influenza published\". Archived from the original on 2014-11-02.\n↑ 7.0 7.1 \"Amantadine, oseltamivir and zanamivir for the treatment of influenza\". National Institute for Health and Care Excellence (NICE). 25 February 2009. Archived from the original on 18 January 2017. Retrieved 16 January 2017.\n↑ 8.0 8.1 8.2 8.3 \"IDSA Continues to Recommend Antivirals for Influenza\". Archived from the original on 24 April 2014. Retrieved 24 April 2014. CS1 maint: unfit URL (link)\n↑ 9.0 9.1 Brownlee S (19 February 2013). \"Tamiflu: Myth and Misconception\". The Atlantic. Archived from the original on 29 December 2014. Retrieved 7 December 2014.\n↑ 10.0 10.1 10.2 Butler D (April 2014). \"Tamiflu report comes under fire\". Nature. 508 (7497): 439–40. Bibcode:2014Natur.508..439B. doi:10.1038/508439a. PMID 24759392.\n↑ 11.0 11.1 11.2 11.3 11.4 11.5 Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S (2013). Jefferson T (ed.). \"The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews\". PLOS ONE. 8 (4): e60348. Bibcode:2013PLoSO...860348M. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.\n↑ 12.0 12.1 12.2 12.3 Ebell MH, Call M, Shinholser J (April 2013). \"Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials\". Family Practice. 30 (2): 125–33. doi:10.1093/fampra/cms059. PMID 22997224.\n↑ Okoli GN, Otete HE, Beck CR, Nguyen-Van-Tam JS (9 December 2014). \"Use of neuraminidase inhibitors for rapid containment of influenza: a systematic review and meta-analysis of individual and household transmission studies\". PLOS ONE. 9 (12): e113633. Bibcode:2014PLoSO...9k3633O. doi:10.1371/journal.pone.0113633. PMC 4260958. PMID 25490762.\n↑ Wang K, Shun-Shin M, Gill P, Perera R, Harnden A (April 2012). Harnden A (ed.). \"Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)\". The Cochrane Database of Systematic Reviews. 4 (4): CD002744. doi:10.1002/14651858.CD002744.pub4. PMC 6599832. PMID 22513907.\n↑ 15.0 15.1 Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ (April 2014). \"Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments\". BMJ. 348: g2545. doi:10.1136/bmj.g2545. PMC 3981975. PMID 24811411.\n↑ Agrawal R, Rewatkar PV, Kokil GR, Verma A, Kalra A (July 2010). \"Oseltamivir: a first line defense against swine flu\". Medicinal Chemistry. 6 (4): 247–51. doi:10.2174/1573406411006040247. PMID 20843284.\n↑ 17.0 17.1 17.2 17.3 17.4 World Health Organization (2017). The selection and use of essential medicines: report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/259481. ISBN 9789241210157. WHO technical report series;1006. License: CC BY-NC-SA 3.0 IGO.\n↑ Ebell, Mark H (12 July 2017). \"WHO downgrades status of oseltamivir\". BMJ: j3266. doi:10.1136/bmj.j3266.\n↑ \"The FDA approves first generic version of widely used influenza drug, Tamiflu\". U.S. Food and Drug Administration (FDA). 4 August 2016. Archived from the original on 8 August 2016. Retrieved 6 August 2016.\n↑ \"Drugs@FDA: FDA-Approved Drugs\". U.S. Food and Drug Administration (FDA). Retrieved 9 January 2020.\n↑ \"Oseltamivir\". International Drug Price Indicator Guide. Retrieved 30 July 2016.\n↑ \"NADAC as of 2019-02-27\". Centers for Medicare & Medicaid Services (CMS). Retrieved 3 March 2019.\n↑ \"The Top 300 of 2020\". ClinCalc. Retrieved 22 December 2018.\n↑ \"Oseltamivir Phosphate - Drug Usage Statistics\". ClinCalc. Retrieved 11 April 2020.\n↑ 25.0 25.1 25.2 \"Tamiflu- oseltamivir phosphate capsule Tamiflu- oseltamivir phosphate powder, for suspension\". DailyMed. 15 November 2019. Retrieved 30 January 2020.\n↑ 26.0 26.1 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.\n↑ Kmietowicz Z (June 2017). \"WHO downgrades oseltamivir on drugs list after reviewing evidence\". BMJ. 357: j2841. doi:10.1136/bmj.j2841. PMID 28607038.\n↑ 28.0 28.1 28.2 28.3 28.4 28.5 \"Influenza Antiviral Medications: Summary for Clinicians\". U.S. Centers for Disease Control and Prevention (CDC). 3 December 2014. Archived from the original on 13 December 2014. Retrieved 9 December 2014.\n↑ 29.0 29.1 29.2 Committee On Infectious Diseases (November 2014). \"Recommendations for prevention and control of influenza in children, 2014-2015\". Pediatrics. 134 (5): e1503-19. doi:10.1542/peds.2014-2413. PMID 25246619.\n↑ 30.0 30.1 30.2 Public Health England (November 2014). \"The use of antivirals for the treatment and prophylaxis of influenza: PHE summary of current guidance for healthcare professionals\" (PDF). Archived (PDF) from the original on 2014-12-08.\n↑ 31.0 31.1 31.2 31.3 31.4 31.5 31.6 31.7 31.8 Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. (April 2014). \"Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children\". The Cochrane Database of Systematic Reviews. 4 (4): CD008965. doi:10.1002/14651858.CD008965.pub4. PMC 6464969. PMID 24718923.\n↑ 32.0 32.1 \"Researchers, regulators and Roche row over stockpiled drug Tamiflu\". Reuters. Archived from the original on 2015-09-24.\n↑ Musher DM, Thorner AR (October 2014). \"Community-acquired pneumonia\". New England Journal of Medicine. 371 (17): 1619–28. doi:10.1056/NEJMra1312885. PMID 25337751.\n↑ Qiu S, Shen Y, Pan H, Wang J, Zhang Q (2015). \"Effectiveness and safety of oseltamivir for treating influenza: an updated meta-analysis of clinical trials\". Infectious Diseases. 47 (11): 808–19. doi:10.3109/23744235.2015.1067369. PMID 26173991.\n↑ Heneghan CJ, Onakpoya I, Jones MA, Doshi P, Del Mar CB, Hama R, et al. (May 2016). \"Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data\". Health Technology Assessment. 20 (42): 1–242. doi:10.3310/hta20420. PMC 4904189. PMID 27246259.\n↑ Malosh RE, Martin ET, Heikkinen T, Brooks WA, Whitley RJ, Monto AS (May 2018). \"Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials\". Clinical Infectious Diseases. 66 (10): 1492–1500. doi:10.1093/cid/cix1040. PMID 29186364.\n↑ Holzinger F, Beck S, Dini L, Stöter C, Heintze C (May 2014). \"The diagnosis and treatment of acute cough in adults\". Deutsches Ärzteblatt International. 111 (20): 356–63. doi:10.3238/arztebl.2014.0356. PMC 4047603. PMID 24882627.\n↑ Hernán MA, Lipsitch M (August 2011). \"Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials\". Clinical Infectious Diseases. 53 (3): 277–9. doi:10.1093/cid/cir400. PMC 3137795. PMID 21677258.\n↑ Dobson J, Whitley RJ, Pocock S, Monto AS (May 2015). \"Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials\". Lancet. 385 (9979): 1729–37. doi:10.1016/S0140-6736(14)62449-1. PMID 25640810.\n↑ Burch J, Corbett M, Stock C, Nicholson K, Elliot AJ, Duffy S, et al. (September 2009). \"Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis\". The Lancet. Infectious Diseases. 9 (9): 537–45. doi:10.1016/S1473-3099(09)70199-9. PMID 19665930.\n↑ \"Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087\". 30 March 2001. Archived from the original on 2014-04-16.\n↑ Jackson RJ, Cooper KL, Tappenden P, Rees A, Simpson EL, Read RC, Nicholson KG (January 2011). \"Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review\". The Journal of Infection. 62 (1): 14–25. doi:10.1016/j.jinf.2010.10.003. PMID 20950645.\n↑ \"Roche – Doing now what patients need next\" (PDF). Archived from the original (PDF) on 2005-11-03.\n↑ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.\n↑ 45.0 45.1 Cohen D (9 April 2014). \"Oseltamivir: another case of regulatory failure?\". BMJ. 348 (apr09 8): g2591. doi:10.1136/bmj.g2591.\n↑ 46.0 46.1 \"Pediatric safety update for Tamiflu\" Archived 2007-09-27 at the Wayback Machine. U.S. Food and Drug Administration (FDA)\n↑ Waknine Y (2006). \"Tamiflu May Be Linked to Risk for Self-Injury and Delirium\". Medscape. Archived from the original on 25 November 2011. Retrieved 17 May 2008.\n↑ \"Prescribing medicines in pregnancy database\". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.\n↑ 49.0 49.1 49.2 Thorlund K, Awad T, Boivin G, Thabane L (May 2011). \"Systematic review of influenza resistance to the neuraminidase inhibitors\". BMC Infectious Diseases. 11 (1): 134. doi:10.1186/1471-2334-11-134. PMC 3123567. PMID 21592407.\n↑ \"Update on oseltamivir resistance to influenza H1N1 (2009) viruses\" (PDF). World Health Organization (WHO). 15 December 2010. Archived (PDF) from the original on 27 January 2011. Retrieved 30 December 2010.\n↑ \"Antiviral Drug Resistance among Influenza Viruses Guidance on the Use of Influenza Antiviral Agents (Current for the 2013–14 Influenza Season)\". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 13 February 2014. Retrieved 21 April 2014.\n↑ Hurt AC (9 June 2011). \"Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation\". Eurosurveillance. Archived from the original on 23 April 2014.\n↑ Downing M (November 2013). \"Antiviral Therapy for Pandemic Influenza A (H1N1) Infection: Dosing, Combination Therapy, and Resistance\" (PDF). National collaborating centre for infectious diseases. Archived from the original (PDF) on 2014-04-19. Retrieved 2014-04-18.\n↑ \"2007–08 U.S. Influenza Season Summary\". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 2011-10-20.\n↑ \"Influenza (Flu) – Weekly Report: Influenza Summary Update Week 53, 2008-2009 Season\". Archived from the original on 2011-10-20.\n↑ \"2010-2011 Influenza Season Summary\". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 2012-01-25.\n↑ \"2011-2012 Influenza Season Week 51 ending December 24, 2011\". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 2013-05-17.\n↑ \"Main surveillance developments in week 51/2011 (19–25 December 2011)\" (PDF). European Centre for Disease Prevention and Control (ECDC). January 2012. Archived (PDF) from the original on 2012-06-10.\n↑ \"CDC Influenza Division Key Points, March 28, 2014\" (PDF). U.S. Centers for Disease Control and Prevention (CDC). 28 March 2014. Archived from the original (PDF) on 2 April 2014. Retrieved 15 April 2014.\n↑ Ward P, Small I, Smith J, Suter P, Dutkowski R (February 2005). \"Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic\". The Journal of Antimicrobial Chemotherapy. 55 Suppl 1: i5–i21. doi:10.1093/jac/dki018. PMID 15709056.\n↑ Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, et al. (April 2007). \"Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors\". JAMA. 297 (13): 1435–42. doi:10.1001/jama.297.13.1435. PMID 17405969.\n↑ \"Antiviral Drug Resistance among Influenza Viruses\". U.S. Centers for Disease Control and Prevention (CDC). 2019-04-17. Retrieved 2020-01-29.\n↑ McKimm-Breschkin JL (January 2013). \"Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance\". Influenza and Other Respiratory Viruses. 7 Suppl 1: 25–36. doi:10.1111/irv.12047. PMC 4942987. PMID 23279894.\n↑ Hay AJ, Hayden FG (June 2013). \"Oseltamivir resistance during treatment of H7N9 infection\". Lancet. 381 (9885): 2230–2. doi:10.1016/S0140-6736(13)61209-X. PMID 23809549.\n↑ 65.0 65.1 Farina V, Brown JD (November 2006). \"Tamiflu: the supply problem\". Angewandte Chemie. 45 (44): 7330–4. doi:10.1002/anie.200602623. PMID 17051628.\n↑ Rawat G, Tripathi P, Saxena RK (May 2013). \"Expanding horizons of shikimic acid. Recent progresses in production and its endless frontiers in application and market trends\". Applied Microbiology and Biotechnology. 97 (10): 4277–87. doi:10.1007/s00253-013-4840-y. PMID 23553030.\n↑ 67.0 67.1 67.2 WIPO April 2006 Avian Flu Drugs: Patent Questions Archived 2009-12-08 at the Wayback Machine\n↑ \"Drug Approval Package: Tamiflu (Oseltamivir Phosphate) NDA# 021087\". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 9 January 2020. Retrieved 9 January 2020.\n↑ FDA Medical Review Archived 2014-04-16 at the Wayback Machine, linked from Tamiflu Drug Approval Package Archived 2014-04-16 at the Wayback Machine\n↑ Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F (July 2003). \"Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations\". Archives of Internal Medicine. 163 (14): 1667–72. doi:10.1001/archinte.163.14.1667. PMID 12885681.\n↑ Heiberg M (14 October 2005). \"Oseltamivir-resistant H5N1 virus isolated from Vietnamese girl\". University of Minnesota. Archived from the original on 14 December 2014. Retrieved 7 December 2014.\n↑ Shannon Brownlee and Jeanne Lenzer (November 2009) \"Does the Vaccine Matter?\" Archived 2010-01-04 at the Wayback Machine, The Atlantic\n↑ Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D (July 2006). \"Neuraminidase inhibitors for preventing and treating influenza in healthy adults\" (PDF). The Cochrane Database of Systematic Reviews (3): CD001265. doi:10.1002/14651858.CD001265.pub2. PMID 16855962. {{ (Retracted, see doi:10.1002/14651858.cd001265.pub3)\n↑ \"Cipla's anti-flu drug gets nod\". Times of India. 2009-05-14. Archived from the original on 2012-10-23. Retrieved 2009-07-29.\n↑ Jefferson T, Doshi P (April 2014). \"Multisystem failure: the story of anti-influenza drugs\". BMJ. 348 (apr10 14): g2263. doi:10.1136/bmj.g2263. PMID 24721793.\n↑ \"WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses Revised February 2010\" (PDF). WHO. Archived (PDF) from the original on 2013-10-27.\n↑ 77.0 77.1 \"Tamiflu campaign\". BMJ. Retrieved 21 January 2020.\n↑ Cohen, D. (April 2013). \"Roche offers researchers access to all Tamiflu trials\". BMJ. 346 (apr04 3): f2157–f2157. doi:10.1136/bmj.f2157. ISSN 1756-1833.\n↑ Savigny MR, Macintire DK (February 2010). \"Use of oseltamivir in the treatment of canine parvoviral enteritis\". Journal of Veterinary Emergency and Critical Care. 20 (1): 132–42. doi:10.1111/j.1476-4431.2009.00404.x. PMID 20230441.\n↑ Macintire, Douglass K. (2006). \"Treatment of Parvoviral Enteritis\". Proceedings of the Western Veterinary Conference. Retrieved 2007-06-09.\n↑ \"Coronavirus COVID-19 (SARS-CoV-2)\". Johns Hopkins ABX Guide. Retrieved 12 April 2020.\nPollack A (5 November 2005). \"Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu\". The New York Times.\nWong SS, Yuen KY (January 2006). \"Avian influenza virus infections in humans\". Chest. 129 (1): 156–68. doi:10.1378/chest.129.1.156. PMC 7094746. PMID 16424427.\nRohloff JC, Kent KM, Postich MJ, Becker MW, Chapman HH, Kelly DE, et al. (1998). \"Practical Total Synthesis of the Anti-Influenza Drug GS-4104\". The Journal of Organic Chemistry. 63 (13): 4545–4550. doi:10.1021/jo980330q.\nKarpf M, Trussardi R (March 2001). \"New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)\". The Journal of Organic Chemistry. 66 (6): 2044–51. doi:10.1021/jo005702l. PMID 11300898.\nAbrecht S, Harrington P, Iding H, Karpf M, Trussardi R, Wirz B, Zutter U (2004). \"The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu®): A Challenge for Synthesis & Process Research\". CHIMIA International Journal for Chemistry. 58 (9): 621–629. doi:10.2533/000942904777677605.\nYeung YY, Hong S, Corey EJ (May 2006). \"A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid\". Journal of the American Chemical Society. 128 (19): 6310–1. doi:10.1021/ja0616433. PMID 16683783.\nTse N, Cederbaum S, Glaspy JA (October 1991). \"Hyperammonemia following allogeneic bone marrow transplantation\". American Journal of Hematology. 38 (2): 140–1. doi:10.1002/ajh.2830380213. PMID 1951305.\nSchneider RU (April 2001). \"The race to develop GS4104\". NZZ Folio (in Deutsch).\n\"FDA Drug Safety Communication: Important safety changes to the influenza drug Tamiflu (oseltamivir phosphate) for oral suspension\". U.S. Food and Drug Administration (FDA). 31 August 2011.\nExternal sites:\nUS NLM: Oseltamivir\nATC code:\nJ05AH02 (WHO)\nCAS Number: 196618-13-0 N 204255-11-8\nPubChem CID: 65028\nDrugBank:\nDB00198 Y\nChemSpider:\nUNII:\n20O93L6F9H\nKEGG:\nC08092 Y\nChEBI:\nCHEBI:7798\nChEMBL:\nChEMBL1229 Y\nLua error in Module:Commons_link at line 47: attempt to index field 'wikibase' (a nil value).\n\"Tamiflu (oseltamivir phosphate) Information\". U.S. Food and Drug Administration (FDA). 11 September 2018.\nRNA virus antivirals (primarily J05, also S01AD and D06BB)\nNS3/4A protease inhibitors (–previr)\nBoceprevir‡\nCiluprevir§\nDanoprevir†\nFaldaprevir‡\nGlecaprevir\nGrazoprevir\nNarlaprevir\nParitaprevir\nSimeprevir\nSovaprevir†\nTelaprevir‡\nVaniprevir\nVedroprevir§\nVoxilaprevir\nNS5A inhibitors (–asvir)\nDaclatasvir#\nElbasvir\nOdalasvir†\nOmbitasvir\nPibrentasvir\nRavidasvir†\nRuzasvir†\nSamatasvir†\nNS5B RNA polymerase inhibitors (–buvir)\nBeclabuvir†\nDasabuvir#\nDeleobuvir§\nFilibuvir§\nGS-6620§\nIDX-184§\nSetrobuvir§\nSofosbuvir#\nTegobuvir§\nTMC-647055§\nRadalbuvir†\nUprifosbuvir†\nElbasvir/grazoprevir\nGlecaprevir/pibrentasvir\nLedipasvir/sofosbuvir#\nOmbitasvir/paritaprevir/ritonavir#\nSofosbuvir/velpatasvir#\nSofosbuvir/velpatasvir/voxilaprevir\nBulevirtide\nviral entry: Pleconaril†\nAnti-influenza agents\nPimodivir†\nadamantane derivatives/M2 inhibitors (Adapromine\nRimantadine)\nneuraminidase inhibitors/release phase (Oseltamivir#\nPeramivir, Laninamivir†)\nMultiple/general\nInterferon alfa 2b\nPeginterferon alfa-2a#\nPeginterferon alfa-2b#\nMultiple/unknown\nCMX521§\nEICAR§\nGalidesivir†\nGS-441524§\nMK-608§\nNITD008§\nMericitabine†\nMerimepodib§\nMoroxydine\nPresatovir†\nRibavirin#\nTaribavirin†\nValopicitabine†\n#WHO-EM\n‡Withdrawn from market\n†Phase III\n§Never to phase III\nSuperinfection\nOrthomyxoviridae\nInfluenza C\nInfluenza D\nInfluenza A virus\nH10N7\n1918 (Spanish flu)\n2009 (Swine flu)\n2009 A/H1N1\nWest Bengal (2008)\nGenetic structure\nTransmission and infection\nGlobal spread\nHuman mortality\nPandemic preparation\nAdamantane derivatives\nNeuraminidase inhibitor\nPeramivir (experimental)\nLive attenuated influenza vaccine\nAudenz\nPandemics and\nInfluenza pandemic (1510)\n\"Russian flu\" (1889–1890)\n\"Spanish flu\" (1918)\n\"Asian flu\" (1957)\n\"Hong Kong flu\" (1968)\n\"Swine flu\" (2009)\n\"Fujian flu\" (H3N2)\n1989–90 UK outbreak\nCentral Luzon H5N6 (2017)\nNon-human\n2007 Australian outbreak\nNon-mammals\nFujian (H5N1)\nAcute bronchitis\n2017–2018 United States flu season\nUS influenza statistics by flu season\n2009 swine flu pandemic\nOutbreak timeline · Pandemic tables\nInfluenza pandemic\nSwine influenza\n2009 A/H1N1 vaccine\nActions with pigs\nTamiflu resistance\nSee also: Spanish flu, H5N1, Bird flu, and Influenza-like illness\nRetrieved from \"https://mdwiki.org/w/index.php?title=Oseltamivir&oldid=911441\"\nCS1 maint: unfit URL\nArticles citing retracted publications\nChemical articles with unknown parameter in Infobox drug\nChemical articles without CAS registry number\nArticles without EBI source\nChemical pages without ChemSpiderID\nChemical pages without DrugBank identifier\nArticles without KEGG source\nArticles without UNII source\nDrug has EMA link\nDrugboxes which contain changes to verified fields\nDrugboxes which contain changes to watched fields\nArticles containing potentially dated statements from December 2010\nArticles containing potentially dated statements from November 2013\nAll articles with vague or ambiguous time\nVague or ambiguous time from January 2020\nCS1 Deutsch-language sources (de)\nArticles with changed CASNo identifier\nAcetamides\nCyclohexenes\nHoffmann-La Roche brands\nGenentech brands\nNeuraminidase inhibitors\nProdrugs\nWorld Health Organization essential medicines\nWiki Project Med\nInternet-in-a-Box\nOffline app\nImport tool\nMed updater\nCreate redirects\nImport history\nText is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. 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"Browse Medicine A-Z\nBrowse Active Ingredient A-Z\nMedicines with Black Triangle\nDiscontinued Medicines\nReport Side Effect\nRMM Directory\nAbout emc\nSearch emc: Enter medicine name or company Start typing to retrieve search suggestions. When suggestions are available use up and down arrows to review and ENTER to select. Continue typing to refine.\nIntronA 30 million IU solution for injection, multidose pen\nThe pharmaceutical company has decided to discontinue this product. Other preparations of this medicine may still be available. This information has been left on emc for reference purposes.\nMerck Sharp & Dohme Limited contact details\ninterferon alfa-2b\nPOM: Prescription only medicine\nSame active ingredients\nPatient Leaflet\nLast updated on emc: 11 Oct 2018\n1. Name of the medicinal product\n2. Qualitative and quantitative composition\n3. Pharmaceutical form\n4. Clinical particulars\n4.1 Therapeutic indications\n4.2 Posology and method of administration\n4.3 Contraindications\n4.4 Special warnings and precautions for use\n4.5 Interaction with other medicinal products and other forms of interaction\n4.6 Fertility, pregnancy and lactation\n4.7 Effects on ability to drive and use machines\n4.8 Undesirable effects\n4.9 Overdose\n5. Pharmacological properties\n5.1 Pharmacodynamic properties\n5.2 Pharmacokinetic properties\n5.3 Preclinical safety data\n6. Pharmaceutical particulars\n6.1 List of excipients\n6.2 Incompatibilities\n6.3 Shelf life\n6.4 Special precautions for storage\n6.5 Nature and contents of container\n6.6 Special precautions for disposal and other handling\n7. Marketing authorisation holder\n8. Marketing authorisation number(s)\n9. Date of first authorisation/renewal of the authorisation\n10. Date of revision of the text\nThis information is intended for use by health professionals\nIntronA 18 million IU solution for injection in multidose pen\nOne pen contains 18 million IU of recombinant interferon alfa-2b produced in E. coli by recombinant DNA technology, in 1.2 mL solution.\nOne mL contains 15 million IU of interferon alfa-2b.\nFor the full list of excipients, see section 6.1.\nSolution for injection.\nClear and colourless solution.\nTreatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or fibrosis.\nChronic hepatitis C\nBefore initiating treatment with IntronA, consideration should be given to the results from clinical trials comparing IntronA with pegylated interferon (see section 5.1).\nAdult patients\nIntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for hepatitis C virus RNA (HCV-RNA) (see section 4.4).\nThe best way to use IntronA in this indication is in combination with ribavirin.\nChildren 3 years of age and older and adolescents\nIntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for HCV-RNA.\nWhen deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that resulted in reduced final adult height in some patients.\nThe decision to treat should be made on a case by case basis (see section 4.4).\nHairy cell leukaemia\nTreatment of patients with hairy cell leukaemia.\nChronic myelogenous leukaemia\nMonotherapy\nTreatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic myelogenous leukaemia.\nClinical experience indicates that a haematological and cytogenetic major/minor response is obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ leukaemic cells in the bone marrow, whereas a minor response is ≥ 34 %, but < 90 % Ph+ cells in the marrow.\nThe combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses and to significantly prolong the overall survival at three years when compared to interferon alfa-2b monotherapy.\nAs maintenance therapy in patients who have achieved objective remission (more than 50 % reduction in myeloma protein) following initial induction chemotherapy.\nCurrent clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the plateau phase; however, effects on overall survival have not been conclusively demonstrated.\nTreatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or epidural involvement, serous effusion, or leukaemia.\nCarcinoid tumour\nTreatment of carcinoid tumours with lymph node or liver metastases and with \"carcinoid syndrome\".\nAs adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.\nTreatment must be initiated by a physician experienced in the management of the disease.\nMultidose presentations must be for individual patient use only.\nThe pen is designed to deliver its contents of 18 million IU in doses ranging from 1.5 to 6 million IU. The pen will deliver a maximum of 12 doses of 1.5 million IU over a period not to exceed 4 weeks.\nThe pen is designed to deliver its contents of 30 million IU in doses ranging from 2.5 to 10 million IU. The pen will deliver a maximum of 12 doses of 2.5 million IU over a period not to exceed 4 weeks.\nThe pen is designed to deliver its contents of 60 million IU in doses ranging from 5 to 20 million IU. The pen will deliver a maximum of 12 doses of 5 million IU over a period not to exceed 4 weeks.\nNot all dose forms and strengths are appropriate for some indications. Appropriate dose form and strength must be selected.\nIf adverse events develop during the course of treatment with IntronA for any indication, modify the dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment with IntronA. At the discretion of the physician, the patient may self-administer the dose for maintenance dose regimens administered subcutaneously.\nThe recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a week (every other day) for a period of 4 to 6 months.\nThe administered dose should be reduced by 50 % in case of occurrence of haematological disorders (white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) or severe thrombocytopaenia (< 70,000/mm3).\nFor all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment (at the maximum tolerated dose), discontinue IntronA therapy.\nIntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) to adult patients, whether administered as monotherapy or in combination with ribavirin.\nChildren 3 years of age or older and adolescents\nIntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination with ribavirin capsules or oral solution administered orally in two divided doses daily with food (morning and evening).\n(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see ribavirin oral solution SPC.)\nRelapse patients (adults)\nIntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are available for 6 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for 6 months.\nNaïve patients (adults)\nThe efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be given alone mainly in case of intolerance or contraindication to ribavirin.\n- IntronA in combination with ribavirin\nBased on the results of clinical trials, in which data are available for 12 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.\nTreatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment sample) and high pre-treatment viral load.\nOther negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into account in order to extend therapy to 12 months.\nDuring clinical trials, patients who failed to show a virologic response after 6 months of treatment (HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).\n- IntronA alone\nThe optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of between 12 and 18 months is advised.\nIt is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point HCV-RNA status should be determined. Treatment should be continued in patients who exhibit negative HCV-RNA.\nNaïve patients (children and adolescents)\nThe efficacy and safety of IntronA in combination with ribavirin has been studied in children and adolescents who have not been previously treated for chronic hepatitis C.\nDuration of treatment for children and adolescents\n• Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders (negative predictive value 96 %). Therefore, it is recommended that children and adolescent patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.\n• Genotype 2/3: The recommended duration of treatment is 24 weeks.\nThe recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell leukaemia, normalisation of one or more haematological variables occurs within one to two months of IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet count and haemoglobin level) may require six months or more. This regimen must be maintained unless the disease progresses rapidly or severe intolerance is manifested.\nThe recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain haematological remission.\nIntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial haematological remission or a clinically meaningful cytoreduction has not been achieved.\nMaintenance therapy\nIn patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).\nAdjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, doxorubicin, teniposide and prednisolone).\nThe usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week (every other day). Patients with advanced disease may require a daily dose of 5 million IU. The treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long as the patient responds to interferon alfa-2b treatment.\nAs induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2 daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered subcutaneously three days a week (every other day) for 48 weeks.\nIf severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to > 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of normal, discontinue interferon alfa-2b therapy.\nAlthough the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at the recommended dose, with dose reduction for toxicity as described.\n- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.\n- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, recent myocardial infarction, severe arrhythmic disorders.\n- Severe renal or hepatic dysfunction; including that caused by metastases.\n- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).\n- Chronic hepatitis with decompensated cirrhosis of the liver.\n- Chronic hepatitis in patients who are being or have been treated recently with immunosuppressive agents excluding short term corticosteroid withdrawal.\n- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant recipients.\n- Pre-existing thyroid disease unless it can be controlled with conventional treatment.\n- Combination of IntronA with telbivudine.\n- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicide attempt.\nCombination therapy with ribavirin\nAlso see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.\nPsychiatric and central nervous system (CNS)\nSevere CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during IntronA therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Among children and adolescents treated with IntronA in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and the patient followed, with psychiatric intervention as appropriate.\nPatients with existence of, or history of severe psychiatric conditions:\nIf treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition.\n- The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3).\nPatients with substance use/abuse:\nHCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.\nChildren and adolescent population: Growth and development (chronic hepatitis C)\nDuring the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off treatment for more than 5 years. Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment.\nCase by case benefit/risk assessment in children\nThe expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1).\n- It is important to consider that the combination therapy induced a growth inhibition that resulted in reduced final adult height in some patients.\n- This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV genotype and viral load).\nWhenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.\nAcute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate interruption of treatment.\nAdverse experiences including prolongation of coagulation markers and liver abnormalities\nModerate to severe adverse experiences may require modification of the patient's dose regimen, or in some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and death in patients with cirrhosis.\nDiscontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of coagulation markers which might indicate liver decomposition.\nAny patient developing liver function abnormalities during treatment with IntronA must be monitored closely and treatment discontinued if signs and symptoms progress.\nLiver enzymes and hepatic function should be closely monitored in cirrhotic patients.\nHypotension may occur during IntronA therapy or up to two days post-therapy and may require supportive treatment.\nNeed for adequate hydration\nAdequate hydration must be maintained in patients undergoing IntronA therapy since hypotension related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.\nPyrexia\nWhile pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.\nPatients with debilitating medical conditions\nIntronA must be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.\nPulmonary conditions\nPulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. While this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.\nOcular adverse events\nOcular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual examinations during IntronA therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should be considered in patients who develop new or worsening ophthalmological disorders.\nObtundation, coma and encephalopathy\nMore significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of IntronA.\nPatients with pre-existing cardiac abnormalities\nAdult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac disease.\nHypertriglyceridemia\nHypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.\nPatients with psoriasis and sarcoidosis\nDue to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.\nKidney and liver graft rejection\nPreliminary data indicates that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.\nAuto-antibodies and autoimmune disorders\nThe development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).\nCases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).\nConcomitant chemotherapy\nAdministration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.\nAll patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.\nInfrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for children and adolescents).\nThyroid supplemental monitoring specific for children and adolescents\nApproximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid abnormalities are detected, the patient's thyroid status should be evaluated and treated as clinically appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).\nHCV/HIV Coinfection\nPatients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia.\nCo-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset.\nHCV/HBV Coinfection\nCases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low.\nAll patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.\nDental and periodontal disorders\nDental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.\nStandard haematological tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be conducted in all patients prior to and periodically during systemic treatment with IntronA.\nDuring treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and symptoms of liver failure are observed. During ALT flare, the following liver function tests must be monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.\nIn patients treated for malignant melanoma, liver function and white blood cell (WBC) count and differential must be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.\nEffect on fertility\nInterferon may impair fertility (see section 4.6 and section 5.3).\nImportant information about some of the ingredients of IntronA\nThis medicinal product contains less than 1 mmol sodium (23 mg) per 1.2 mL, i.e., essentially \"sodium-free\".\nInteraction studies have only been performed in adults.\nNarcotics, hypnotics or sedatives must be administered with caution when used concomitantly with IntronA.\nInteractions between IntronA and other medicinal products have not been fully evaluated. Caution must be exercised when administering IntronA in combination with other potentially myelosuppressive agents.\nInterferons may affect the oxidative metabolic process. This must be considered during concomitant therapy with medicinal products metabolised by this route, such as the xanthine derivatives theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline levels must be monitored and dose adjusted if necessary.\nPulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).\nAdministration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration) (see section 4.4).\nA clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see section 4.3).\nWomen of childbearing potential/contraception in males and females\nWomen of childbearing potential have to use effective contraception during treatment. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon.\nIntronA must be used with caution in fertile men.\nRibavirin causes serious birth defects when administered during pregnancy. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SPC).\nThere are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.\nRibavirin therapy is contraindicated in women who are pregnant.\nIt is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior to initiation of treatment.\nPatients are to be advised that they may develop fatigue, somnolence, or confusion during treatment with IntronA, and therefore it is recommended that they avoid driving or operating machinery.\nSee ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.\nIn clinical trials conducted in a broad range of indications and at a wide range of doses (from 6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were often reversible within 72 hours of interruption or cessation of treatment.\nIn clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is presented from clinical trials in naïve patients treated for one year. Severity was generally mild to moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and post-marketing. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.\nTable 1 Adverse reactions reported during clinical trials or following the marketing use of IntronA alone or in combination with ribavirin\nSystem Organ Class\nInfections and infestations\nVery common:\nCommon:\nUncommon:\nRarely:\nNot known:\nPharyngitis*, infection viral*\nBronchitis, sinusitis, herpes simplex (resistance), rhinitis\nPneumonia§, sepsis\nHepatitis B reactivation in HCV/HBV co-infected patients\nBlood and lymphatic system disorders\nVery rarely:\nLeukopaenia\nThrombocytopaenia, lymphadenopathy, lymphopenia\nPure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura\nImmune system disorders§\nSarcoidosis, exacerbation of sarcoidosis\nSystemic lupus erythematosus, vasculitis, rheumatoid arthritis (new or aggravated), Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis§\nHypothyroidism§, hyperthyroidism§\nDiabetes, aggravated diabetes\nMetabolism and nutrition disorders\nHypocalcaemia, dehydration, hyperuricemia, thirst\nHyperglycaemia, hypertriglyceridaemia§, increased appetite\nPsychiatric disorders§\nDepression, insomnia, anxiety, emotional lability*, agitation, nervousness\nConfusion, sleep disorder, libido decreased\nSuicide ideation\nSuicide, suicide attempts, aggressive behaviour (sometimes directed against others), psychosis including hallucinations\nHomicidal ideation, mental status change§, mania, bipolar disorders\nNervous system disorders§\nDizziness, headache, concentration impaired, mouth dry\nTremor, paresthesia, hypoesthesia, migraine, flushing, somnolence, taste perversion\nCerebrovascular haemorrhage, cerebrovascular ischaemia, seizure, impaired consciousness, encephalopathy\nMononeuropathies, coma§\nVision blurred\nConjunctivitis, vision abnormal, lacrimal gland disorder, eye pain\nRetinal haemorrhages§, retinopathies (including macular oedema), retinal artery or vein obstruction§, optic neuritis, papilloedema, loss of visual acuity or visual field, cotton-wool spots§\nSerous retinal detachment\nEar and labyrinth\nVertigo, tinnitus\nHearing loss, hearing disorder\nCardiac disorders\nPalpitation, tachycardia\nMyocardial infarction, cardiac ischaemia\nCongestive heart failure, pericardial effusion, arrhythmia\nVascular disorders\nPeripheral ischaemia, hypotension§\nRespiratory, thoracic and mediastinal disorders\nDyspnoea*, coughing*\nEpistaxis, respiratory disorder, nasal congestion, rhinorrhea, cough nonproductive\nPulmonary infiltrates§, pneumonitis§\nPulmonary fibrosis, pulmonary arterial hypertension#\nNausea/vomiting, abdominal pain, diarrhoea, stomatitis, dyspepsia\nStomatitis ulcerative, right upper quadrant pain, glossitis, gingivitis, constipation, loose stools\nPancreatitis, ischaemic colitis, ulcerative colitis, gingival bleeding\nPeriodontal disorder NOS, dental disorder NOS§, tongue pigmentation\nHepatobiliary disorders\nHepatotoxicity, (including fatality)\nSkin and subcutaneous tissue disorders\nAlopecia, pruritus*, skin dry*, rash*, sweating increased\nPsoriasis (new or aggravated)§, rash maculopapular, rash erythematous, eczema, erythema, skin disorder\nStevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme\nMusculoskeletal and connective tissue disorders\nMyalgia, arthralgia, musculoskeletal pain\nRhabdomyolysis, myositis, leg cramps, back pain\nRenal and urinary disorders\nMicturition frequency\nRenal failure, renal insufficiency, nephrotic syndrome\nReproductive system and breast disorders\nAmenorrhea, breast pain, dysmenorrhea, menorrhagia, menstrual disorder, vaginal disorder\nGeneral disorders and administration site conditions\nInjection site inflammation, injection site reaction*, fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, irritability, chest pain, malaise\nInjection site pain\nInjection site necrosis, face oedema\nWeight decrease\n*These events were only common with IntronA alone\n§See section 4.4\n#Class label for interferon products, see below Pulmonary arterial hypertension\nThese undesirable effects have also been reported with IntronA alone.\nThe undesirable effects seen with hepatitis C are representative of those reported when IntronA is administered in other indications, with some anticipated dose-related increases in incidence. For example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of patients, respectively), in comparison with the mild to moderate severity usually associated with lower doses. Undesirable effects were usually managed by dose adjustment.\nCardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease (see section 4.4).\nCases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.\nA wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies (see also section 4.4).\nClinically significant laboratory abnormalities, most frequently occurring at doses greater than 10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.\nChildren and adolescent population\nChronic Hepatitis C - Combination therapy with ribavirin\nIn clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric- specific concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4).\nFurthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropaenia.\nThe adverse reactions listed in Table 2 are based on experience from the two multicentre children and adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.\nTable 2 Adverse reactions very commonly and commonly reported during clinical trials in children and adolescent patients treated with IntronA in combination with ribavirin\nInfection and infestations\nViral infection, pharyngitis\nFungal infection, bacterial infection, pulmonary infection, otitis media, tooth abscess, herpes simplex, urinary tract infection, vaginitis, gastroenteritis\nNeoplasms benign, malignant and unspecified (including cysts and polyps)\nNeoplasm (unspecified)\nAnaemia, neutropaenia\nThrombocytopaenia, lymphadenopathy\nHypothyroidism§,\nHyperthyroidism§, virilism\nHypertriglyceridemia§, hyperuricemia, increased appetite\nDepression, emotional lability, insomnia\nSuicidal ideation, aggressive reaction, confusion, behaviour disorder, agitation, somnambulism, anxiety, nervousness, sleep disorder, abnormal dreaming, apathy\nHeadache, dizziness\nHyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence\nConjunctivitis, eye pain, abnormal vision, lacrimal gland disorder\nFlushing, pallor\nDyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhea, sneezing\nDiarrhoea, vomiting, nausea, abdominal pain\nMouth ulceration, stomatitis ulcerative, stomatitis, right upper quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder\nHepatic function abnormal\nAlopecia, rash\nPhotosensitivity reaction, maculopapular rash, eczema, acne, skin disorder, nail disorder, skin discolouration, pruritus, dry skin, erythema, bruise, sweating increased\nArthralgia, myalgia, musculoskeletal pain\nEnuresis, micturition disorder, urinary incontinence\nFemale: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder\nMale: testicular pain\nInjection site inflammation, injection site reaction, fatigue, rigors, pyrexia§, influenza-like symptoms§, malaise, irritability\nChest pain, asthenia, oedema, injection site pain\nGrowth rate decrease (height and/or weight decrease for age)§\nInjury and poisoning\nSkin laceration\nReporting of suspected adverse reactions\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.\nNo case of overdose has been reported that has led to acute clinical manifestations. However, as for any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is indicated.\nPharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05\nIntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.\nThe activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity of the recombinant interferon alfa-2b with the activity of the international reference preparation of human leukocyte interferon established by the World Health Organisation.\nThe interferons are a family of small protein molecules with molecular weights of approximately 15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or various synthetic and biological inducers. Three major classes of interferons have been identified: alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain several different molecular species of interferon. More than 14 genetically distinct human alpha interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.\nInterferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species specificity. Studies with other interferons have demonstrated species specificity. However, certain monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.\nThe results of several studies suggest that, once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon's therapeutic effects.\nRecombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both animal and human cell culture systems as well as human tumour xenografts in animals. It has demonstrated significant immunomodulatory activity in vitro.\nRecombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.\nCurrent clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity and mortality has been observed.\nInterferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of depression were observed.\nChronic hepatitis C in adult patients\nIn adult patients receiving interferon in combination with ribavirin, the achieved sustained response rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a ribavirin dose > 10.6 mg/kg, p < 0.01).\nIntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.\nIntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were followed for an additional 6 months after the end of treatment for the determination of sustained virologic response. Sustained virologic response rates for treatment groups treated for one year with IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.\nCo-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. The increased response rate to the combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).\nResponse rates in these trials were increased with compliance. Regardless of genotype, patients who received IntronA in combination with ribavirin and received ≥ 80 % of their treatment had a higher sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment (56 % vs. 32 % in trial C/I98-580).\nTable 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by genotype and viral load\nHCV Genotype\nC95-132/I95-143\nI/R\nC/I98-580\nAll Genotypes\nGenotype 1\n≤ 2 million copies/mL\n> 2 million copies/mL\nGenotype 2/3\nI IntronA (3 MIU 3 times a week)\nI/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)\nHCV/HIV Co-infected patients\nTwo trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, patients who received IntronA plus ribavirin, were less likely to respond than patients who received pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.\nTable 4 Sustained virological response based on genotype after IntronA in combination with ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in HCV/HIV co-infected patients\npegylated interferon alfa-2b (1.5 µg/kg/ week) + ribavirin\n(800 mg)\nIntronA (3 MIU TIW) + ribavirin\np valuea\npegylated interferon alfa-2b (100 or 150c µg/week) + ribavirin\n(800- 1,200 mg)d\np valueb\n27 % (56/205)\n44 % (23/52)\n21 % (9/43)\nGenotype 1, 4\n6 % (8/129)\n7 % (2/27)\nMIU = million international units; TIW = three times a week.\na: p value based on Cochran-Mantel Haenszel Chi square test.\nb: p value based on chi-square test.\nc: subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated interferon alfa-2b.\nd: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.\n1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.\n2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.\nRelapse patients\nA total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV (< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was sustained when measured 6 months after the end of treatment.\nLong-Term efficacy data\nIn a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic response and assess the impact of continued viral negativity on clinical outcomes. 462 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study.\nThe Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with a 95 % Confidence Interval of [95 %, 99 %].\nSVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).\nChronic hepatitis C in children and adolescent population\nThree clinical trials have been conducted in children and adolescents; two with standard interferon and ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.\nChildren and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1,64 % ≤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).\nStudy results are summarized in Table 5.\nTable 5 Sustained virological response in previously untreated children and adolescents\nIntronA 3 MIU/m2 3 times a week\nribavirin 15 mg/kg/day\nOverall Responsea (n=118)\n54 (46 %)*\nGenotype 1 (n=92)\nGenotype 2/3/4 (n=26)\n*Number (%) of patients\na Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period\nA five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.\nSVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).\nResults from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin\nIn a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 μg/m2 plus ribavirin 15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs section 4.4). The study results are summarized in Table 6.\nTable 6 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects\n26/27 (96 %)\nGenotype 3c\n12/12 (100 %)\n2/3 (67 %)\na: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of detection=125 IU/mL.\nb: n = number of responders/number of subjects with given genotype, and assigned treatment duration.\nc: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.\nThe pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2 and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly and as a 30-minute intravenous infusion. The mean serum interferon concentrations following subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon injections were approximately two to three hours, and six to seven hours, respectively. Serum levels were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and intramuscular administration resulted in bioavailabilities greater than 100 %.\nAfter intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular administration of medicinal product, becoming undetectable four hours after the infusion. The elimination half-life was approximately two hours.\nUrine levels of interferon were below the detection limit following each of the three routes of administration.\nInterferon neutralising factor assays were performed on serum samples of patients who received IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. The detectable titres are low in almost all cases and have not been regularly associated with loss of response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was observed apparently due to the low titres.\nMultiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or adolescents.\nTable 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin capsules when administered to children or adolescents with chronic hepatitis C\nRibavirin\n15 mg/kg/day as 2 divided doses\n(n = 17)\nIntronA\n3 MIU/m2 3 times a week\nTmax (hr)\nCmax (ng/mL)\n3,275 (25)\nAUC*\n29,774 (26)\nApparent clearance L/hr/kg\nNot done\n*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA\nTransfer into seminal fluid\nSeminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.\nAlthough interferon is generally recognised as being species specific, toxicity studies in animals were conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in monkeys given 100 x 106 IU/kg/day for 3 months.\nIn studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been observed (see section 4.4).\nResults of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups (corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-related anovulatory and abortifacient effects in rhesus monkeys.\nMutagenicity studies with interferon alfa-2b revealed no adverse events.\nIntronA plus ribavirin\nNo studies have been conducted in juvenile animals to examine the effects of treatment with interferon alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with ribavirin).\nEdetate disodium\nM-cresol\nWater for injections q.s.\nThis medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.\nChemical and physical in-use stability has been demonstrated for 27 days at 2°C – 8°C.\nFrom a microbiological point of view, once opened, the product may be stored for a maximum of 27 days at 2°C – 8°C. Other in-use storage times and conditions are the responsibility of the user.\nStore in a refrigerator (2°C – 8°C).\nDo not freeze.\nFor storage conditions of the medicinal product, see section 6.3.\n1.2 mL of solution (corresponding to 18 MIU) is contained in a pen made of a cartridge (type I glass) sealed at one end with a cap (aluminium) containing a liner (bromobutyl rubber) and at the other end by a plunger (bromobutyl rubber).\nIntronA is supplied as:\n- Pack of 1 pen, 12 injection needles and 12 cleansing swabs\n- Pack of 2 pens, 24 injection needles and 24 cleansing swabs\nNot all pack sizes may be marketed.\nNot all dose forms and strengths are appropriate for some indications. Please make sure to select an appropriate dose form and strength.\nIntronA, solution for injection in multidose pen is injected subcutaneously after attaching an injection needle and dialing the prescribed dose.\nRemove the pen from the refrigerator approximately 30 minutes before administration to allow the injectable solution to reach room temperature (not more than 25°C).\nDetailed instructions for the use of the product are provided with the package leaflet (refer to \"How to self inject IntronA\").\nEach pen is intended for a maximum four-week use period and must then be discarded. A new injection needle must be used for each dose. After each use, the injection needle must be discarded safely and the pen must be returned immediately to the refrigerator. A maximum of 48 hours (two days) of exposure to 25°C is permitted over the four-week use period to cover accidental delays in returning the pen to the refrigerator.\nSufficient needles and swabs are provided to use the IntronA pen for administering the smallest measurable doses. Instruct the patient that any extra needles and swabs that remain after the final dose has been taken from the pen must be discarded appropriately and safely.\nAs with all parenteral medicinal products, prior to administration inspect IntronA, solution for injection, visually for particulate matter and discolouration. The solution should be clear and colourless.\nMerck Sharp & Dohme B.V.\nWaarderweg 39\nEU/1/99/127/031\nDate of first authorisation: 9 March 2000\nDate of latest renewal: 9 March 2010\nDetailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.\n© Merck Sharp & Dohme Limited 2018. All rights reserved\nSPC.INA-PEN.18.UK.6477.T-0116\nMerck Sharp & Dohme Limited\nHertford Road, Hoddesdon, Hertfordshire, EN11 9BU\nCall MSD customer services on 01992 452094\nhttp://www.msd-uk.com\nMedical Information e-mail\nBookmark this medicine\nTo bookmark a medicine you must sign up and log in.\nEmail this medicine\nTo email a medicine you must sign up and log in.\nView medicine changes\nTo view the changes to a medicine you must sign up and log in.\nLegal and privacy policy |\nGlossary |\nThis site uses cookies. By continuing to browse the site you are agreeing to our policy on the use of cookies. Continue"

"Medication name\nEuropean prescription medicines info\nHome / L / Lartruvo\nLartruvo (olaratumab) – Summary of product characteristics - L01XC27\nLartruvo\nLartruvo: Summary of product characteristics\nLartruvo: Conditions or restrictions regarding supply and use\nLartruvo: Labelling\nLartruvo: Package leaflet\nMedication name Lartruvo\nATC Code L01XC27\nSubstance olaratumab\nManufacturer Eli Lilly Nederland B.V.\n1. NAME OF THE MEDICINAL PRODUCT\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION\n3. PHARMACEUTICAL FORM\n4. CLINICAL PARTICULARS\n4.1 Therapeutic indications\n4.2 Posology and method of administration\n4.3 Contraindications\n4.4 Special warnings and precautions for use\n4.5 Interaction with other medicinal products and other forms of interaction\n4.6 Fertility, pregnancy and lactation\n4.7 Effects on ability to drive and use machines\n4.8 Undesirable effects\n4.9 Overdose\n5. PHARMACOLOGICAL PROPERTIES\n5.1 Pharmacodynamic properties\n5.2 Pharmacokinetic properties\n5.3 Preclinical safety data\n6. PHARMACEUTICAL PARTICULARS\n6.1 List of excipients\n6.2 Incompatibilities\n6.3 Shelf life\n6.4 Special precautions for storage\n6.5 Nature and contents of container\n6.6 Special precautions for disposal and other handling\n7. MARKETING AUTHORISATION HOLDER\n8. MARKETING AUTHORISATION NUMBER(S)\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION\n10. DATE OF REVISION OF THE TEXT\nThis medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.\n1.NAME OF THE MEDICINAL PRODUCT\nLartruvo 10 mg/mL concentrate for solution for infusion\n2.QUALITATIVE AND QUANTITATIVE COMPOSITION\nOne mL of concentrate for solution for infusion contains 10 mg of olaratumab.\nEach 19 mL vial contains 190 mg of olaratumab.\nOlaratumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.\nExcipient with known effect\nEach 19mL vial contains approximately 22 mg (1 mmol) sodium.\nEach 50 mL vial contains approximately 57 mg (2.5 mmol) sodium.\nFor the full list of excipients, see section 6.1.\n3.PHARMACEUTICAL FORM\nConcentrate for solution for infusion (sterile concentrate).\nThe concentrate is clear to slightly opalescent and colourless to slightly yellow solution without visible particles.\n4.CLINICAL PARTICULARS\n4.1Therapeutic indications\nLartruvo is indicated in combination with doxorubicin for the treatment of adult patients with advanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin (see section 5.1).\n4.2Posology and method of administration\nOlaratumab therapy must be initiated and supervised by physicians experienced in oncology. Patients should be monitored during the infusion for signs and symptoms of infusion-related reactions (IRRs) in a setting with available resuscitation equipment (see section 4.4).\nPosology\nThe recommended dose of olaratumab is 15 mg/kg administered by intravenous infusion on days 1 and 8 of each 3 week cycle until disease progression or unacceptable toxicity. Lartruvo is administered in combination with doxorubicin for up to 8 cycles of treatment, followed by Lartruvo monotherapy in\npatients whose disease has not progressed. Doxorubicin is given on day 1 of each cycle following the Lartruvo infusion.\nPremedication\nPremedication with an H1 antagonist (e.g., diphenhydramine) and dexamethasone (or equivalent medicinal products) should be given, intravenously, 30–60 minutes prior to the olaratumab doses on days 1 and 8 of cycle 1 in all patients. For subsequent cycles, premedication with an H1 antagonist (e.g., diphenhydramine) should be given intravenously 30–60 minutes prior to each dose of olaratumab.\nFor patients who experience Grade 1 or 2 IRR, the infusion should be interrupted and paracetamol, H1 antagonist and dexamethasone (or equivalent medicinal products) administered as needed. For all subsequent infusions, premedication with the following (or equivalent medicinal products) diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone, should be given.\nIn the event that intravenous administration of an H1 antagonist is not possible, equivalent alternative premedication should be given (e.g. oral diphenhydramine hydrochloride at least 90 minutes prior to the infusion).\nPosology adjustments for olaratumab\nFor dose adjustment recommendations related to doxorubicin, refer to the current doxorubicin prescribing information.\nInfusion-related reactions (IRRs)\nRecommendations for the management of olaratumab IRRs are provided in table 1.\nTable 1 – Management recommendations for infusion-related reactions (IRRs)\nManagement recommendations\ngradea\n(any occurrence)\n• Stop the infusion\n• Paracetamol, H1 antagonist and dexamethasone should be\nadministered as needed (see premedication section)\n• Once the reaction has resolved, resume infusion at a 50 %\ndecreased infusion rate.b\n• Monitor patient for worsening of condition.\n• For subsequent infusions, please see premedication section.\n• Immediately and permanently discontinue treatment with\nolaratumab (see section 4.4).\naGrade per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03\nbOnce the infusion rate has been reduced for a Grade 1 or 2 infusion-related reaction, it is recommended that the lower infusion rate be utilized for all subsequent infusions. The infusion duration should not exceed 2 hours.\nOther non-haematology toxicities\nFor serious Grade > 3 non-haematologic toxicity deemed related to olaratumab, the dose of olaratumab should be withheld until toxicity is ≤ Grade 1 or has returned to pretreatment baseline. For subsequent infusions, the dose should be reduced to 12 mg/kg for serious Grade 3 toxicities and to 10 mg/kg for Grade 4 toxicities. If a Grade 3 toxicity recurs despite the dose reduction, the dose should be reduced further to 10 mg/kg. In case of recurrence of a Grade 4 toxicity, treatment with olaratumab should be permanently discontinued.\nIf neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week occurs, administration of olaratumab should be temporarily discontinued until the absolute neutrophil count is 1,000 / µL or higher and then the dose of olaratumab should be resumed at the reduced dose of 12 mg/kg. If neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week recurs despite dose reduction, the dose should be reduced further to 10 mg/kg.\nElderly (> 65 years)\nData on very elderly patients (> 75 years) are very limited (see sections 4.8 and 5.1).\nNo dose reductions other than those recommended for the general patient population are necessary.\nThere have been no formal studies with olaratumab in patients with renal impairment. PopPK data suggest that no dose adjustments are required in patients with mild or moderate renal impairment. There are no data regarding olaratumab administration in patients with severe renal impairment (calculated creatinine clearance < 30 mL/min) (see section 5.2).\nHepatic impairment\nThere have been no formal studies with olaratumab in patients with hepatic impairment. PopPK data suggest that no dose adjustments are required in patients with mild hepatic impairment. There are very limited data regarding olaratumab administration in patients with moderate hepatic impairment. There are no data in patients with severe hepatic impairment (see section 5.2).\nThe safety and efficacy of olaratumab in children aged 0 to 18 years of age have not yet been established. No data are available.\nMethod of administration\nAfter dilution in sodium chloride 9 mg/mL (0.9 %) solution for injection, olaratumab is administered as an intravenous infusion over approximately 60 minutes. In order to accommodate larger infusion volumes that may be needed for patients requiring higher doses, the duration of infusion should be increased such that the maximum infusion rate of 25 mg/minute is not exceeded.\nFor instructions on dilution of the medicinal product before administration, see section 6.6.\n4.3Contraindications\nHypersensitivity to the active substance or to any of the excipients listed in section 6.1.\n4.4Special warnings and precautions for use\nInfusion-related reactions\nInfusion-related reactions (IRRs), including anaphylactic reactions, were reported in clinical trials with olaratumab. The majority of these reactions occurred during or following the first olaratumab infusion. Symptoms of IRRs included flushing, shortness of breath, bronchospasm, or fever/chills, and in some cases manifested as severe hypotension, anaphylactic shock, or fatal cardiac arrest. Severe IRRs such as anaphylactic reactions can occur despite the use of premedication. Patients should be monitored during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. For management and dose adjustments in patients who experience Grade 1 or 2 IRR during the infusion, see section 4.2. In patients who have experienced a previous Grade 1 or 2 IRR, premedication with diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone is recommended. Olaratumab should be immediately and permanently discontinued in patients who experience Grade 3 or 4 IRR (see sections 4.2 and 4.8).\nPatients receiving olaratumab and doxorubicin are at risk of neutropenia (see section 4.8). Neutrophil count should be checked prior to Olaratumab dosing on Day 1 and Day 8 of each cycle. Neutrophil count should be monitored during the treatment with olaratumab and doxorubicin and supportive care should be administered such as antibiotics or G-CSF as per local guidelines. For dosage adjustments related to neutropenia, refer to section 4.2.\nHaemorrhagic events\nPatients receiving olaratumab and doxorubicin are at risk of haemorrhagic events (see section 4.8). Platelet counts should be checked prior to olaratumab dosing on Day 1 and Day 8 of each cycle. Coagulation parameters should be monitored in patients with conditions predisposing to bleeding, such as anticoagulant use. In a study of olaratumab in combination with liposomal doxorubicin, there was one case of fatal intracranial haemorrhage in a patient who had experienced a fall while on treatment.\nAnthracycline pre-treated patients\nThe risk of cardiac toxicity rises with increasing cumulative doses of anthracyclines, including doxorubicin. There are no data for the combination of olaratumab and doxorubicin in anthracycline pre-treated patients, including pre-treatment with doxorubicin (see section 4.1).\nSodium restricted diet\nThis medicinal product contains 22 mg sodium per each 19 mL vial and 57 mg sodium per each 50 mL vial. To be taken into consideration by patients on a controlled sodium diet.\nDoxorubicin can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses and is higher in individuals with a history of cardiomyopathy, mediastinal irradiation or pre-existing cardiac disease. To minimise doxorubicin-related cardiotoxicity, the use of appropriate cardio- protective measures (LVEF measurement, such as ECHO or MUGA scan, ECG monitoring, and/or use of cardioprotective agents) should be considered and planned in all patients before the start and throughout the treatment.\nPlease refer to doxorubicin SmPC for recommendation on cardiac monitoring.\nIn the phase 2 trial, patients in both treatment groups that received 5 or more cycles of doxorubicin received dexrazoxane prior to each dose of doxorubicin from cycle 5 onwards to minimize the risk of doxorubicin-related cardiotoxicity (see sections 4.8 and 5.1).\nAs doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the toxicity of doxorubicin is enhanced in patients with hepatic impairment. Refer to doxorubicin SmPC for appropriate monitoring of hepatic function and doxorubicin dose adjustments in patients with impaired liver function.\n4.5Interaction with other medicinal products and other forms of interaction\nOlaratumab is a human monoclonal antibody. In a dedicated DDI study, no pharmacokinetic interactions were observed in patients between olaratumab and doxorubicin.\nNo other formal DDI studies with olaratumab and medicinal products commonly used in cancer patients, including those with STS (e.g. antiemetics, analgesics, anti-diarrheal drugs, oral contraceptives, etc.), have been performed.\nAs monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal\nproducts is not anticipated to affect the pharmacokinetics of olaratumab. Conversely, olaratumab is not anticipated to affect the pharmacokinetics of co-administered medicinal products.\nAdministration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving olaratumab in combination with doxorubicin.\n4.6Fertility, pregnancy and lactation\nWomen of childbearing potential/contraception in females\nWomen of childbearing potential should be advised to avoid becoming pregnant while on olaratumab and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months following the last dose of olaratumab.\nThere are no or limited amount of data from the use of olaratumab in pregnant women. Reproductive and development toxicity study conducted with an anti-murine PDGFRα antibody in mice showed foetal malformations and skeletal alterations (see section 5.3).\nBased on its mechanism of action (see section 5.1), olaratumab has the potential to cause foetal harm. Olaratumab is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefit justifies the potential risk to the foetus.\nIt is not known whether olaratumab is excreted in human milk. Human IgG is excreted in human milk, therefore breast-feeding is not recommended during treatment with olaratumab and for at least\n3 months following the last dose.\nThere are no data on the effect of olaratumab on human fertility.\n4.7Effects on ability to drive and use machines\nOlaratumab may have minor influence on the ability to drive and use machines. Due to frequent occurrence of fatigue, patients should be advised to use caution when driving or operating machinery.\n4.8Undesirable effects\nSummary of the safety profile\nOlaratumab-treated patients from Phase 2 study\nIn the olaratumab plus doxorubicin arm, the most serious (Grade ≥3) adverse drug reactions (ADRs) observed were neutropenia (54.7 %) and musculoskeletal pain (7.8 %).\nThe most frequently occurring ADRs were nausea, musculoskeletal pain, neutropenia and mucositis.\nThe most frequent ADRs associated with permanent treatment discontinuation occurred in 3 (4.7 %) patients of which the most frequent were infusion-related reactions (3.1 %) and mucositis (1.6 %).\nKnown toxicities reported for doxorubicin, observed in the combination of olaratumab and doxorubicin include fatigue, anaemia, thrombocytopenia and alopecia. Please refer to the doxorubicin SmPC for complete descriptions of all adverse events associated with doxorubicin treatment\nTabulated list of adverse reactions\nADRs which were reported in patients with soft tissue sarcoma treated with olaratumab in combination with doxorubicin in the Phase 2 study are listed below in Table 2 in MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: Very common (≥ 1/10)\nCommon (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥ 1/10,000 to < 1/1,000) Very rare (< 1/10,000)\nWithin each frequency grouping, ADRs are presented in order of decreasing seriousness.\nTable 2: Adverse reactions in patients receiving olaratumab plus doxorubicin for soft tissue sarcoma during the Phase 2 portion of a Phase 1b/2 study\nSystem organ class\nAdverse Reactiona\nFrequency overall\nGrade 3/4 frequency\nBlood and lymphatic\nsystem disorders\nMusculoskeletal and\nPainb\nGeneral disorders and\nInfusion-related\nadministrative site\naRefer to NCI CTCAE Criteria (Version 4.03) for each Grade of toxicity\nbMusculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in extremity.\nDescription of selected ADRs\nPrescription drugs listed. Manufacturer: \"Eli Lilly Nederland B.V.\"\nCymbalta - Eli Lilly Nederland B.V.\nCialis - Eli Lilly Nederland B.V.\nAdcirca (tadalafil lilly) - Eli Lilly Nederland B.V.\nAriclaim - Eli Lilly Nederland B.V.\nForsteo - Eli Lilly Nederland B.V.\nYentreve - Eli Lilly Nederland B.V.\nIRRs were reported in 12.5 % of patients and mainly present as chills, fever or dyspnoea. Severe IRRs, also including a fatal case (see section 4.4) were reported in 3.1 % of patients and mainly presented with shortness of breath, loss of consciousness and hypotension. All severe IRRs occurred during or immediately after the first administration of olaratumab.\nIn the phase 2 trial, the incidence of neutropenia was 59.4 % (all Grades) and 54.7 % (Grade 3) in the olaratumab plus doxorubicin arm and 38.5 % (all Grades) and 33.8 % (Grade 3) in the doxorubicin alone arm. The rate of febrile neutropenia was 12.5 % in the olaratumab plus doxorubicin arm and 13.8 % in the doxorubicin alone arm. For dose adjustments, refer to section 4.2\nIn the phase 2 trial the incidence of Musculoskeletal pain was 64.1 % (all Grades) and 7.8 % (Grade 3) in the olaratumab plus doxorubicin arm and 24.6 % (all Grades) and 1.5 % (Grade 3) in the doxorubicin alone arm. In the majority of patients the pain was related to the patients' underlying\ncancer or metastases or pre-existing or concomitant conditions. The majority of these events occurred in the first 4 cycles. The pain can last from few days to up to 200 days. In some patients there was a recurrence of pain .The pain did not worsen with time or during recurrence.\nNo clinically meaningful difference in doxorubicin-related cardiotoxicity was observed between the two treatment arms of the study. The rate of cardiac arrhythmias was similar in both arms (15.6 % in the Investigational Arm and 15.4 % in the Control Arm). The rate of treatment-emergent cardiac dysfunction was comparable between the two treatment arms (7.8 % in the Investigational Arm and 6.2 % in the Control Arm).\nIn the phase 2 trial, the frequency of haemorrhagic events considered related to any study drug was 3.1 % in either treatment arm. All of these events were Grade 1/2 and were confounded by multiple factors. Three Grade ≥3 events, including one fatal, have been reported across the clinical development programme of olaratumab (see section 4.4).\nToxicity in the elderly\nThere was a higher incidence of Grade ≥3 adverse reactions, adverse reactions leading to discontinuation and a higher rate of haematological toxicity in the elderly population compared to the overall study population (see section 4.2). The rates of discontinuation were comparable between treatment arms across all age groups.\nReporting of suspected adverse reactions\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.\n4.9Overdose\nThere is no experience with Lartruvo overdose in human clinical trials. Lartruvo has been administered in a Phase 1 study up to 20 mg/kg on days 1 and 8 of a 21 day cycle without reaching a maximum tolerated dose. In case of overdose, use supportive therapy. There is no known antidote to Lartruvo overdose.\n5.PHARMACOLOGICAL PROPERTIES\n5.1Pharmacodynamic properties\nPharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC27\nOlaratumab is an antagonist of platelet derived growth factor receptor-α (PDGFR-α), expressed on tumour and stromal cells. Olaratumab is a targeted, recombinant, fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds PDGFR-α, blocking PDGF AA, -BB, and -CC binding and receptor activation. As a result, in vitro olaratumab inhibits PDGFR-α pathway signalling in tumour and stromal cells. In addition, in vivo olaratumab has been shown to disrupt the PDGFR-α pathway in tumour cells and inhibit tumour growth.\nImmunogenicity\nAs with all therapeutic proteins, there is the potential for immunogenicity.\nOverall, a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies were detected in clinical trial samples.\nClinical efficacy and safety\nThe efficacy and safety of olaratumab was assessed in a Phase 1b/2, multi-centre study in anthracycline naïve patients with histologically or cytologically confirmed, advanced soft tissue sarcoma not amenable to receive surgery or radiotherapy with curative intent. Patients with gastrointestinal stromal tumours (GIST) or Kaposi sarcoma were not enrolled. The Phase 2 portion of the study was a randomised, open label study of olaratumab plus doxorubicin versus doxorubicin alone. A total of 133 patients were randomised, of whom 129 received at least one dose of study treatment (64 in the olaratumab plus doxorubicin arm and 65 in the doxorubicin arm). Patients were required to have histologically or cytologically confirmed, advanced soft tissue sarcoma and ECOG performance status of 0-2. Randomisation was stratified by PDGFR-α expression (positive versus negative), number of previous lines of treatment (0 versus 1 or more lines), histological tumour type (leiomyosarcoma, synovial sarcoma, and others) and ECOG performance status (0 or 1 versus 2).\nPatients were randomised in a 1:1 ratio to either olaratumab (15 mg/kg) on Day 1 and Day 8 plus doxorubicin (75 mg/m²) on Day 1 of each 21-day cycle for up to 8 cycles or doxorubicin (75 mg/m2) alone on Day 1 of each 21-day cycle, also for up to 8 cycles. Olaratumab and doxorubicin were administered by intravenous infusion. During Cycles 5 to 8 on both arms, dexrazoxane (dosed at a ratio of 10:1 to the administered dose of doxorubicin) could be administered on Day 1 of each cycle at the investigator's discretion to reduce potential doxorubicin-related cardiotoxicity. All patients receiving more than 4 cycles of doxorubicin received dexrazoxane. Patients in the olaratumab plus doxorubicin arm could continue on olaratumab monotherapy until disease progression, unacceptable toxicity or any other reason for treatment discontinuation occurred.\nDemographics and baseline characteristics were quite similar between treatment arms in the phase 2 portion of the clinical trial. The median age was 58 years with 42 patients ≥ 65 years of age. 86.4 % of the patients were Caucasian. More than 25 different soft tissue sarcoma subtypes were represented in this trial, the most frequent being leiomyosarcoma (38.4 %), undifferentiated pleomorphic sarcoma (18.1 %) and liposarcoma (17.3 %). Other subtypes were infrequently represented. Patients had received 0-4 previous lines of therapy for treatment of advanced disease but had not previously received treatment with anthracyclines. The number of patients receiving post-study systemic therapy was similar between arms. Ten patients in the olaratumab plus doxorubicin arm and 5 patients in the doxorubicin arm received post-study radiotherapy only. 3 patients in the olaratumab plus doxorubicin arm and 1 patient in the doxorubicin arm had post-study surgery only. 2 patients in the olaratumab plus doxorubicin arm and none in the doxorubicin arm received both post-study radiotherapy and surgery.\nThe median cumulative dose of doxorubicin was 487.6 mg/m2 in the olaratumab plus doxorubicin arm and 299.6 mg/m2 in the doxorubicin alone arm. The primary efficacy outcome measure was progression free survival (PFS) by investigator assessment. Key secondary efficacy outcome measures were overall survival (OS) and objective response rate (ORR) (see Table 3). The study met its primary endpoint (PFS). PFS according to a post-hoc, blinded, independent assessment was 8.2 months vs\n4.4 months; HR = 0.670; p = 0.1208. A statistically significant improvement in OS was seen in the olaratumab plus doxorubicin arm in comparison to treatment with doxorubicin alone in the overall population. The main analysis was performed in the following two subgroups: Leiomyosarcoma (LMS) and non-LMS (other). Subgroups analysis of OS is shown in figure 2. Difference in objective response rate [complete response (CR) + partial response (PR)] according to investigator assessment was not statistically significant (18.2 % vs 11.9 % in patients randomised to olaratumab plus doxorubicin compared to patients randomized to doxorubicin respectively).\nEfficacy results are shown in Table 3 and Figures 1 and 2.\nTable 3. Summary of survival data – ITT population\nLartruvo plus doxorubicin\nDoxorubicin alone\n(n = 66)\nProgression free survival, months*\nMedian (95 % CI)\n6.6 (4.1, 8.3)\nHazard ratio (95 % CI)\n0.672 (0.442, 1.021)\n0.0615**\nOverall survival, months\n26.5 (20.9, 31.7)\n14.7 (9.2, 17.1)\nAbbreviations: CI = confidence interval\n* By investigator assessment\n**Met phase 2 protocol defined significance level of 0.19\nFigure 1. Kaplan-Meier curves of overall survival for Lartruvo plus doxorubicin versus doxorubicin alone\nFigure 2. Forest plot for subgroup analysis of overall survival (ITT population)\nThe European Medicines Agency has deferred the obligation to submit the results of studies with olaratumab in one or more subsets of the paediatric population in soft tissue sarcoma (see section 4.2 for information on paediatric use).\nThis medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.\nThe European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary .\n5.2Pharmacokinetic properties\nOlaratumab is administered as an intravenous infusion only.\nThe population pharmacokinetic (PopPK) model-based mean (CV %) volume of distribution of olaratumab at steady state (Vss) was 7.7 L (16 %).\nThe PopPK model-based mean (CV %) clearance for olaratumab was 0.56 L/day (33 %). This corresponds to a mean terminal half-life of approximately 11 days.\nAge, sex, and race had no clinically meaningful effect on the PK of olaratumab based on a PopPK analysis. Clearance and volume of distribution had a positive correlation with body weight.\nNo formal studies have been conducted to evaluate the effect of renal impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n = 43), or moderate (CLcr 30-59 mL/min, n = 15) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n = 85). No data were available from patients with severe renal impairment (CLcr 15-29 mL/min).\nNo formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN, or total bilirubin > 1.0-1.5 times ULN and any AST level, n = 16), or moderate (total bilirubin > 1.5-3.0 times ULN, n = 1) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN, n = 126). No data were available from patients with severe hepatic impairment (total bilirubin > 3.0 times ULN and any AST level).\n5.3Preclinical safety data\nNon-clinical data reveal no special hazard for humans based on repeat dose toxicity studies in monkeys.\nNo animal studies have been performed to test olaratumab for potential of carcinogenicity, genotoxicity, or fertility impairment. Administration of an anti-murine PDGFR- α surrogate antibody to pregnant mice during organogenesis at 50 and 150 mg/kg resulted in increased malformations (abnormal eyelid development) and skeletal alterations (frontal/parietal additional ossification site). The foetal effects in mice administered the surrogate antibody occurred at exposures less than the AUC exposure at the maximum recommended human dose of 15 mg/kg olaratumab.\n6.PHARMACEUTICAL PARTICULARS\n6.1List of excipients\nMannitol (E421)\nGlycine (E640)\nL-Histidine monohydrochloride monohydrate\nPolysorbate 20 (E432)\nWater for injections\n6.2Incompatibilities\nThe medicinal product should not be administered or mixed with dextrose containing solutions.\n6.3Shelf life\nUnopened vial 2 years.\nAfter dilution\nThis product is preservative free and therefore the prepared dosing solution should be used immediately. If not used immediately, the dosing solution should be stored under refrigeration for up to 24 hours at 2 °C to 8 °C and up to an additional 8 hours at room temperature (up to 25 °C) assuming\ndilution has taken place using acceptable aseptic techniques. Storage times include the duration of infusion.\n6.4Special precautions for storage\nStore in a refrigerator (2° C - 8° C). Do not freeze.\nKeep the vial in the outer carton in order to protect from light.\nFor storage conditions after dilution of the medicinal product, see section 6.3.\n6.5Nature and contents of container\n19 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, an aluminium seal and a polypropylene cap.\nPack of 1 vial of 19 mL.\nPack of 2 vials of 19 mL.\nNot all pack sizes may be marketed.\n6.6Special precautions for disposal and other handling\nThe infusion solution should be prepared using aseptic technique to ensure the sterility of the prepared solution.\nEach vial is intended for single use only. Do not shake the vial. The content of the vials should be inspected for particulate matter and discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and colourless to slightly yellow without visible particles) prior to administration. If particulate matter or discolouration is identified, the vial must be discarded. The dose and volume of olaratumab needed should be calculated to prepare the infusion solution. Vials contain 190 mg or 500 mg as a 10 mg/mL solution of olaratumab. Only use sodium chloride\n9 mg/mL (0.9 %) solution for injection as a diluent.\nIn case of prefilled intravenous infusion container usage\nBased on the calculated volume of olaratumab, the corresponding volume of sodium chloride\n9 mg/mL (0.9 %) solution for injection should be removed from the prefilled 250 mL intravenous container. The calculated volume of olaratumab should be aseptically transferred to the intravenous container. The final total volume in the container should be 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution.\nIn case of empty intravenous infusion container usage\nThe calculated volume of olaratumab should be aseptically transferred into an empty intravenous infusion container. A sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection should be added to the container to make the total volume 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution.\nOlaratumab infusion solution should be administered via an intravenous line over 60 minutes through a separate infusion line. The line with sodium chloride 9 mg/mL (0.9 %) solution for injection should be flushed at the end of the infusion.\nAny unused portion of olaratumab left in a vial should be discarded, as the product contains no antimicrobial preservatives.\nAny unused medicinal product or waste material should be disposed of in accordance with local requirements.\n7.MARKETING AUTHORISATION HOLDER\nEli Lilly Nederland B.V.\nPapendorpseweg 83\n3528 BJ Utrecht\n8.MARKETING AUTHORISATION NUMBER(S)\nEU/1/16/1143/001-003\n9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION\nDate of first authorisation: 9 November 2016\n10.DATE OF REVISION OF THE TEXT\nPrescription drugs listed:\nPandemrix\nZoledronic acid mylan\nVelphoro\nIntrinsa\nDetailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.\nprescription drugs listed\nHome AdvertisingPrivacyContact usCookie Policy"

"Anti-money laundering (AML) compliance in the gaming sector was once again a hot topic during the recent ACAMS Annual AML and Financial Crime Conference. During the keynote session, it was noted that compliance in the industry has improved significantly, with an increasing number of suspicious activity reports (SARs) being submitted to FinCEN—57,000 SARs were submitted in 2017 versus only 27,000 in 2013.\nHowever, the industry must pay more attention to know your customer (KYC), follow documented procedures, keep AML compliance officers involved, and identify customers' patterns of activity.\nAnother major concern that was addressed in a separate session is assessing patron-related risks. During this session, the panel—which included senior AML compliance staff from Stations Casino, Caesars Casino and Cosmopolitan Las Vegas—discussed how to verify patron identities, create risk profiles, conduct due diligence on high-volume patrons, mitigate risks and identify patterns such as structuring.\nBenjamin J. Floyd, Senior Vice President, AML / OFAC Compliance Officer at Caesars Casino, says that his organization takes an enterprise approach to patron-related risks. They evolved from an ad-hoc approach to one where they focus on high-risk players/patrons. They have also become more sophisticated by using more factors to evaluate risks, and with the data they have collected over the last three and a half years, the casino has been able to focus on high-risk guests, not just the top players.\nWhen discussing how due diligence in casinos differs from in banks, it was agreed that given the volume of patrons and the nature of the relationships, casinos cannot know everyone the same way as banks. According to Paul Camacho, Vice President of AML Compliance at Stations Casinos, the information that is most valuable to law enforcement is in employees' heads. Transaction information is important, but so too is what hosts learn about the players.\nKrystal Saab, Director of AML Compliance at Cosmopolitan Las Vegas, stressed the importance of training employees and of ensuring management builds relationships with hosts, which makes them more likely to share concerns or suspicions about patrons. As noted by the panel, the transaction pattern of a successful doctor and a small-scale fraudster can look very similar, and it is human intelligence that can help tell them apart.\nIn closing, the panel recommended that risk identification and segmentation should go beyond the top 50 players because many high rollers are good patrons. In addition, gaming should rely on more than one risk intelligence provider so they can verify the data. They should also engage with these providers if they find errors so that the overall quality of the products increase and everyone can work together to reduce illicit behavior.\nMissed my thoughts from Day 1 at the ACAMS conference? Catch my blog story here."

"SECOND AMENDED AND RESTATED FINANCIAL AND INVESTOR RELATIONS AGREEMENT This Agreement Is Dated Effective as of January 28, 2011.\nThis Agreement is dated effective as of January 28, 2011.\n\"U.S. Securities Act\"; shall mean the United States Securities Act of 1933, as amended.\n\"Distribution Compliance Period\"; shall mean the period beginning when the Securities were first offered to an ACM Contacted Investor or the date of the closing of the final Placement, whichever is later, and ending forty (40) days after such date.\n\"Distributor\"; shall mean any underwriter, dealer (as defined under Section 2(a)(12) of the U.S. Securities Act), or other person who participates, pursuant to a contractual arrangement, in the distribution of the Securities offered or sold in reliance on Regulation S.\nii) an up-front cash payment to Helix.\n\"Investor\"; shall mean an ACM Contacted Investor who is not a resident of Canada or the United States who purchases Helix treasury shares by way of a private placement.\n\"Strategic Partner\"; shall mean a corporate entity involved in the pharmaceutical industry who completes a Transaction with Helix.\n\"Regulation S\"; shall mean Regulation S promulgated pursuant to the U.S. Securities Act.\n\"Transaction\"; shall mean an agreement made between Helix and the Strategic Partner for the development of a therapeutic whether by way of a joint venture, license agreement, development agreement or other such arrangement, which may involve an Initial Cash Payment.\nHelix hereby retains ACM to provide the Company, on a non-exclusive basis, with investor relations and financial advisory services on the terms and conditions of this Agreement, and ACM hereby agrees to provide Helix with such services.\nperforming such other tasks as may reasonably be required by management of Helix in support of the activities outlined above.\nAs compensation for the Investor Relations Services, Helix shall pay ACM a monthly retainer of CHF 30,000.\nHelix hereby engages ACM to find and introduce to Helix potential Investors, not residents of Canada or the United States, in respect of private placements (\"Placements\") of Helix treasury shares (\"Securities\"). ACM will only find and introduce to Helix Investors who fit within the definition of an \"accredited investor\", as set out in Schedule \"A\" attached.\nACM will provide Helix with the names and contact information of any potential Investors. Helix will then advise ACM whether the potential Investor has already been introduced to Helix, or whether such potential Investor may be an \"ACM Contacted Investor\" for purposes of this Agreement.\nShould an ACM Contacted Investor successfully complete a Placement with Helix within six months of such investor being disclosed to Helix by ACM, then ACM shall have earned and be entitled to a fee equal to 12.5% of the funds raised. Such fee shall be payable to ACM within 10 business days following the closing of the Placement, and the receipt by Helix of the gross proceeds of the Placement.\nACM acknowledges that this Agreement and any fee ultimately payable to ACM as a result of a Placement may be subject to approval of such regulatory authorities as may have jurisdiction over Helix and the Placements, including but not limited to The Toronto Stock Exchange (\"TSX\"), NYSE Amex and the Securities and Exchange Commission of the United States.\nThe terms and conditions of the Placements and the acceptance thereof will be in the sole and exclusive discretion of Helix.\nACM will only contact ACM Contacted Investors for purposes of this Agreement, and will only provide and disclose to ACM Contacted Investors, information which has been approved by Helix and ACM will ensure that any ACM Contacted Investor is provided with any new or updated information provided to ACM by Helix on a timely basis.\nIf ACM sells any of the Securities to a dealer (as defined under Section 2(a)(12) of the U.S. Securities Act) or other person receiving a fee in respect of the Securities sold, prior to the end of the Distribution Compliance Period, ACM shall send a confirmation or other notice to the purchaser stating that the purchaser is subject to the same restrictions on offers and sales that apply to ACM.\nthat the Securities will be listed and posted for trading on a stock exchange or that application has been or will be made to list and post the Securities for trading on a stock exchange.\nHelix hereby engages ACM to find and introduce to Helix potential strategic partners, (\"Strategic Partners\") in respect of a Transaction related to one or more of Helix's therapeutics under development.\nDuring the term of this Agreement ACM will provide Helix with the names and contact information of any potential Strategic Partners. Helix will then advise ACM in writing whether such potential Strategic Partner may be an \"ACM Strategic Partner\" for purposes of this Agreement.\n10% of the Initial Cash Payment made as an up-front payment up to a maximum fee of Cdn$1,000,000.\nIt is agreed that the fee shall only apply to the Initial Cash Payment associated with the Transaction and there shall be no fees paid or accruing due with respect to any subsequent payments including, but not limited to, co-development proceeds, milestone payments, or royalties associated with the Transaction. Such fee shall be payable to ACM within 10 business days following the closing of the Transaction, and the receipt by Helix of the Initial Cash Payment.\nACM acknowledges that this Agreement and any fee ultimately payable to ACM as a result of a Transaction may be subject to approval of such regulatory authorities as may have jurisdiction over Helix and the Transaction, including but not limited to the TSX, NYSE Amex and the Securities and Exchange Commission of the United States.\nThe terms and conditions of the Transaction and the acceptance and completion thereof will be in the sole and exclusive discretion of Helix.\nACM will only contact ACM Strategic Partners for purposes of this Agreement, and will only provide and disclose to ACM Strategic Partners, information which has been approved by Helix and ACM will ensure that any ACM Strategic Partners is provided with any new or updated information provided to ACM by Helix on a timely basis.\nACM may have access to information belonging to Helix that is confidential and proprietary in nature. ACM agrees that all such information will be kept in confidence and will be dealt with only in accordance with the Confidentiality Agreement dated as of July 1, 2009 between Helix and ACM. ACM further acknowledges and agrees that nothing in this Agreement or such Confidentiality Agreement permits ACM to disclose any of such confidential information to any Investor, which disclosure is strictly prohibited.\nIt is mutually agreed and understood that Helix will be responsible for all information, statements, and representations made and for any descriptive information regarding Helix prepared and contained in any information provided by Helix to ACM.\nNotwithstanding anything to the contrary contained in this Agreement, ACM shall not disseminate any written or printed material on behalf of Helix nor undertake any advertising on behalf of Helix without obtaining Helix's prior approval thereto.\ndelivery and performance of this Agreement have been duly authorized by all necessary corporate action on its part and that this Agreement constitutes its legal, valid and binding obligation, enforceable against it in accordance with its terms.\nACM further represents and warrants to Helix that (i) ACM, its directors, officers, employees, agents, consultants and partners, if any, have been and will continue to be duly licensed, registered, or otherwise officially recognized or approved as required by applicable law in all jurisdictions where ACM does or intends to do business, including all jurisdictions in which ACM may contact Investors, such that ACM may lawfully carry out the transactions contemplated by this Agreement; and (ii) neither the entering into of this Agreement or the transactions contemplated hereby will violate any law applicable to ACM nor constitute a violation of, or, with or without notice or lapse of time or both, a default under, or conflict with, any other agreement, document or instrument to which ACM is a party or by which ACM or any of ACM's property may be bound.\nACM shall not, and shall cause its directors, officers, employees, agents, consultants and partners (if any) to not, directly or indirectly, buy, sell, borrow, pledge, or otherwise trade in any securities of Helix commencing from the date hereof until the expiry of 48 hours after Helix issues a news release disclosing the last of any Placement, or the closing of the last Transaction, in respect of which ACM is entitled to receive a fee pursuant to this Agreement.\nThis Agreement and the services provided by ACM in connection with the transactions contemplated herein shall be governed by and construed in accordance with the laws of the Province of Ontario.\nIn performing services pursuant to this Agreement, ACM is not authorized to contract on behalf of Helix or otherwise directly or indirectly bind Helix in any way.\nThis Agreement shall terminate on December 31, 2011. Notwithstanding the foregoing, either party may terminate this Agreement upon 30 days' written notice to the other. Any fees which have been earned but have not been paid prior to termination shall remain payable. Section 5 of this Agreement shall survive termination of this Agreement.\nFINANCIAL AND INVESTOR RELATIONS AGREEMENT BETWEEN HELIX BIOPHARMA CORP. AND ACM ALPHA CONSULTING MANAGEMENT EST.\nperson — means (i) an individual, (ii) a corporation, (iii) a partnership, trust, fund and an association, syndicate, organization, or other organized group of persons, whether incorporated or not, and (iv) an individual or other person in that person's capacity as a trustee, executor, administrator, or other legal representative.\nspouse — means an individual who is married to another individual and is not living separate and apart within the meaning of the Divorce Act (Canada), from the other individual, or who is living with another individual in a marriage-like relationship.\n5. A person in respect of which all of the owners of interests, direct, indirect or beneficial, except the voting securities required by law to be owned by directors, are persons that are described in paragraphs 1, 2, 3 or 4 above."

"European Union: GDPR Vs AML – When The Titans Clash\nby G. Vrikis & Associates LLC\nG. Vrikis & Associates LLC\nThe key and most far reaching changes in recent years has undoubtedly been the introduction of the General Data Protection Regulation (GDPR), as well as the introduction, strengthening and expansion of rules and regulations relating to the prevention and suppression of money laundering and terrorist financing – commonly referred to as Anti Money Laundering laws and regulations or \"AML\").\nThe General Data Protection Regulation (GDPR) is designed to protect the data privacy of EU citizens. Every company that legally processes the data of EU citizens, regardless of where that company is located, must comply with GDPR policies. The fines for non-compliance are indeed quite significant, as they can reach as high up to €20 million or up to 4% of the company's annual sales (whichever is greater).\nSo Where Does the Clash Occur?\nOne of the main pillars of GDPR is the right of EU citizens to have their data erased from the data processor's systems forever. By way of example, if an EU citizen, whose data you have legally collected as they were doing business with you, instructs you that they no longer wish for you to be retaining their data, you need to be in a position to erase all such data from your systems (including any backups, mailing lists, marketing lists, etc).\nOn the other side of the equation, AML regulations state that when you investigate suspicious activity, you must save and keep such data and transactions for five years or again be faced with fines due to non-compliance.\nThe question which a lot of clients raise is exactly this: which of the two sets of regulations do I follow so that I am in compliance with both and don't get fined?\nArticles 6 and 17 of GDPR\nFortunately, although it might not be immediately clear, GDPR has provided for such eventualities and has included language that protects both data controllers and data processors.\nArticle 6 provides the legal basis for data controllers to collect the data of EU citizens, which is to comply with AML regulations. Secondly, it provides the legal basis for data processors to process the data to support \"legitimate interests\", namely, to detect suspicious activity so you can be compliant with the AML regulations.\nThereafter, Article 17 clarified things even further, by indicating that legal requirements take precedence over the right to erasure. As such, if a regulation requires you to save the data, as AML regulations do, the right to erasure does not take effect until after that legal period ends in accordance with the AML regulation time-period.\nCyprus Examples\nAlthough no Court Decision has been issued as of yet on this matter, relevant guidance can be obtained from recent decisions issued by the Office of the Commissioner of Data Protection:\nIn a decision published in June 2019, the Commissioner found that the controller was regulated by AML national legislation, which requires the retention of data for at least five years to ensure that regulators, companies, and customers have access to key business records regarding financial transactions. As such, it was deemed that there was no violation as the processing was lawful under the provision Art 17(1)(b) GDPR providing that \"the processing is necessary for compliance with a legal obligation which requires processing by Union or Member State law to which the controller is subject or for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller\".\nIn a decision published in October 2019, the Commissioner found that, pursuant to the applicable national social insurance and tax law, the controller was required to keep records of all expenses including salaries. In order to comply with this obligation, the controller was obliged to keep the complainant's passport information, employment contract and salary information. Moreover, according to the national law on statute of limitations, the controller was allowed to keep the complainant's dismissal records for a period of six years after the dismissal as the complainant could appeal the decision of the controller to the relevant court. As such, there was no breach in refusing to delete the data of the person from the data controller's system.\nOriginally Published by , November 2020\nCyprus Corporate/Commercial Law Compliance Corporate and Company Law Government, Public Sector Money Laundering Privacy Data Protection Privacy Protection\nPOPULAR ARTICLES ON: Privacy from European Union\nCyprus Corporate/Commercial Law Compliance Corporate and Company Law Government, Public Sector\nMoney Laundering Privacy Data Protection Privacy Protection\nPersonal Data Protection And COVID-19 Test Results G. Vrikis & Associates LLC\nData Protection In The Employment Sector During Covid-19 Outbreak Kinanis LLC\nThe GDPR: New Opportunities, New Obligations Harris Kyriakides\nThe GDPR And The Effect On The Medical Profession Elias Neocleous & Co LLC\nTen GDPR Questions You Should Know The Answer To G. Vrikis & Associates LLC\nData Privacy Comparative Guide Dr. K. Chrysostomides & Co LLC\nCoronavirus (COVID-19) - What Companies Must Consider With Regards To Data Protection Ernst & Young Cyprus\nPersonal Data Protection – Commissioner Issues A Fine Against Local Bank G. Vrikis & Associates LLC\nCase C-311/18 Data Protection Commissioner V Facebook Ireland And Maximillian Schrems: Landmark CJEU Decision Invalidates EU – U.S. Privacy Shield A. Karitzis & Associates L.L.C"

"The Anti-Money Laundering and Know Your Customer Policy (the \"AML/KYC Policy\") of SOVEREIGN Trading Limited and its affiliates (\"we\", \"our\", \"us\" or \"SOVEREIGN\") is established to prevent and mitigate possible risks of SOVEREIGN being involved in illegal or illicit activities and to enable SOVEREIGN meet its legal and regulatory obligations in this area. This AML/KYC Policy is subject to changes and updates by SOVEREIGN from time to time to ensure compliance with applicable legislation and global AML/KYC practices.\nFurthermore, Politically Exposed Person includes also family members or persons known to be close associates of any individual identified in (a) – (g) above.\n\"PRC\" means the People's Republic of China (excluding the special administrative regions of Hong Kong and Macau, and Taiwan).\n\"Prohibited Jurisdiction\" means the jurisdictions designated by SOVEREIGN as a Prohibited Jurisdiction in respect of any Service from time to time.\n\"Sanctioned Jurisdiction\" means any country or territory to the extent that such country or territory is the subject of any sanction issued by the United Nations, United States and/or the European Union.\n\"Sanctioned Person\" means any individual or entity (a) identified on a sanctions list issued by the United Nations, United States and/or the European Union; (b) organized, domiciled or resident in a Sanctioned Jurisdiction; or (c) otherwise the subject or target of any sanctions, including by reason of ownership or control by one or more individuals or entities described in clauses (a) or (b).\n\"Service\" means the (i) sale or issuance of digital tokens to a person by SOVEREIGN; (ii) advisory, brokerage, trading and exchange services in respect of digital tokens provided by SOVEREIGN; and (iii) other services provided by SOVEREIGN from time to time.\n\"User\" means a person using SOVEREIGN services, with or without prior registration and authorization of SOVEREIGN, including for the purchase of tokens from SOVEREIGN.\nInformation required to comply with governmental rules, anti-money laundering (\"AML\") or \"know-your-customer\" (\"KYC\") policies. We may require you to provide information including scanned or depicted documents from you, such as a photo of your passport or other identity card to show proof of identity as well as documentation that evidences your proof of address or documents or online database information to confirm your identity. We also may collect information about your device for fraud prevention, KYC or AML purposes and other information as may be required by terms of SOVEREIGN Token Sale Terms and Conditions. Such information will only be necessary if requested and may be required prior to activation of your account. EEA Users: This information is processed pursuant to our obligations under applicable law.\nSOVEREIGN will screen a User prior to providing any Service to such User, and will continue to screen such User on an ongoing basis, to ensure that such User is not a Sanctioned Person, from a Sanctioned Jurisdiction and/or a person from a Prohibited Jurisdiction. If a User is a Sanctioned Person, from a Sanctioned Jurisdiction and/or a person from a Prohibited Jurisdiction, SOVEREIGN will refuse to provide Services to such User or discontinue provision of Services. In carrying out this screening SOVEREIGN shall ensure to adopt software to enable comprehensive screening to be carried out and which captures all sanctions that SOVEREIGN is bound to follow.\nSOVEREIGN, in line with international requirements, adopts a risk-based approach to combating money laundering and terrorist financing. By adopting a risk-based approach, SOVEREIGN is able to ensure that measures to prevent or mitigate money laundering and terrorist financing are commensurate to the identified risks.\n(d). if a person purports to act on behalf of the User, (i) identify the person and take reasonable measures to verify the person's identity on the basis of documents, data or information based on a reliable and independent source; and (ii) verify the person's authority to act on behalf of the User.\nTo identify a User who is an individual, SOVEREIGN will collect information from the User such as his full name, date of birth, nationality, place of residence, email address, and/or the identity document type. SOVEREIGN will, depending on the level of risk, verify the identity of the User with documents such as his national ID, passport and/or driver's licence and utility bill.\nTo identify a User who is a legal entity, SOVEREIGN will collect information from the User such as its full legal name, registration number, establishment date, jurisdiction of establishment and lists of directors (as applicable to the entity). SOVEREIGN will, depending on the level of risk, verify the User with documents such as Memorandum and Articles of Association (or equivalent), additional beneficial ownership information and documents, and a detailed corporate chart (as applicable to the entity).\nIf the User is not physically present for identification purposes, SOVEREIGN may adopt more stringent standards to verify the identity of the User.\n(c). identifying transactions that are complex, unusually large in amount or of an unusual pattern and have no apparent economic or lawful purpose.\nTo continuously monitor the business relationship with a User, SOVEREIGN shall on a periodic basis according to the risk rating of the User, carry out a file review to ensure that information held about the User is up-to-date and that identification documents held are still valid. In addition, on more frequent basis, SOVEREIGN shall monitor transactional activity to identify any red-flags or 'out of the norm' activity.\nAs part of the second line of defense, the Money Laundering Reporting Officer will carry out checks to ensure that regular and effective on-going monitoring is being effected and ensure that irregular or suspicious transactions are effectively escalated.\nIn certain circumstances, the risk may be higher and SOVEREIGN will need to take additional checks. These include, for example, situations where the User is from a non-reputable jurisdiction (for example on the Financial Action Task Force's recommendations), the User is a politically exposed person or the User's behavior and activities raises other red flags.\n(b). where a business relationship has been established, obtain approval from senior management to continue the business relationship, take reasonable measures to verify the beneficial owner's identity, and take reasonable measures to establish the User's or beneficial owner's source of wealth and source of funds that will be involved in the business relationship.\nSOVEREIGN will keep (a) transaction records, for a period of ten (10) years beginning on the date on which a transaction is completed; and (b) other information collected by SOVEREIGN for AML/KYC purposes, throughout the continuance of the business relationship with the User and for a period of ten (10) years beginning on the date on which the business relationship with the User ends.\nAll of our employees and officers receive ongoing AML/KYC training that is refreshed at least once every year to ensure they are familiar with our AML/KYC policy and all applicable laws and regulations. New employees receive training within thirty (30) days of their start date. All documentation related to compliance training including materials, tests, results, attendance and date are maintained. In addition, our compliance training program is updated as necessary to reflect current laws and regulations.\nThe Money Laundering Reporting Officer is the person, duly authorized by SOVEREIGN, whose duty is to ensure the effective implementation and enforcement of the AML/KYC Policy. It is the Money Laundering Reporting Officer's responsibility to supervise all aspects of SOVEREIGN's anti-money laundering and counter-terrorist financing. All our employees will report any suspicious behavior or activities to the Money Laundering Reporting Officer.\nWhere SOVEREIGN suspects that the User is involved in any money laundering, terrorist financing or other illegal activities, it will report any relevant knowledge or suspicion to governmental and regulatory authorities. SOVEREIGN has no obligation to notify a User of any such suspicious transaction report which, on the other hand, SOVEREIGN and its employees can be held liable for tipping off. This is criminal offence under punishable by a fine and/or imprisonment."

"On 30 January 2018, the Bank of Italy published a note dated 23 January 2018 containing several \"good practice\" recommendations in order to adequately and efficiently implement policies in the field of anti-money laundering (\"AML\") legislation and politically exposed persons (\"PEP\").\nSuch recommendations aim to help credit and financial institutions—as well as all others obliged entities according to the AML framework—to comply with AML legislation and avoid (or, at least, reduce) risks related to business relationships and transactions performed with PEPs.\nPursuant to the Directive (EU) 2015/849 of 20 May 2015 on the prevention of the use of the financial system for the purposes of money laundering or terrorist financing (the so called \"AML Directive\"), a PEP is defined as a natural person who is or who has been entrusted with prominent public functions.\nd. conduct enhanced, ongoing monitoring of those business relationships with PEPs.\nMoreover, obliged entities shall take reasonable measures to determine whether the beneficiaries of a life or other investment-related insurance policy and/or, where required, the beneficial owner of the beneficiary are PEPs.\nThe mentioned systems and measures shall cover PEPs as well as family members or persons known to be close associates of PEPs (Article 23 of the AML Directive).\nLastly, the AML Directive provides that where a PEP is no longer entrusted with a prominent public function, obliged entities shall, for at least 12 months, be required to take into account the continuing risk posed by that person and to apply appropriate and risk-sensitive measures until such time as that person is deemed to pose no further risk specific to politically exposed persons (Article 22 of the AML Directive).\nItaly transposed the AML Directive into its legal system by means of Legislative Decree no. 90 of 25 May 2017, amending Legislative Decree no. 231 of 21 November 2007 (the \"Italian AML Decree\").\nAccording to Article 1 of the Italian AML Decree, a PEP is a natural person who is or who has been entrusted (within a year) with prominent public functions (e.g., Prime Minister, Ministers, Vice-Ministers, etc.) and includes, inter alia, members of a political party's central body (e.g., the national president of a political party), members of board of directors of companies directly or indirectly controlled by a State, by a Region, or by certain municipalities (e.g., cities with not less than 15,000 inhabitants, provincial capitals, etc.), majors of cities with not less than 15,000 inhabitants, directors of ASLs (i.e., entities in charge of healthcare) and hospitals.\nUnder Italian AML Decree, and similarly to the provisions of the AML Directive, obliged entities shall conduct an enhanced customer due diligence in case of business relationships, transactions and professional services where clients and/or beneficial owners are PEPs (Article 24, par. 5). Moreover, in case of high risk of money laundering and financial terrorism, enhanced customer due diligence applies even to clients that, originally identified as PEPs, have not been qualified in such a way for more than a year (Article 24, par. 6). The same provision applies in connection with insurance policies, in case the beneficial owner of the beneficiary was a PEP.\nFurthermore, as per the AML Directive, Article 25 of the Italian AML Decree provides that obliged entities implement adequate and risk-based procedures to determine whether the customer or the beneficial owner of the customer is a PEP and, in case of business relationships, professional services or transactions with PEPs, adopt the following measures: obtain senior management (or their delegated) approval for establishing or continuing business relationships with PEPs; take adequate measures to establish the source of wealth and source of funds involved in the business relationships or transactions with PEPs; conduct enhanced, ongoing monitoring of those business relationships or professional services with PEPs.\ni. internal auditors should expressly take into account the PEPs' matter and verify the adequacy of the implemented policies and procedures.\nThe wide definition of PEPs recently adopted by the Italian Legislator has increased the number of business relationships and transactions relevant under the AML legislation. The Bank of Italy's recommendations are a good way to draw obliged entities' attention to such matter.\n See Article 3, no. 9, of the AML Directive. Such definition includes: heads of State, heads of government, ministers, and deputy or assistant ministers; members of parliament or of similar legislative bodies; members of the governing bodies of political parties; members of supreme courts, of constitutional courts, or of other high-level judicial bodies, the decisions of which are not subject to further appeal, except in exceptional circumstances; members of courts of auditors or of the boards of central banks; ambassadors, chargés d'affaires, and high-ranking officers in the armed forces; members of the administrative, management, or supervisory bodies of State-owned enterprises; directors, deputy directors, and members of the board or equivalent function of an international organization.\n See Article 2 of the AML Directive.\n See Article 21 of the AML Directive. Those measures shall be taken no later than at the time of the payout or at the time of the assignment, in whole or in part, of the policy. Where there are higher risks identified, in addition to applying the customer due diligence measures laid down in Article 13, Member States shall require obliged entities to: inform senior management before payout of policy proceeds; and conduct enhanced scrutiny of the entire business relationship with the policyholder.\n Pursuant to Article 3, no. 10, of the AML Directive, \"family members\" include the following: the spouse, or a person considered to be equivalent to a spouse, of a politically exposed person; the children and their spouses, or persons considered to be equivalent to a spouse, of a politically exposed person; the parents of a politically exposed person.\n Pursuant to Article 3, no. 11, of the AML Directive, \"persons known to be close associates\" means: natural persons who are known to have joint beneficial ownership of legal entities or legal arrangements, or any other close business relations, with a politically exposed person; natural persons who have sole beneficial ownership of a legal entity or legal arrangement which is known to have been set up for the de facto benefit of a politically exposed person.\n Italian AML Decree defines family members of PEPs and persons known to be close associates of PEPs as in the AML Directive.\n See Article 3 of the Italian AML Decree.\n Rules similar to those provided for under the AML Directive apply to insurance policy beneficiaries.\n The Risk Appetite Framework is a document that establishes, in connection with the maximum risks of the company, the company business model, and the strategic plan, the risk appetite and relevant limits, the tolerance threshold, risk management policies, and the process in order to define and implement them."

"This additional notice explains how the Accuity risk and compliance services (the \"Risk and Compliance Services\") allow our customers to look-up information about individuals. This notice explains how we use this information.\nMore information about the data controllers for our Risk and Compliance Services is set out in the contact us section of this notice.\nThe Risk and Compliance Services contain information that our customers can use to screen individuals to prevent and detect fraud, terrorism, money laundering, bribery and corruption, and other crimes. To do this, we allow our customers to conduct checks against the personal information we hold in the Risk and Compliance Services.\nPublicly-available sources and data suppliers from which we obtain data to validate or supplement the information we hold, such as government watch lists, court and insolvency records, electoral registers and public company information.\nData used to identify individuals, such as names, identification documents.\nInformation about business activities, such as affiliation with and ownership of businesses.\nInformation about court judgments and criminal activity, such as details of offences and court dispositions.\nSanctions lists, watch lists and lists of politically exposed persons, including your presence on such lists and you (or your family members' or business associates') affiliations with government officials.\nInformation from public media, such as information in published news sources that may reveal connections to suspected criminal activity.\nand please also refer to https://www.lexisnexis.com/en-us/privacy/world-compliance-privacy-info.page for further information.\nAllowing our customers to comply with their regulatory requirements: the Risk and Compliance Services enable our customers to check whether doing business with a client or potential client could create a risk of financial crime, such as corruption or money laundering. For example, when individuals apply for an account, the bank may search their names against sanctions lists, watch lists, lists of politically exposed persons, media reports and other publicly-available information, to determine whether opening an account creates a risk of violating regulatory requirements, and the bank will be responsible to carry out their own due diligence.\nIf your information is included in the Risk and Compliance Services, then this will be available to customers who use the Risk and Compliance Services. These are primarily organisations in the regulated sectors (e.g. financial services or payment service providers), or other businesses that must screen individuals for compliance with counter-terrorism, anti-corruption and anti-money laundering regulations, anywhere in the world.\nWe retain your personal information for as long as necessary to provide the Risk and Compliance Services and for other essential purposes such as complying with our legal obligations, resolving disputes, maintaining security, detecting and preventing fraud and abuse, and enforcing our agreements.\nWe retain identification data (such as names and addresses) whilst there is a continuing need for us to utilise it. We keep this retention under review and we will remove data as and when we no longer require it.\nYour personal information may be stored and processing in your region or another country where Reed Business Information, its group companies and our service providers maintain servers and facilities, including Australia, Brazil, France, Germany, Italy, Ireland, the Netherlands, Singapore, South Africa, the United Kingdom, and the United States. We take steps including through our contracts, intended to ensure that the information continues to be protected wherever it is located in a manner consistent with the standards of protection required under applicable law.\nWhere personal information is transferred from the European Economic Area or Switzerland to a country that has not received an adequacy decision by the European Commission, we rely on adequate safeguards, such as the European Commission-approved Standard Contractual Clauses and the EU-U.S. and Swiss-U.S. Privacy Shield Frameworks, to transfer the data.\nAccuity Inc. has certified certain of their services to the EU-U.S. and Swiss-U.S. Privacy Shield Frameworks as set forth by the U.S. Department of Commerce. Please view these entities' Privacy Shield Notice here. To learn more about the Privacy Shield program, and to view these entities' certification, please visit www.privacyshield.gov.\nWhere your personal information is included in the Risk and Compliance Services, we process your personal information for our and our licensees' legitimate interests, which are: to deliver our products to our customers and their end users; to detect or prevent fraud; to protect the security of our systems customers and users; to further develop our products; to conduct direct marketing; to operate our business (by processing payments/invoices and conduct credit checks on customers, suppliers and leads, perform sales and customer relations management, supplier management, as well as incidental processing in our back office for these purposes); to provide customer service or support; and to enable our customers to comply with their legal obligations.\nWhere the personal information we process includes sensitive or criminal offence data (as defined by the relevant law), we are able to process this data because it is necessary for a legal obligation, there is a substantial public interest, the information was manifestly made public or we have obtained a license for such processing in accordance with the applicable law.\nIf you would like more information about the factors we considered you can ask us using the contact us information below.\na copy or portability of your personal information."

"The FCA launched their finalised guidance on the treatment of Politically Exposed Persons (PEP) for anti-money laundering purposes in July 2017; you can read it in full here, this article has consolidated the key points.\nNB: When PEPs are referenced, read also 'or their family or known close associates'.\nGuidance issued to satisfy the duty of section 333U of the Financial Services and Markets Act 2000.\nFirms must take appropriate but proportionate measures in meeting financial crime obligations. A case-by-case basis is required when assessing all PEPs.\nGuidance provides clarity on the definition of PEP in a UK context and it is unlikely that a large number of UK customers should be treated as PEPs.\nWhere a UK customer does meet the definition, the firm is required to recognise the lower risk of such customers as illustrated later in the guidelines.\nFirms must, however, apply more stringent approaches where the customer is assessed as having a greater risk.\nThis guidance covers obligations when opening new (or monitoring existing) relationships for any institution overseen by the FCA. It is only applicable to business relationships undertaken in the UK.\no risk factors are associated with that customer unrelated to their position or connection to a PEP.\nWhy are PEPs a risk?\nFamily and close associates are not themselves PEPs solely as a result of their connection to a PEP but rather they may benefit from, or be used to facilitate, the abuse of public funds by the PEP.\nAppropriate risk management systems and procedures must be in place to determine if a customer or beneficial owner of a customer is a PEP.\no A firm may choose to use commercial databases that contain lists of PEPs, family members and known close associates.\nOnce confirmed, a firm must assess the level of risk associated with that PEP and as a result, calculate the extent to which EDD measures need to be carried out. This all needs to be clearly documented.\nA business relationship should not be terminated unless the risks posed by a PEP are higher than the firm can adequately mitigate.\no Conduct enhanced ongoing monitoring of the business relationship.\nWho should be treated as a PEP?\no Directors, deputy directors, and members of the board of international organisations.\nFCA would expect firms to understand the nature of each position and whether this gives rise to the risk of abuse of power; middle-ranking and junior officials could act on behalf of a PEP and, therefore, the risk may rise from customer due diligence to EDD.\nA PEP no longer entrusted with a prominent public function should continue to be viewed as a PEP for at least a 12-month period after the date they ceased to be entrusted with a public function.\nWho should be considered a family member/known close associate?\nChildren and their spouses or civil partner.\nBrothers and sisters are also possibilities.\nAs soon as a PEP leaves office, the family members should immediately be treated as ordinary customers subject to normal customer due diligence obligations.\no An individual who has sole beneficial ownership of a legal entity or a legal arrangement that is known to have been set up for the benefit of a PEP.\nDo all PEPS pose the same risk?\no The potential of the product to be misused for purposes of corruption.\no Is in a country with certain political, economic and judicial characteristics similar to the UK.\no Credible allegations of financial misconduct.\nFamily members of a low risk PEP are often considered to themselves be lower risk.\no Appointment to a public office that appears inconsistent with personal merit.\nThe nature and extent of the EDD should be appropriate and proportional to the risk of that PEP.\no Business relationship should be subject to more frequent/thorough reviews.\nFirms providing long-term insurance contracts must take reasonable measures to determine whether any beneficiaries of its insurance policies are PEPs. This must be done before any payment is made.\nWhen a PEP is a beneficial owner of a corporate customer, the firm should not automatically treat other beneficial owners/shareholders as a PEP or known close associate but can do so once they have assessed the relationship based on information available.\nThe guidelines steer firms towards \"commercial databases that contain lists of PEPs, family members and known close associates\" and our Red Flag Alert database is the perfect tool for this purpose. Not only do we track all PEPs, but this information is also plugged directly into your database and any key changes are sent directly to your inbox – in short, Red Flag Alert makes PEP compliance seamless and promotes proactive best practice.\nFor a free consultation with one of our team, please get in touch with Richard West at richard.west@redflagalert.com or 0344 412 6699."

"Regulation of Representatives in Agency Adjudicative Proceedings\nProject: Regulation of Representatives in Agency Adjudicative Proceedings\nRecommendation number: 2021-9\nAdopted on: December 16, 2021\nMany agencies have adopted rules governing the participation and conduct of attorneys and non-attorneys who represent parties in adjudicative proceedings. These rules may address a wide array of topics, including who can represent parties in adjudications, how representatives must conduct themselves, and how the agency enforces rules of conduct.[1] Some agencies have drafted their own rules. Others have adopted rules developed by state bar associations or the American Bar Association's (ABA) Model Rules of Professional Conduct. Agencies provide public access to their rules in different ways, including publishing them in the Federal Register and Code of Federal Regulations and posting them on their websites. Some agencies have provided explanatory materials to help representatives, parties, and the public understand how the rules operate.\nAgency authority to set qualifications for who may serve as a representative depends on whether the potential representative is an attorney or non-attorney. For attorneys, the generally applicable Agency Practice Act provides, with some exceptions, that \"any individual who is a member in good standing of the bar of the highest court of a State may represent a person before an agency,\"[2] though some statutes authorize agencies to impose additional qualification requirements. Agencies generally have greater discretion under the Administrative Procedure Act and agency- or program-specific statutes to determine whether persons who are not attorneys may act as representatives and, if they may, to establish the qualifications for doing so.\nAs a general matter, agencies have legal authority to establish rules governing the conduct of representatives and to take actions against representatives found to have violated such rules.[3] Courts have consistently found such authority inherent in agencies' general rulemaking power or their power to protect the integrity of their processes.[4] Agencies' disciplinary authority is not limitless, however, and agencies must determine what their governing statutes allow.\nAgencies that adopt rules governing representatives will need to make a number of decisions as they decide the type of rules to adopt and how they will apply those rules. They must determine whether the rules will apply only to attorney representatives or will also apply to other representatives. They must decide whether to borrow language from rules drafted by other entities (state bars, ABA) or to draft their own rules. They must determine the particular conduct that the rules will regulate and whether to apply the same rules to attorneys and non-attorneys. And if they decide to adopt rules governing who may practice before the agency, they must ensure that they comply with the Agency Practice Act for rules applied to attorneys and determine the qualification standards, if any, they will establish for non-attorneys.\nOnce agencies have decided to adopt rules, they also must determine how to enforce those rules. Agencies may enforce rules in various ways, ranging from reminders or warnings to more serious actions, including disqualifying a representative from appearing in the current adjudication or future adjudications or imposing a monetary penalty. Agencies must determine that they have the legal authority to undertake any such actions. Agencies also must determine whether to implement a program for reciprocal discipline, which involves imposing discipline on a representative found to have engaged in misconduct by another jurisdiction, or for referral procedures, which involve reporting attorneys' misconduct to another jurisdiction for purposes of taking possible disciplinary action.\nAgencies that have adopted rules must ensure that representatives, parties, and the public can easily access the rules. Agencies also must decide whether to provide additional explanatory materials and, if so, ensure that those are also easily accessible.\nThis Recommendation recognizes that agency adjudicative proceedings vary widely in their purpose, complexity, and governing law. Some processes are trial-like; others are informal. Some are adversarial; others are non-adversarial. Given the extensive variation in agencies' needs and available resources, this Recommendation focuses primarily on setting forth the various options agencies should consider in deciding whether to adopt rules and deciding on the content of those rules. It takes no position on whether agencies should allow non-attorney representatives. For agencies that decide to adopt rules for attorneys and, if they elect to do so, for non-attorneys, the Recommendation offers best practices for seeking to ensure that those rules are disseminated widely and that representatives, parties, and the public can understand the rules and how agencies go about enforcing them.\nAlthough the Recommendation does not endorse harmonization of rules for its own sake, it does urge agencies to consider whether achieving greater uniformity among different adjudicative components within the agency or even across adjudicative components of multiple agencies might prove valuable for representatives who practice before a variety of components or agencies. It also recommends that the Administrative Conference's Office of the Chairman consider preparing model rules that agencies can use when drafting their own rules.\nAdoption of Rules Governing Participation and Conduct\n1. For federal agency adjudication systems in which parties are represented—either by attorneys or non-attorney representatives—agencies should consider adopting rules governing the participation and conduct of representatives in adjudicative proceedings to promote the accessibility, fairness, integrity, and efficiency of adjudicative proceedings.\n2. Agencies should consider whether to adopt or reference rules promulgated by other authorities or professional organizations or instead draft their own rules. Agencies should ensure that the rules are appropriate for the adjudicative proceedings they conduct and consider whether any modifications to adopted rules should be included. Agencies should consider whether any rules applicable to attorneys should be applied to non-attorneys and whether they should be modified before doing so.\n3. Possible topics that agencies might consider in their rules include representatives' actions that are likely to occur during a particular adjudication and actions that might occur outside a particular adjudication but that might still adversely affect the conduct of agency adjudications. Topics agencies might consider include the following:\na. Engaging in conduct that disrupts or is intended to disrupt an adjudication;\nb. Making unauthorized ex parte contacts with agency officials;\nc. Engaging in representation of a client that conflicts with other interests, including representation of another client, or the attorney's personal interests;\nd. Filing frivolous claims or asserting frivolous defenses;\ne. Engaging in conduct that is prejudicial to the administration of justice, including conduct not limited to that occurring during an adjudication;\nf. Failing to provide competent representation;\ng. Improperly withdrawing from client representation;\nh. Unreasonably delaying the conduct of an adjudication;\ni. Making a material intentional false statement;\nj. Improperly seeking to influence the conduct of a judge or official;\nk. Being convicted of a crime or being subject to an official finding of a civil violation that reflects adversely on the attorney's fitness to represent clients before the agency; and\nl. Knowingly disobeying or attempting to disobey agency rules (including conduct rules) or adjudicators' directions, or knowingly assisting others in doing so.\n4. Agencies should consider whether divergence among rules governing different types of adjudicative proceedings would create needless complexity in practicing before the agency. This might entail harmonizing rules among different components of the agency. It might also involve harmonization of style or language across rules as well as cross-referencing of other rules of the agency. Agencies should also consider whether to harmonize rules across agencies, especially in cases in which the same representatives commonly appear before a group of agencies (e.g., financial agencies).\nAgency Action in Response to Allegations of a Violation of Rules\n5. Agencies should specify in their rules how they will respond to an allegation of a violation of their conduct rules, and they should publish these rules consistent with Paragraphs 9 through 12. Among other topics, agencies should address:\na. Who can make a complaint and how to make it;\nb. How notice of a complaint should be provided to the representative who is the subject of the complaint;\nc. Who adjudicates the complaint;\nd. The procedure for adjudicating the complaint, including any rules governing the submission of evidence and the making of arguments;\ne. The manner in which a decision will be issued, including any applicable timeline for issuing a decision;\nf. Procedures for appealing a decision;\ng. Who is responsible for enforcing the decision within the agency and communicating the decision to other relevant authorities; and\nh. The process for identifying and dismissing complaints that are frivolous, repetitive, meant to harass, or meant primarily to delay agency action, including any consequences for persons filing such complaints.\nAgency Action in Response to a Violation of Rules\n6. Rules should address what actions an agency may take in the case of a violation of the rules consistent with their authority to do so, including informal warnings short of sanctions and the range of available sanctions.\n7. For rules applicable to attorneys, agencies should consider whether to adopt any reciprocal disciplinary procedures or referral procedures.\nWho Can Practice Before Agencies\n8. Agencies should, in compliance with the Agency Practice Act (5 U.S.C. § 500), only establish additional rules governing which attorney representatives can practice before the agencies if authorized to do so by separate statute. With respect to non-attorneys, agencies should determine what rules, if any, they will establish to govern who can practice before the agencies.\n9. Agencies should publish their rules governing representatives' conduct in the Federal Register and codify them in the Code of Federal Regulations.\n10. When agencies adopt rules promulgated by another entity, which may in some instances be copyrighted, they should ensure that the rules are reasonably available to the public such as by providing links on the agencies' websites or other mechanisms for easily accessing those rules.\n11. Agencies should also publish their rules governing representatives' conduct on a single webpage or in a single document on their websites and clearly label them using a term such as \"Rules of Conduct for Representatives.\" The agency should indicate clearly whether the rules apply only to attorneys, non-attorneys, or both.\n12. On the webpage or in the document described in Paragraph 11, agencies should also publish information concerning qualifications for representatives (including for non-attorneys as applicable), how to file a complaint, and a summary of the disciplinary process.\n13. On the webpage or in the document described in Paragraph 11, agencies should consider providing comments, illustrations, and other explanatory materials to help clarify how the rules work in practice.\n14. Agencies should consider publishing disciplinary actions, or summaries of them, on the webpage or in the document described in Paragraph 11 so as to promote transparency regarding the types of conduct that lead to disciplinary action. When necessary to preserve recognized privacy interests, the agency may consider redacting information about particular cases or periodically providing summary reports describing the rules violated, the nature of the misconduct, and any actions taken.\nModel Rules\n15. ACUS's Office of the Chairman should consider promulgating model rules of conduct that would address the topics in this Recommendation. The model rules should account for variation in agency practice and afford agencies the flexibility to determine which rules apply to their adjudicative proceedings. In doing so, the Office of the Chairman should seek the input of a diverse array of agency officials and members of the public, including representatives who appear before agencies, and the American Bar Association.\n[1] See George M. Cohen, Regulation of Representatives in Agency Adjudicative Proceedings (Dec. 3, 2021) (report to the Admin. Conf. of the U.S.).\n[2] 5 U.S.C. § 500(b).\n[3] See, e.g., 5 U.S.C. § 301.\n[4] See, e.g., Checkovsky v. SEC, 23 F.3d 452, 456 (D.C. Cir. 1994); Davy v. SEC, 792 F.2d 1418, 1421 (9th Cir. 1986); Polydoroff v. ICC, 773 F.2d 372, 374 (D.C. Cir. 1985); Touche Ross & Co. v. SEC, 609 F.2d 570, 580–82 (2d Cir. 1979); Koden v. U.S. DOJ, 564 F.2d 228, 233 (7th Cir. 1977)."

"Related provisions for CONC 2.2.9\nAppointed representatives (60)\nAuthorised persons (34)\nEuropean Economic Area (27)\nAuthorisation (25)\nGroup companies (23)\nInvestment activities (22)\nMortgages and home financing activities (18)\nFinancial Conduct Authority Handbook (18)\nInsurance activities (18)\nProviders (18)\nNon United Kingdom (16)\nSUP 12.4.3G 14/01/2005 RP\nIn assessing, under SUP 12.4.2 R(2)1(a) and (b), whether an appointed representative or prospective appointed representative is solvent and otherwise 1suitable, a firm should determine, among other matters, whether the person is likely to be adversely influenced by its financial position in the conduct of the business for which the firm is responsible. This might arise, for example, if the person has cashflow problems and is not able to service its debts. Guidance for firms on\nIn assessing, under SUP 12.4.2 R (2)(b), whether an appointed representative or prospective appointed representative is otherwise 1suitable to act for the firm in that capacity, a firm should consider:(1) whether the person is fit and proper; guidance on the information that firms should take reasonable steps to obtain and verify is given in SUP 12 Annex 2; and(2) the fitness and propriety (including good character and competence) and financial standing of the controllers, directors,\nIn determining, under SUP 12.4.2 R (2)(c), whether an appointed representative or prospective appointed representative has any close links which would be likely to prevent the firm's effective supervision, a firm should consider the guidance to threshold condition 2C or 3B as applicable20 in COND 2.3.20\nThis chapter gives guidance to a firm, which is considering appointing an appointed representative, on how the provisions of section 39 of the Act (Exemption of appointed representatives) work. For example, it gives guidance on the conditions that must be satisfied for a person to be appointed as an appointed representative. It also gives guidance to a firm on the implications, for the firm itself, of appointing an appointed representative.\nThe chapter also sets out the FCA'srules, and guidance on these rules, that apply to a firm before it appoints, when it appoints and when it has appointed an appointed representative. The main purpose of these rules is to place responsibility on a firm for seeking to ensure that: (1) its appointed representatives are fit and proper to deal with clients in its name; and (2) clients dealing with its appointed representatives are afforded the same level of protection as if they had\n2This chapter also sets out guidance about section 39A of the Act, which is relevant to a UK MiFID investment firm that is considering appointing an FCA registered tied agent. It also sets out the FCA'srules, and guidance on those rules, in relation to the appointment of an EEA tied agent by a UK MiFID investment firm.\n(1) Under section 19 of the Act (The general prohibition), no person may carry on a regulated activity in the United Kingdom, or purport to do so, unless he is an authorised person, or he is an exempt person in relation to that activity.(2) A person will be an exempt person if he satisfies the conditions in section 39(1) of the Act, guidance on which is given in SUP 12.2.2 G. A person who is exempt as a result of satisfying these conditions is referred to in the Act as an appointed\nSUP 12.2.2AG 01/04/2014 RP\n(1) 15Under sections 20(1) and (1A) of the Act (Authorised persons acting without permission), if an authorised person carries on a regulated activity in the United Kingdom, or purports to do so, otherwise than in accordance with his permission, he is to be taken to have contravened a requirement imposed by the FCA (in the case of a FCA-authorised person) or the FCA and the PRA (in the case of a PRA-authorised person).(2) In addition, under section 23(1A) of the Act (Contravention\nSUP 12.6.10G 01/11/2007 RP\nThe rules and guidance relating to training and competence in SYSC 3 and SYSC 5 and 6 in TC for a firm carrying on retail business 6extend to any employee of the firm in respect of whom the relevant rules apply. For these purposes, an employee of a firm includes: (1) an individual who is an appointed representative of a firm; and(2) an individual who is employed or appointed by an appointed representative of a firm (whether under a contract of service or for services) in connection\nSUP 12.9.5R 01/11/2007 RP\n2If a UK MiFID investment firm appoints an EEA tied agent this section applies to that firm as though the EEA tied agent were an appointed representative.\nFEES 4.4.9D 01/04/2013 RP\n3To the extent that a firm4 has provided the information required by FEES 4.4.7 D to the FCA as part of its compliance with another provision of the Handbook, it is deemed to have complied with the provisions of that direction.444\nPERG 4.12.1G 01/07/2005 RP\nSection 39 of the Act makes provision exempting appointed representatives from the need to obtain authorisation. An appointed representative is a person who is a party to a contract with an authorised person which permits or requires the appointed representative to carry on certain regulated activities. SUP 12 (Appointed representatives) contains guidance relating to appointed representatives.\nSUP 10A.17.2G 01/04/2013 RP\nIf the firm or its advisers have further questions, they should contact the FCA's Contact Centre (see SUP 10A.12.6 G).\nGEN 5.1.1G 01/04/2013 RP\n1This chapter contains:2(1) guidance for firms, authorised payment institutions and authorised electronic money institutions8 and their 7appointed representatives, agents7or tied agents5on the circumstances in which the FCA11 permits them 7to reproduce the FSA and FCA logos11;28811711(2) rules on the use by firms of the Key facts logo.2\nSection 39 of the Act (Exemption of appointed representatives) exempts appointed representatives from the need to obtain authorisation (or, in relation to an appointed representative with a limited permission, provides that sections 20(1) and (1A) and 23(1A) of the Act do not apply in relation to the carrying on of the regulated activity which is comprised in the business for which his principal has accepted responsibility and for which he does not have limited permission)1. An\nPERG 8.12.12AG 01/04/2014 RP\n6Article 16(1A) applies to non-real time financial promotions and solicited real time financial promotions made:(1) by an appointed representative who is carrying on an activity to which sections 20(1) and (1A) and 23(1A) of the Act do not apply as a result of section 39(1D) of the Act; and(2) for the purposes of the appointed representative's business of carrying on a controlled activity which is also a regulated activity to which sections 20(1) and (1A) and 23(1A) of the Act\nThe purpose of this guidance is to help persons consider whether they need authorisation or a variation of their Part 4A permission. Businesses new to regulation who act only as introducers of insurance business are directed in particular to PERG 5.6.2 G(article 25(1): arranging (bringing about) deals in investments) to PERG 5.6.9 G (Exclusion: Article 72C (Provision of information on an incidental basis)) and PERG 5.15.6 G (Flow chart: Introducers) to help consider whether they\n1The purpose of the rules and guidance in this section is to ensure that, in addition to the notifications made under SUP 12.7 (Appointed representatives; notification requirements), the FCA6 receives regular and comprehensive information about the appointed representatives engaged by a firm, so that the FCA6 is in a better position to pursue the statutory objective6 of the protection of consumers.3666\nICOBS 1.1.4G 06/01/2008 RP\nGuidance on the application provisions is in ICOBS 1 Annex 1 (Part 4)."

"8cfr2144\n8 CFR 214.4\nDenial of certification, denial of recertification, or withdrawal of SEVP certification.\nThis resource is a reference aid for authorized users of the NAFSA Adviser's Manual. This resource is a reference aid for authorized users of the NAFSA Adviser's Manual. This is not an official edition of the Code of Federal Regulations. Last updated to reflect: 87 FR 75891 (December 12, 2022), Removal of Obsolete procedures and Requirements Related to F, J, and M Nonimmigrants.\nThis is not an official edition of the Code of Federal Regulations. For information on the official edition of the Code of Federal Regulations published by the Government Printing Office, visit the Government Printing Office website. Click here for the e-CFR version of 8 CFR 214.4.\n§ 214.4 Withdrawal of school approval.\n8 CFR 214.4(a)\n(a) General --\n8 CFR 214.4(a)(1)\n(1) Denial of certification.The petitioning school will be notified of the reasons and its appeal rights if a petition for certification is denied, in accordance with the provisions of 8 CFR 103.3(a)(1)(iii). A petitioning school denied certification may file a new petition for certification at any time.\n(2) Denial of recertification or withdrawal on notice. The school must wait at least one calendar year from the date of denial of recertification or withdrawal on notice before being eligible to petition again for SEVP certification if a school's petition for recertification is denied by SEVP pursuant to § 214.3(h)(2)(v), or its certification is withdrawn on notice pursuant to paragraph (b) of this section. Eligibility to re-petition will be at the discretion of the Director of SEVP. SEVP certification of a school or school system for the attendance of nonimmigrant students, pursuant to sections 101(a)(15)(F) and/or 101(a)(15)(M) of the Immigration and Nationality Act, will be withdrawn on notice subsequent to out-of-cycle review, or recertification denied, if the school or school system is determined to no longer be entitled to certification for any valid and substantive reason including, but not limited to, the following:\n8 CFR 214.4(a)(2)(i)-(xix)\n8 CFR 214.4(a)(2)(i)\n(i) Failure to comply with §214.3(g)(1) without a subpoena.\n8 CFR 214.4(a)(2)(ii)\n(ii) Failure to comply with §214.3(g)(2).\n8 CFR 214.4(a)(2)(iii)\n(iii) Failure of a DSO to notify SEVP of the attendance of an F-1 transfer student as required by 8 CFR 214.2(f)(8)(ii).\n8 CFR 214.4(a)(2)(iv)\n(iv) Failure of a DSO to identify on the Form I-20 or successor form which school within the system the student must attend, in compliance with 8 CFR 214.3(k).\n8 CFR 214.4(a)(2)(v)\n(v) Willful issuance by a DSO of a false statement, including wrongful certification of a statement by signature, in connection with a student's school transfer or application for employment or practical training.\n8 CFR 214.4(a)(2)(vi)\n(vi) Conduct on the part of a DSO that does not comply with the regulations.\n8 CFR 214.4(a)(2)(vii)\n(vii) The designation as a DSO of an individual who does not meet the requirements of 8 CFR 214.3(l)(1).\n8 CFR 214.4(a)(2)(viii)\n(viii) Failure to provide SEVP with the school's Form I-17 bearing the names, titles, and signatures of DSOs as required by 8 CFR 214.3(l)(2).\n8 CFR 214.4(a)(2)(ix)\n(ix) Failure to submit statements of DSOs as required by 8 CFR 214.3(l)(3).\n8 CFR 214.4(a)(2)(x)\n(x) Issuance of Forms I-20 or successor form to students without receipt of proof that the students have met scholastic, language, or financial requirements as required by 8 CFR 214.3(k)(2).\n8 CFR 214.4(a)(2)(xi)\n(xi) Issuance of Forms I-20 or successor form to aliens who will not be enrolled in or carry full courses of study, as defined in 8 CFR 214.2(f)(6) or 214.2(m)(9).\n8 CFR 214.4(a)(2)(xii)\n(xii) Failure to operate as a bona fide institution of learning.\n8 CFR 214.4(a)(2)(xiii)\n(xiii) Failure to employ adequate qualified professional personnel.\n8 CFR 214.4(a)(2)(xiv)\n(xiv) Failure to limit advertising in the manner prescribed in 8 CFR 214.3(j).\n8 CFR 214.4(a)(2)(xv)\n(xv) Failure to maintain proper facilities for instruction.\n8 CFR 214.4(a)(2)(xvi)\n(xvi) Failure to maintain accreditation or licensing necessary to qualify graduates as represented in the school's Form I-17.\n8 CFR 214.4(a)(2)(xvii)\n(xvii) Failure to maintain the physical plant, curriculum, and teaching staff in the manner represented in the Form I-17.\n8 CFR 214.4(a)(2)(xviii)\n(xviii) Failure to comply with the procedures for issuance of Forms I-20 or successor form as set forth in 8 CFR 214.3(k).\n8 CFR 214.4(a)(2)(xix)\n(xix) Failure of a DSO to notify SEVP of material changes, such as changes to the school's name, address, or curricular changes that represent material change to the scope of institution offerings (e.g., addition of a program, class or course for which the school is issuing Forms I-20 or successor form, but which does not have Form I- 17 approval), as required by 8 CFR 214.3(f)(1).\n(3) Automatic withdrawal. A school that is automatically withdrawn and subsequently wishes to enroll nonimmigrant students in the future may file a new petition for SEVP certification at any time. The school must use the certification petition procedures described in 8 CFR 214.3(h) to gain access to SEVIS for submitting its petition. Past compliance with the recordkeeping, retention, reporting and other requirements of 8 CFR 214.3(f), (g), (j), (k), and (l), and with the requirements for transition of students under paragraph (i) of this section will be considered in the evaluation of a school's subsequent petition for certification. SEVP certification will be automatically withdrawn:\n(i) As of the date of termination of operations, if an SEVP-certified school terminates its operations.\n(ii) As of a school's certification expiration date, if an SEVP-certified school does not submit a completed recertification petition in the manner required by 8 CFR 214.3(h)(2).\n(iii) Sixty days after the occurrence of the change of ownership if the school failed to update its information in accordance with § 214.3(h)(1) or properly file a new petition, SEVP will review the petition if the school properly files such petition to determine whether the school still meets the eligibility requirements of § 214.3(a)(3) and is still in compliance with the recordkeeping, retention, reporting and other requirements of § 214.3(f), (g), (j), (k), and (l). SEVP will review the petition if the school properly files such petition to determine whether the school still meets the eligibility requirements of 8 CFR 214.3(a)(3) and is still in compliance with the recordkeeping, retention, reporting and other requirements of 8 CFR 214.3(f), (g), (j), (k), and (l). SEVP will institute withdrawal proceedings in accordance with paragraph (b) of this section if, upon completion of the review, SEVP finds that the school is no longer eligible for certification, or is not in compliance with the recordkeeping, retention, reporting and other requirements of § 214.3(f), (g), (j), (k), and (l), or failed to file a new petition within the allowable 60-day timeframe.\n(iv) If an SEVP-certified school voluntarily withdraws from its certification.\n8 CFR 214.4(b)\n(b) Withdrawal on notice. SEVP will initiate an out-of-cycle review and serve the school with an NOIW if SEVP has information that a school or school system may no longer be entitled to SEVP certification prior to the school being due for its two-year recertification. The NOIW will inform the school of:\n8 CFR 214.4(b)(1)\n(1) The grounds for withdrawing SEVP certification.\n(2) The 30-day deadline from the date of the service of the NOIW for the school to submit sworn statements, and documentary or other evidence, to rebut the grounds for withdrawal of certification in the NOIW. An NOIW is not a means for the school to submit evidence that it should have previously submitted as a part of its established reporting requirements.\n(3) The school's right to submit a written request (including e-mail) within 30 days of the date of service of the NOIW for a telephonic interview in support of its response to the NOIW.\n8 CFR 214.4(c)\n(c) Assistance of counsel. The school or school system shall also be informed in the notice of intent to withdraw certification that it may be assisted or represented by counsel of its choice qualified under part 292 of this chapter, at no expense to the Government, in preparation of its answer or in connection with the interview.\n8 CFR 214.4(d)\n(d) Allegations admitted or no answer filed. If the school or school system admits all of the allegations in the notice of intent to withdraw certification, or if the school or school system fails to file an answer within the 30-day period, SEVP will withdraw the certification previously granted and notify the designated school official of the decision. No appeal of SEVP's decision will be accepted if all allegations are admitted or no answer is filed within the 30-day period.\n8 CFR 214.4(e)\n(e) Allegations denied. If the school or school system denies the allegations in the notice of intent to withdraw approval, then the school or school system shall, in its answer, provide all information or evidence on which the answer is based.\n8 CFR 214.4(f)\n(f) Interview requested.\n(1) If in its answer to the notice of intent to withdraw certification the school or school system requests an interview, the school or school system will be given notice of the date set for the interview.\n(2) A summary of the information provided by the school or school system at the interview shall be prepared and included in the record. At the discretion of SEVP, the interview may be recorded.\n8 CFR 214.4(g)\n(g) Decision. The decision of SEVP will be in accordance with 8 CFR 103.3(a)(1).\n8 CFR 214.4(h)\n(h) Appeals. A school may file an appeal of a denial or withdrawal no later than 15 days after the service of the decision by ICE. The appeal must state the reasons and grounds for contesting the denial or withdrawal. The appeal must be accompanied by the fee as provided in 8 CFR 103.7(d)(15).\n8 CFR 214.4(i)\n(i) Operations at a school when SEVP certification is relinquished or withdrawn, or whose recertification is denied and on the SEVIS access termination date.\n8 CFR 214.4(i)(1)\n(1) General. A school whose certification is relinquished or withdrawn, or whose recertification is denied may, at SEVP discretion, no longer be able to create Initial student records or issue new Forms I-20, Certificate of Eligibility for Nonimmigrant Student Status, or successor form, for initial attendance. Schools must comply with the instructions given in the notice of withdrawal or denial with regard to management of status for their Initial and continuing F and/or M students. All other SEVIS functionality, including event reporting for students, will remain unchanged until the school's SEVIS access termination date. The school must continue to comply with the recordkeeping, retention, reporting and other requirements of 8 CFR 214.3(f), (g), (j), (k), and (l) until its SEVIS access termination date.\n(2) SEVIS access termination. In determining the SEVIS access termination date, SEVP will consider the impact that such date will have upon SEVP, the school, and the school's nonimmigrant students in determining the SEVIS access termination date. In most situations, SEVP will not determine a SEVIS access termination date for that school until the appeals process has concluded and the denial or withdrawal has been upheld unless a school whose certification is withdrawn or whose recertification is denied is suspected of criminal activity or poses a potential national security threat. The school will no longer be able to access SEVIS, and SEVP will automatically terminate any remaining Active SEVIS records for that school on the SEVIS access termination date.\n(3) Legal obligations and ramifications for a school and its DSOs when a school is having SEVP certification denied or withdrawn. Schools are obligated to their students to provide the programs of study to which they have committed themselves in the students' application for enrollment and acceptance process. Schools are obligated to the U.S. government to comply with the recordkeeping, retention, reporting and other requirements contained in 8 CFR 214.3. With any new petition for SEVP certification, SEVP will consider the extent to which a school has fulfilled these obligations to students and the U.S. government during any previous period of SEVP certification.\nLaw Links Adviser's Manual 360 NAFSA Regulatory Engagement"

"Related provisions for LR 12.4.5\n1 - 11 of 11 items.\nShareholder (11)\nGroup companies (8)\nEuropean Economic Area (5)\nRecognised investment exchanges (5)\nAssociates of a firm (4)\nControllers (4)\nNon United Kingdom (3)\nNon European Economic Area (2)\nLR 9.6.11R 01/07/2005 RP\nA listed company must notify a RIS of any change to the board including:(1) the appointment of a new director stating the appointees name and whether the position is executive, non-executive or chairman and the nature of any specific function or responsibility of the position;(2) the resignation, removal or retirement of a director (unless the director retires by rotation and is re-appointed at a general meeting of the listed company's shareholders);(3) important changes to the\nLR 9.5.5R 01/07/2005 RP\nA listed company must ensure that for a rights issue the following are notified to a RIS as soon as possible:(1) the issue price and principal terms of the issue; and(2) the results of the issue and, if any rights not taken up are sold, details of the sale, including the date and price per share.\n(1) If a listed company makes an open offer, placing, vendor consideration placing, offer for subscription of equity shares or an issue out of treasury (other than in respect of an employees' share scheme)3 of a class already listed, the price must not be at a discount of more than 10% to the middle market price of those shares at the time of announcing the terms of the offer for an open offer or offer for subscription of equity shares8 or at the time of agreeing the placing for\n(1) Any decision by the board to submit to shareholders a proposal for the listed company to be authorised to purchase its own equity shares must be notified to a RIS as soon as possible.(2) A notification required by paragraph (1) must set out whether the proposal relates to:(a) specific purchases and if so, the names of the persons from whom the purchases are to be made; or(b) a general authorisation to make purchases.(3) The requirement set out in paragraph (1) does not apply\nIn addition to the requirements set out in DTR 4.1 a listed company1 must include in its annual financial report1, where applicable, the following:1(1) a statement of the amount of interest capitalised by the group during the period under review with an indication of the amount and treatment of any related tax relief;(2) any information required by LR 9.2.18 R (Publication of unaudited financial information);(3) [deleted]1313(4) details of any long-term incentive schemes as required\nLR App 1.1.1 01/07/2018 RP\n1Note: The following definitions relevant to the listing rules are extracted from the Glossary.ActThe Financial Services and Markets Act 2000.admission or admission to listing admission of securities to the official list .admission to tradingadmission of securities to trading on an RIE's market for listedsecurities.advertisement(as defined in the PD Regulation) announcements:(a)relating to a specific offer to the public of securities or to an admission to trading on a regulated"

"Related provisions for SUP 13.7.3F\n1 - 20 of 58 items.\nAuthorised persons (25)\nGroup companies (23)\nAuthorisation (22)\nEuropean Economic Area (20)\nNon United Kingdom (15)\nSenior management (13)\nInsurance activities (11)\nAppointed representatives (11)\nFinancial Conduct Authority Handbook (10)\nSUP 10C.14.5R 10/12/2018 RP\n(1) A firm must notify the FCA no later than ten3business days after an FCA-approved SMF manager ceases to perform an FCA-designated senior management function.(2) It must make that notification by submitting to the FCA a completed Form C (SUP 10C Annex 5R4).(3) If: (a) the firm is also making an application for approval for that approved person to perform a controlled function within the same firm or group; and(b) ceasing to perform the FCA-designated senior management function\n(1) A firm must notify the FCA as soon as practicable after it becomes aware, or has information which reasonably suggests, that it will submit a qualified Form C for an FCA-approved SMF manager.(2) Form C is qualified if the information it contains:(a) relates to the fact that the firm has dismissed, or suspended, the FCA-approved SMF manager from its employment; (b) relates to the resignation by the FCA-approved SMF manager while under investigation by the firm, the FCA or any\nSUP 10C.14.10G 10/12/2018 RP\n(1) A firm can submit Form C or Form E (and any MiFID Article 4 SMR Information Form3 required by SUP 10C.10.9BD)4 to the FCA in advance of the cessation date. (2) If the actual cessation date turns out to be different from the one notified in advance, the firm should notify the FCA.(3) If the firm:4(a) does not submit Form C (including a qualified one) following notification under SUP 10C.14.7R; or4(b) submits a form in advance under (1) but it turns out that there is no requirement\nSUP 10C.14.13R 10/12/2018 RP\nIf an FCA-approved SMF manager's title, name or national insurance number changes, the firm for which the person performs an FCA-designated senior management function must notify the FCA on Form D (SUP 10C Annex 6R4), of that change within seven business days of the firm4 becoming aware of the matter.\n(1) If any of the details relating to:(a) the arrangements in relation to any of a firm'sFCA-approved SMF managers; or(b) any FCA-designated senior management functions of one of its FCA-approved SMF managers;are to change, the firm must notify the FCA on Form D (SUP 10C Annex 6R4).(2) The notification under (1) must be made as soon as reasonably practicable after the firm becomes aware of the proposed change.(3) This rule does not apply to anything required to be notified under\n(1) If a firm becomes aware of information which would reasonably be material to the assessment of the fitness and propriety of an FCA-approved SMF manager, or of candidate to be one (see FIT), it must inform the FCA either:(a) on Form D; or(b) if it is more practical to do so and with the prior agreement of the FCA, by email or fax;as soon as practicable and, in any case, within seven business days.(2) This rule does not apply to anything required to be notified under SUP 10C.14.7R\nIf a firm is required to notify the FCA about an FCA-approved SMF manager under any of the following:(1) section 63(2A) of the Act (Duty to notify regulator of grounds for withdrawal of approval); or2(2) [deleted]2(3) section 64C of the Act (Requirement for 4authorised persons to notify regulator of disciplinary action);it must give that notification:(4) under SUP 10C.14.5R (Form C) if that rule applies; (5) under SUP 10C.14.7R (Qualified Form C) if that rule applies; or(6) (in\nTable: Explanation of the sections of the Act mentioned in SUP 10C.14.22R4\n1Section\nSummary of relevant parts\nOther Handbook material\nSection 63(2A) (Duty to notify regulator of grounds for withdrawal of approval)\nAt least once a year, each firm must, in relation to every SMF manager for whom an approval has been given on the application of that firm:\n(a) consider whether there are any grounds on which the FCA could withdraw the approval; and\n(b) if the firm is of the opinion that there are such grounds, notify the FCA of those grounds.\nFIT sets out guidance on the factors a firm should take into account when assessing the fitness and propriety of an approved person.\nSection 64C of the Act (Requirement for 4authorised persons to notify regulator of disciplinary action)\nIf:\n(a) a firm takes disciplinary action in relation to an SMF manager; and\n(b) the reason, or one of the reasons, for taking that action is a reason specified in SUP 15.11.6R;\nthe firm should notify the FCA of that fact.\nSUP 15.11 (Notification of COCON breaches and disciplinary action)\nAn example of when a notification should be made using Form C rather than Form D is when a firm is required to notify the FCA under section 64C of the Act that it has dismissed an SMF manager.\nSUP 15.14.12D 13/01/2018 RP\nA notification required by regulation 71(8)(c) of the Payment Services Regulations and SUP 15.14.10D must be submitted by the account servicing payment service provider to the FCA: (1) in the form specified in SUP 15 Annex 10(2) by electronic means made available by the FCA; and\t(3) immediately after the first occasion on which it denies the account information service provider or the payment initiation service provider in question access to a payment account.\nA notification required under SUP 15.14.15D must be submitted by the account servicing payment service provider to the FCA:(1) in the form specified in SUP 15 Annex 10; (2) by electronic means made available by the FCA; and (3) immediately after it restores access to the payment account(s) for the account information service provider or payment initiation service provider.\nSUP 15.14.18G 13/01/2018 RP\nRegulation 99(1) of the Payment Services Regulations provides that, if a payment service provider becomes aware of a major operational or security incident, the payment service provider must, without undue delay, notify the FCA. The purpose of this section is to direct the form and manner in which such notifications must made and the information they must contain, in exercise of the power in regulation 100(2) of the Payment Services Regulations.\nSUP 10A.14.10R 01/04/2013 RP\n(1) A firm must notify the FCA as soon as practicable after it becomes aware, or has information which reasonably suggests, that it will submit a qualified Form C in respect of an FCA-approved person.(2) Form C is qualified if the information it contains:(a) relates to the fact that the firm has dismissed, or suspended, the FCA-approved person from its employment; or(b) relates to the resignation by the FCA-approved person while under investigation by the firm, the FCA or any\nIf an FCA-approved person's title, name or national insurance number changes, the firm for which the person performs an FCA controlled function must notify the FCA on Form D (SUP 10C Annex 6R)5 of that change within seven business days of the firm becoming aware of the matter.\nIf a firm becomes aware of information which would reasonably be material to the assessment of an FCA-approved person's, or a FCA candidate's, fitness and propriety (see FIT), it must inform the FCA on Form D, or (if it is more practical to do so and with the prior agreement of the FCA) by e-mail or fax, as soon as practicable.\nSUP 10A.14.21G 10/12/2018 RP\n(1) If, in relation to a firm which has completed the relevant Form A (SUP 10A Annex 4D), any of the details relating to arrangements and FCA controlled functions are to change, the firm must notify the FCA on Form D (SUP 10C Annex 6R5). (2) The notification under (1) must be made as soon as reasonably practicable after the firm becomes aware of the proposed change.(3) This also applies in relation to an FCA controlled function for which an application was made using Form E.(4)\nAn example of where a firm should use Form D is when an individual who is appointed by one appointed representative becomes employed by another appointed representative but continues to perform the customer function for the firm. The firm should notify the FCA by completing Section 1.07 of Form D.\nSUP 13.6.5DG 04/12/2017 RP\n15If any of the details in a branch passport notification change, a UK MiFID investment firm is required to notify the FCA by completing the form in Annex VI of MiFID ITS 4A. [Note: article 18(1) of MiFID ITS 4A]\nSUP 13.6.5EG 04/12/2017 RP\n15If any of the details in a tied agent passport notification change, a UK MiFID investment firm is required to notify the FCA, by completing the form in Annex VII of MiFID ITS 4A. [Note: article 19(1) of MiFID ITS 4A]\nSUP 13.6.5FG 04/12/2017 RP\n15If a UK MiFID investment firm closes a branch or stops using a tied agent, it is required to notify the FCA using the form in Annex X of MiFID ITS 4A. [Note: articles 18(4) and 19(4) of MiFID ITS 4A]\nSUP 13.6.5GG 04/12/2017 RP\n(1) 15Each of the forms in MiFID ITS 4A referred to in SUP 13.6.5DG to SUP 13.6.5FG is replicated in SUP 13 Annex 1AR. (2) These versions should be used for the purposes of notifications to the FCA.(3) The forms should be submitted in accordance with SUP 13.8.1R.\nSUP 13.6.16G 01/04/2013 RP\n7Standard forms are17 available from the FCA and PRA authorisations teams17 (see SUP 13.12 (Sources of further information)) to give the notices to the appropriate UK regulator17 described in SUP 13.6.5 G (1), SUP 13.6.5B G, SUP 13.6.7 G (1), SUP 13.6.8 G and SUP 13.6.10 G (1).171717\n(1) When the FCA15 receives a notice from a UK MiFID investment firm (see SUP 13.6.5BG (1)), it is required by regulation 11A(3) to inform the relevant Host State regulator of the proposed change as soon as reasonably practicable.15(2) The FCA is required to use the forms in Annex XI, Annex XII or Annex XIII of MiFID ITS 4A, as applicable.15(3) The firm in question may make the change once the period of one month beginning with the day on which it gave notice has elapsed.1571\nMAR 9.5.5G 03/07/2017 RP\nQ.\tHow do we go about applying to be an ARM? A.\tIn summary: (1) You should complete:(a) all of the questions in the application form at MAR 9 Annex 1D; and(b) the notification form for the list of members of the management body at MAR 9 Annex 2D.(2) You should sign the MIS confidentiality agreement at MAR 9 Annex 10D.(3) You should provide the documents referred to in: (a) (1)(a) and (b) together with supporting documentation to the FCA as set out in MAR 9.2.6D; and(b) (2) to\nMAR 9.5.12G 03/07/2017 RP\nQ.\tI intend to apply to be authorised to provide the data reporting service of an APA. May I establish connectivity requirements while my application for authorisation is being considered?A. Yes. The MIS confidentiality agreement is available on our website at www.fca.org.uk/markets/market-data-regimes/market-data-reporting-mdp together with instructions on how to obtain the Market Interface Specification (MIS) for connectivity.\nSUP 15.3.27AR 01/07/2014 RP\n19A full-scope UK AIFM must notify the FCA of material changes under SUP 15.3.26 R in the following manner:(1) for the management of a new AIF or a new investment compartment of an AIF, by using the form in SUP 15 Annex 6A R; (2) for changes of senior personnel whose appointment is not required to be approved by the FCA under section 59 of the Act, by using the form in SUP 15 Annex 6B R; and(3) for all other material changes, by using the form in SUP 15 Annex 6C R .\nSUP 15.3.30D 01/07/2014 RP\n(1) 19A small registered UK AIFM must notify the FCA of changes in the following manner:(a) for the management of a new AIF or a new investment compartment of an AIF, by using the form in SUP 15 Annex 6A R;(b) (a) does not apply where:(i) the management of the new AIF or investment compartment would result in the AIFM exceeding the relevant threshold of assets under management so that it will no longer meet the conditions in regulation 9 (meaning of \"small AIFM\") of the AIFMD\nIf the firm or its advisers have further questions, they should contact the FCA's Contact Centre (see SUP 10A.12.6 G).\nRCB 3.6.5D 01/04/2013 RP\nUnless otherwise stated, the issuer or the owner, as the case may be, must send the relevant forms and information to the FCA's address marked for the attention of the \"Covered Bonds Team, Capital Markets Sector\" by any of the following methods:(1) post; or(2) leaving it at the FCA's address and obtaining a time-stamped receipt; or(3) email to rcb@fca.org.uk.\nSUP 15.7.4R 25/05/2018 RP\nUnless stated in the notification rule, or on the relevant form (if specified), a written notification required from a firm under any notification rule must be:2(1) given to or addressed for the attention of the firm's usual supervisory contact at the FCA4 and77(2) delivered to the FCA4 by one of the methods in SUP 15.7.5AR6.777\n1 A data reporting services provider must promptly complete the notification form for changes to the membership of the management body form at MAR 9 Annex 6D to inform the FCA of any change to the membership of its management body before any change to the membership of its management body or when this is impossible within 10 working days after the change.\nMAR 9.3.10D 03/07/2017 RP\nA data reporting services provider must promptly complete the ad hoc notification form in MAR 9 Annex 9D to notify the FCA in respect of all matters required by MiFID RTS 13.\nSUP 13.7.3G 01/04/2013 RP\nIf a UK firm is passporting under the UCITS Directive, regulation 12(1) states that the UK firm must not make a change in its programme of operations, or the activities to be carried on under its EEA right, unless the relevant requirements in regulation 12(2) have been complied with. These requirements are:5(1) the UK firm has given a notice to the FCA15 and to the Host State regulator stating the details of the proposed change; or15(2) if the change arises as a result of circumstances\n(1) 13If any of the details in an investment services and activities passport notification change, a UK MiFID investment firm is required to notify the FCA by completing the form in Annex I of MiFID ITS 4A.[Note: article 7(1) of MiFID ITS 4A](2) When communicating a change to investment services and/or activities, ancillary services or financial instruments, the firm is required to list all: (a) the investment services and/or activities and ancillary services that it currently\n13If any of the details in the notification for the provision of arrangements to facilitate access to an MTF or an OTF change, the investment firm operating the MTF or the OTF is required to notify the FCA by completing the form in Annex IV of MiFID ITS 4A.\t[Note: article 11(1) of MiFID ITS 4A]\nSUP 13.7.6AG 07/03/2016 RP\n5For further details on giving the notices to the appropriate UK regulator, as described in SUP 13.7.3 G (1), SUP 13.7.3AG and SUP 13.7.3BG12, UK firms may wish to use the standard electronic15 form available from the FCA and PRA authorisation teams 15(see SUP 13.12 (Sources of further information)).15151551515\nSUP 13.12.2G 01/04/2013 RP\nTo contact the FCA and/or PRA authorisations teams, please see the details provided on that regulator's website.5534\nThe issuer must send to the FCA, information relating to the asset pool, in the form set out in RCB 3 Annex 2D (asset notification form), and information relating to the regulated covered bonds issued under the programme, in the form set out in RCB 3 Annex 3 D (asset and liability profile form).1\nThe issuer must send the asset notification form1 to the FCA each month following the registration date, and the asset and liability profile form to the FCA1 within one month of the end of each quarter following the registration date.1\n1If the issuer or the owner (as the case may be) proposes to add or remove assets to or from the asset pool which change the level of over collateralisation by 5% or more, it must notify the FCA using the form set out in RCB 3 Annex 2 D (asset notification form) at least 5 business days prior to the proposed transfer, giving expected details of the size and composition of the transfer.\nA firm notifying the FCA of its withdrawal of an application for approval must use Form B (SUP 10C Annex 4R6).\n(1) If:434(a) (i) the scope of appointment of an appointed representative is extended to cover insurance distribution activities15 for the first time; and42(ii) the appointed representative is not included on the Financial Services Register as carrying on insurance distribution activities15 in another capacity; or42(b) the scope of appointment of an appointed representative ceases to include insurance distribution activity15;42the appointed representative's principal must give\n(1) As soon as a firm has reasonable grounds to believe that any of the conditions in SUP 12.4.2 R,SUP 12.4.6 R,11SUP 12.4.8A R4, SUP 12.4.10A R or SUP 12.4.10B R11 (as applicable) are not satisfied, or are likely not to be satisfied, in relation to any of its appointed representatives, it must complete and submit to the FCA the form in SUP 12 Annex 4 R (Appointed representative notification form), in accordance with the instructions on the form.3(2) In its notification under\nSUP 12.7.8AR 26/01/2017 RP\n(1) 8Subject to (2A), a 9firm other than a credit union must submit the form as set out in SUP 12 Annex 4 R online at http://www.fca.org.uk using the FCA'sonline notification and application system12.91010(2) A credit union must submit the form in SUP 12 Annex 4 R in the way set out in SUP 15.7.4 R to SUP 15.7.9 G (Form and method of notification).(2A) If the notification:9(a) relates to an appointed representative whose scope of appointment covers only credit-related regulated"

"This chapter applies to every SMCR firm5.\nThis chapter is also relevant to FCA-approved SMF managers of an SMCR firm5.\nthe SMCR firms to which this chapter does not apply.\n2This chapter does not apply to an overseas SMCR firm5 other than in relation to an establishment maintained by it or its appointed representative in the United Kingdom.\n2SUP 10C.1.4R reflects the provisions of section 59(8) of the Act and, where relevant, the Treaty.\nIt preserves the principle of Home State prudential regulation.\nFor an EEA SMCR firm5, the effect is to reserve to the Home State regulator the assessment of fitness and propriety of a person performing a function in the exercise of an EEA right. A member of the governing body, or the notified3 UK branch manager, of an EEA SMCR firm5, acting in that capacity, will not, therefore, have to be approved by the FCA under the Act.\nconsidered, for example, the position of a branch manager based in the United Kingdom who may also be performing a function in relation to the carrying on of a regulated activity not covered by the EEA right of the firm. In so far as the function is within the description of an FCA controlled function, the firm will need to seek approval for that person to perform that FCA controlled function.\n2Generally, where an overseas manager of an overseas SMCR firm5 has responsibilities in relation to its branch in the United Kingdom that are strategic only, they will not need to be an FCA-approved SMF manager.\nHowever, where an overseas manager is responsible for implementing that strategy for its branch in the United Kingdom, and has not delegated that responsibility to an SMF manager in the United Kingdom, they will potentially be performing an FCA controlled function if the detailed conditions in this chapter defining the relevant FCA controlled function are met.\nUK firms providing services into or out of the United Kingdom on a cross-border basis.\nThis chapter does not deal with an approved person who is approved under SUP 10A.1.16BR (Appointed representatives).\nSUP 10A.1.15R to SUP 10A.1.16DG (Appointed representatives) deal with the approved persons regime for appointed representatives of SMCR firms5.\nIn general this chapter does not apply to appointed representatives of SMCR firms5. SUP 10A applies instead.\nIn theory, a person employed by an appointed representative of an SMCR firm5 could come within one of the controlled functions in this chapter. If so, that person will be performing a senior management function and this chapter would apply. However, the FCA thinks that such a situation should rarely arise unless the person is seconded to the firm5.\nIf a person is an approved person under this chapter and under SUP 10A for the same firm, this chapter applies to FCA-designated senior management functions under this chapter and SUP 10A applies to controlled functions under SUP 10A. It is unlikely that such a scenario would normally5 arise in practice.\na nominee in relation to a voluntary arrangement under Parts II (Company Voluntary Arrangements) and VIII (Individual Voluntary Arrangements) of the Insolvency (Northern Ireland) Order 1989.\n5For Swiss general insurers, references in this chapter to parts of the PRA Rulebook for 'Solvency II firms' are to be read as references to the corresponding parts of the PRA Rulebook applying to large non-directive insurers.\n5Swiss general insurers are in the large non-directive insurers sector of the PRA Rulebook and the PRA applies to them, in relation to their controlled functions, provisions equivalent to those applying to third country branches in the Solvency II firms sector of the PRA Rulebook. The FCA includes them as third country undertakings of Solvency II firms and so they must follow the requirements for Solvency II firms set out in this chapter.\n5See MIPRU 2.2 (Allocation of the responsibility for insurance distribution activity or MCD credit intermediation activity) for how the FCA's senior managers regime for SMCR firms is adjusted for a firm carrying on insurance distribution activity or MCD credit intermediation activity."

"APER\nAPER 4\nAPER 4.4 Statement of Principle 4\nAPER 4.4.1G 01/04/2013\nAPER 4.4.1AG 07/03/2016 RP\n2The Statement of Principle 4 (see APER 2.1A.3 R1) is in the following terms: \"An approved person must deal with the FCA, the PRA and other regulators in an open and cooperative way and must disclose appropriately any information of which the FCA or the PRA would reasonably expect notice.\"\n2For the purpose of this Statement of Principle, regulators in addition to the FCA and the PRA are those which have recognised jurisdiction in relation to regulated activities and a power to call for information from the approved person in connection with their 1accountable function or (in the case of an individual performing an accountable higher management function)1 in connection with the business for which they are1 responsible. This may include an exchange or an overseas regulator.\nAPER 4.4.3G 07/03/2016 RP\n1In the opinion of the FCA, conduct of the type described in APER 4.4.4G, APER 4.4.7G or APER 4.4.9G does not comply with Statement of Principle 4.\n1Failing to report promptly in accordance with his firm's internal procedures (or if none exist direct to the regulator concerned), information which it would be reasonable to assume would be of material significance to the regulator concerned), whether in response to questions or otherwise, falls within APER 4.4.3 G. The regulator concerned is:\nthe FCA if it would be reasonable to assume that it would be of material significance to it;2\nthe PRA if it would be reasonable to assume that it would be of material significance to it;2\nboth the FCA and the PRA if it would be reasonable to assume that it would be of material significance to both of them.2\nThere is no duty on an approved person to report such information directly to the regulator concerned2 unless he is one of the approved persons responsible within the firm for reporting matters to the regulator concerned.2However, if an approved person takes steps to influence the decision so as not to report to the regulator concerned or acts in a way that is intended to obstruct the reporting of the information to the regulator concerned, then the FCA1 will, in respect of that information, view that individual1 as being one of those within the firm who has taken on responsibility for deciding whether to report that matter to the regulator concerned.\n1In determining whether or not an approved person's conduct under APER 4.4.4 G complies with Statement of Principle 4, the following are factors which, in the opinion of the FCA, are to be taken into account:\nthe likely significance to the regulator concerned (as defined in APER 4.4.4 G1) of the information which it was reasonable for the individual to assume;\nwhether the information related to the individual himself or to his firm;\nwhether any decision not to report the matter internally was taken after reasonable enquiry and analysis of the situation.\n1Where the approved person is, or is one of the approved persons who is, responsible within the firm for reporting matters to the regulator concerned (as defined in APER 4.4.4G), failing promptly to inform the regulator concerned of information of which they are aware and which it would be reasonable to assume would be of material significance to the regulator concerned, whether in response to questions or otherwise, falls within APER 4.4.3G.\n1In determining whether or not an approved person's conduct under APER 4.4.7G complies with Statement of Principle 4, the following are factors which, in the opinion of the FCA, are to be taken into account:\nthe likely significance of the information to the regulator concerned (as defined in APER 4.4.4G) which it was reasonable for the approved person to assume;\nwhether any decision not to inform the regulator concerned (as defined in APER 4.4.4G) was taken after reasonable enquiry and analysis of the situation.\n1Failing without good reason to:\ninform a regulator of information of which the approved person was aware in response to questions from that regulator;\nattend an interview or answer questions put by a regulator, despite a request or demand having been made;\nsupply a regulator with appropriate documents or information when requested or required to do so and within the time limits attaching to that request or requirement;\nfalls within APER 4.4.3 G."

"The FCA may, at any time, require an issuer to publish such information in such form and within such time limits as it considers appropriate to protect investors or to ensure the smooth operation of the market.\nIf an issuer fails to comply with a requirement under paragraph (1) the FCA may itself publish the information (after giving the issuer an opportunity to make representations as to why it should not be published).\nAn issuer must take all reasonable care to ensure that any information it notifies to a RIS is not misleading, false or deceptive and does not omit anything likely to affect the import of the information.\n1The duty imposed by DTR 1A.3.2 R does not apply to an issuer's obligation under DTR 5.8.12 R to make public the information contained in a vote holder notification made to it under DTR 5.1.2 R.\na RIS for release as soon as it opens."

"SUP 8\nSUP 8.8 Revoking waivers\nSUP 8.8.1G 01/04/2013 RP\nThe appropriate regulator1 may revoke a waiver at any time. In deciding whether to revoke a waiver, the appropriate regulator1 will consider whether the conditions in section 138A(4)1 of the Act are no longer satisfied (see SUP 8.3.1 G), and whether the waiver is otherwise no longer appropriate.\nIf the appropriate regulator1 proposes to revoke a waiver, or revokes a waiver with immediate effect, it will:\ngive the firm written notice either of its proposal, or of its action, giving reasons;\nstate in the notice a reasonable period (usually 28 days) within which the firm can make representations about the proposal or action; if a firm wants to make oral representations, it should inform the appropriate regulator1 as quickly as possible , specify who will make the representations and which matters will be covered; the appropriate regulator1 will inform the firm of the time and place for hearing the representations and may request a written summary;\nafter considering any representations, in the case of a proposed revocation, give the firm written confirmation of its decision to revoke the waiver or not; or, in the case of a revocation that has already taken effect, either confirm the revocation or seek the firm's consent to a new waiver.\nIf the waiver that has been revoked has previously been published, the appropriate regulator1 will publish the revocation unless it is satisfied that it is inappropriate or unnecessary to do so, having regard to any representations made by the firm."

"Related provisions for SUP 8.8.1\n1 - 19 of 19 items.\nGroup companies (9)\nFinancial Conduct Authority Handbook (8)\nFirms structure and internal systems (6)\nConsumer credit activities (5)\nMortgages and home financing activities (5)\nUnder section 138A(4) of the Act, the appropriate regulator9 may not give a waiver unless it is satisfied that:99(1) compliance by the firm with the rules, or with the rules as unmodified, would be unduly burdensome, or would not achieve the purpose for which the rules were made; and(2) the waiver would not adversely affect the advancement of, in the case of the PRA, any of its objectives and, in the case of the FCA, any of its operational objectives.99\nSUP 8.3.1AG 01/04/2013 RP\nEven if the conditions in section 138A(4)9 of the Act are satisfied, the appropriate regulator9will consider other relevant factors before giving a waiver, such as whether the waiver would be compatible with European law, including relevant EC Directives.299\nThe appropriate regulator9 is required by section 138B9 of the Act to publish a waiver unless it is satisfied that it is inappropriate or unnecessary to do so (see SUP 8.6).99\n9The FCA must consult the PRA before publishing or deciding not to publish a waiver which relates to:(1) a PRA-authorised person; or(2) an authorised person who has as a member of its immediate group a PRA-authorised person;unless the waiver relates to rules made by the FCA under sections 247 or 248 of the Act.\nSUP 8.3.10G 01/04/2013 RP\nUnder section 138A(1) of the Act the appropriate regulator9 may give a waiver with the consent of a firm. This power may be used by the appropriate regulator9 in exceptional circumstances where the appropriate regulator9 considers that a waiver should apply to a number of firms (for example, where a rule unmodified may not meet the particular circumstances of a particular category of firm). In such cases the appropriate regulator9 will inform the firms concerned that the waiver\nFor an application for a waiver of the presumption of contravention of a binding rule, which is actionable under section 138D9 of the Act, the appropriate regulator9 would normally wish to be satisfied that the evidential rule is itself unduly burdensome or does not achieve the purpose of the rule.299\nThe appropriate regulator4 is required by sections 138B(1) and (2)4 of the Act to publish a waiver unless it is satisfied that it is inappropriate or unnecessary to do so. If the appropriate regulator4 publishes a waiver, it will not publish details of why a waiver was required or any of the supporting information given in a waiver application.444\nWhen considering whether it is satisfied under section 138B(2)4, the appropriate regulator4 is required by section 138B(3)4 of the Act:444(1) to take into account whether the waiver relates to a rule contravention of which is actionable under section 138D4 of the Act (Actions for damages); Schedule 5 identifies such rules;4(2) to consider whether its publication would prejudice, to an unreasonable degree, the commercial interests of the firm concerned, or any other member of its\nWaivers can affect the legal rights of third parties, including consumers. In the appropriate regulator's4 view it is important that the fact and effect of such waivers should be transparent. So the fact that a waiver relates to a rule that is actionable under section 138D4 of the Act (see SUP 8.6.2 G (1)) will tend to argue in favour of publication.44\nIn considering whether commercial interests would be prejudiced to an unreasonable degree (see SUP 8.6.2 G (2)), the appropriate regulator4 will weigh the prejudice to firms' commercial interests against the interests of consumers, markets and other third parties in disclosure. In doing so the appropriate regulator4 will consider factors such as the extent to which publication of the waiver would involve the premature release of proprietary information to commercial rivals, for\nUnder section 138A12of the Act (Modification or waiver of rules), the appropriate regulator12 may, on the application or with the consent of a firm, direct that its 9rules:121299(1) are not to apply to the firm; or(2) are to apply to the firm with such modifications as may be specified.\nFEES 4.4.9D 01/04/2013 RP\n3To the extent that a firm4 has provided the information required by FEES 4.4.7 D to the FCA as part of its compliance with another provision of the Handbook, it is deemed to have complied with the provisions of that direction.444\nIf the appropriate regulator1 gives a firm a waiver, then the relevant rule no longer applies to the firm. But:1(1) if a waiver directs that a rule is to apply to a firm with modifications, then contravention of the modified rule could lead to appropriate regulator1 enforcement action and (if applicable) a right of action under section 138D1 of the Act (Actions for damages); and11(2) if a waiver is given subject to a condition, it will not apply to activities conducted in breach\n1If the appropriate regulator2, in the course of carrying on supplementary supervision of a financial conglomerate, is considering exercising its powers under section 138A2 of the Act (Modification or waiver of rules), regulation 4 of the Financial Groups Directive Regulations contains special provisions. The appropriate regulator2 must, in broad terms, do two things. Where required by those regulations, it must obtain the consent of the relevant competent authorities of the group.\nCREDS 10.1.3G 03/01/2017 RP\nRelevance to Credit Unions\nThe Principles for Businesses (PRIN)\nThe Principles for Businesses (PRIN) set out 3high-level requirements 3imposed by the FCA3. They provide a general statement of regulatory requirements. The Principles apply to all10credit unions. In applying the Principles to credit unions, the FCA3 will be mindful of proportionality. In practice, the implications are likely to vary according to the size and complexity 3of the credit union.\nSenior Management Arrangements, Systems and Controls (SYSC)\nSYSC 1,3SYSC 4 to 10 and SYSC 213 apply to all credit unions in respect of the carrying on of their regulated activities and unregulated activities in a prudential context. SYSC 4.5 (Management responsibilities maps for relevant authorised persons), SYSC 4.7 (Senior management responsibilities for relevant authorised persons: allocation of responsibilities), SYSC 4.9 (Handover procedures and material), SYSC 5.2 (Certification regime) and SYSC 18 apply3 to all credit unions in respect of both their regulated activities and their unregulated activities3.\n3Code of Conduct (COCON)\nThis contains rules and guidance that are directly applicable to a credit union'sSMF managers, certification employees and (from 2017) other conduct rules staff. There is also guidance for credit unions on giving their staff training about COCON.\nThreshold Conditions (COND)\nIn order to become authorised under the Act all firms must meet the threshold conditions. The threshold conditions must be met on a continuing basis by credit unions. Failure to meet one of the conditions is sufficient grounds for the exercise by the FCA3 of its powers.\nThe Fit and Proper test for Approved Persons (FIT)\nThe purpose of FIT is to set out and describe the criteria that a firm should3 consider when assessing the fitness and propriety of a person (1)3 in respect of whom an application is being made for approval to undertake a controlled function under the approved persons regime, (2)3 who has already been approved, (3) who is a certification employee or (4) whom a firm is considering appointing to be a certification employee3.\nIt also sets out and describes criteria that the FCA will consider when assessing the fitness and propriety of a candidate for a controlled function position and that it may consider when assessing the continuing fitness and propriety of approved persons.3\nGEN contains rules and guidance on general matters, including interpreting the Handbook, statutory status disclosure, the FCA's3 logo and insurance against financial penalties.\nThis manual sets out the fees applying to credit unions.\n3Prudential sourcebook for Mortgage and Home Finance Firms, and Insurance Intermediaries (MIPRU)\nMIPRU applies to any credit union carrying out insurance mediation activity or home finance mediation activity, or using these services. In particular, it sets out requirements for allocation of responsibility for the credit union'sinsurance mediation activity (MIPRU 2), for the use of home finance intermediaries (MIPRU 5) and for professional indemnity insurance (MIPRU 3).\nConduct of Business sourcebook (COBS)\nA credit union which acts as a CTF provider or provides a cash-deposit ISA will need to be aware of the relevant requirements in COBS. COBS 4.6 (Past, simulated past and future performance), COBS 4.7.1 R (Direct offer financial promotions), COBS 4.10 (Systems and controls and approving and communicating financial promotions), COBS 13 (Preparing product information) and COBS 14 (Providing product information to clients) apply with respect to accepting deposits as set out in those provisions, COBS 4.1 and BCOBS. A credit union that communicates with clients, including in a financial promotion, in relation to the promotion of deferred shares and credit union subordinated debt will need to be aware of the requirements of COBS 4.2 (Fair, clear and not misleading communications) and COBS 4.5 (Communicating with retail clients).4\n3Insurance: Conduct of Business sourcebook (ICOBS)\nICOBS applies to any credit union carrying on non-investment insurance activities, such as arranging or advising on general insurance contracts to be taken out by members. But ICOBS does not apply to a credit union taking out an insurance policy for itself, such as a policy against default by members on their loans where the credit union is the beneficiary of the policy, since in this circumstance the credit union would not be acting as an insurance intermediary, but would itself be the customer. Credit unions are reminded that they are subject to the requirements of the appropriate legislation, including the Credit Unions Act 1979, relating to activities a credit union may carry on.\n3Mortgages and Home Finance: Conduct of Business sourcebook (MCOB)\nMCOB applies to any credit union that engages in any home finance activity. MCOB rules cover advising and selling standards, responsible lending (including affordability assessment), charges, and the fair treatment of customers in payment difficulties.\nBanking: Conduct of Business sourcebook (BCOBS)\nBCOBS sets out rules and guidance for credit unions on how they should conduct their business with their customers. In particular there are rules and guidance relating to communications with banking customers3and financial promotions (BCOBS 2), distance communications (BCOBS 3), information to be communicated to banking customers3(BCOBS 4), post sale requirements (BCOBS 5), and cancellation (BCOBS 6). 3The rules in BCOBS 3.1 that relate to distance contracts may apply 3to a credit union. This is because the Distance Marketing Directive3applies where there is \"an organised distance sales or service-provision scheme run by the supplier\" (Article 2(a)), i.e. if the credit union routinely sells any of its services by post, telephone, fax or the internet3.\nThe following provisions of SUP are relevant to credit unions: 11SUP 1A11 (The FCA's 3 approach to supervision), SUP 2 (Information gathering by the FCA or PRA 3 on its own initiative), SUP 3.1 to SUP 3.8 (Auditors), SUP 5 (Skilled persons), SUP 6 (Applications to vary or cancel Part 4A10permission), SUP 7 (Individual requirements), SUP 8 (Waiver and modification of rules), SUP 9 (Individual guidance), 11SUP 10C (FCA senior management regime for approved persons in relevant authorised persons),3SUP 11 (Controllers and Close links), SUP 15 (Notifications to the FCA or PRA 3) and SUP 16 (Reporting Requirements).\nCredit unions are reminded that they are subject to the requirements of the Act and SUP 11 on close links, and are bound to notify the FCA3 of changes. It may be unlikely, in practice, that credit unions will develop such relationships. It is possible, however, that a person may acquire close links with a 3credit union3 within the meaning of the Act by reason of holding the prescribed proportion of deferred shares in the credit union.\nIn relation to SUP 16, credit unions are exempted from the requirement to submit annual reports of 3close links.\n3Consumer Credit sourcebook (CONC)\nCONC contains rules that apply to firms carrying on credit-related regulated activities. PERG 2.7.19IG provides guidance on relevant exemptions. Most credit union lending is therefore outside the scope of CONC. However, subject to the constraints in the Credit Unions Act 1979 or the Credit Unions (Northern Ireland) Order 1985 (as relevant), credit unions may undertake credit-related regulated activities to which CONC does apply if the activity is carried out by way of business. This could include lending under a borrower-lender-supplier agreement, or debt adjusting or debt counselling where the credit union is not the lender. A credit union carrying on such activities should consider whether it requires permission to do so. Further information can be found on the FCA's website.\nDecision, Procedure and Penalties manual (DEPP)\nDEPP is relevant to credit unions because it sets out:\n(1) the FCA's10 decision-making procedure for giving statutory notices. These are warning notices, decision notices and supervisory notices (DEPP 1.2 to DEPP 5); and\n(2) the FCA's10 policy with respect to the imposition and amount of penalties under the Act (see DEPP 6).\nDispute Resolution: Complaints (DISP)\nDISP sets out rules and guidance in relation to treating complainants fairly and the Financial Ombudsman Service.\nCompensation (COMP)\nCOMP sets out rules relating to the scheme for compensating consumers when authorised firms are unable, or likely to be unable, to satisfy claims against them.10\nThe Enforcement Guide (EG) describes the FCA's10 approach to exercising the main enforcement powers given to it by the Act and by other legislation.2\nFinancial crime: a guide for firms (FC)\nFC provides guidance on steps that a firm can take to reduce the risk that it might be used to further financial crime."

"1BIPRU 14 applies to a BIPRU firm.\nBIPRU 14.2 deals with the calculation of the capital requirement for CCR for trading book positions arising from financial derivative instruments, securities financing transactions and long settlement transactions. The approaches used to calculate exposure values and risk weighted exposure amounts for these positions are largely based on the approaches applicable to non-trading book positions (BIPRU 3, BIPRU 4, BIPRU 5 and BIPRU 13). However, there are some treatments that are specific to the trading book. These are set out in BIPRU 14.2.\nThe calculation of the capital requirement for CCR for trading book positions is the first element of the counterparty risk capital component in BIPRU 14.2.1 R. The second element of the counterparty risk capital component is for unsettled transactions in both the trading book and the non-trading book. It is calculated under BIPRU 14.3.\nBIPRU 14.4 sets out the treatment for free deliveries."

"Related provisions for BIPRU 9.13.7\n1 - 16 of 16 items.\nSkills, knowledge and expertise (3)\nFinancial Conduct Authority Handbook (2)\nPrudential obligations (1)\nBIPRU 9.12.1R 01/01/2007 RP\nBIPRU 9.12 applies to the calculation of risk weighted exposure amounts of securitisation positions under the IRB approach.[Note:BCD Annex IX Part 4 point 37 (part)]\nFor an originator, a sponsor, or for other firms which can calculate KIRB, the risk weighted exposure amounts calculated in respect of its positions in a securitisation may be limited to that which would produce an amount in respect of its credit risk capital requirement equal to the sum of 8% of the risk weighted exposure amount which would be produced if the securitised assets had not been securitised and were on the balance sheet of the firm plus the expected loss amounts of\nBIPRU 9.12.20R 01/04/2013 RP\n(1) If:(a) a firm'sIRB permission allows it to use this treatment; and(b) the conditions in (2)(16) are satisfied,a firm may attribute to an unrated position in an asset backed commercial paper programme a derived rating as laid down in (3).(2) Positions in the commercial paper issued from the programme must be rated positions.(3) Under the ABCP internal assessment approach, the unrated position must be assigned by the firm to one of the rating grades described in (5). The position\n(1) Subject to any permission of the type described in BIPRU 9.12.28 G, the risk weight to be applied to the exposure amount must be:12.5 (S[L+T] - S[L]) / T(2) The remaining provisions of this paragraph define the terms used in the formulae in (1) and (3).(3) 2(4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) In these expressions, Beta [x; a, b]refers to the cumulative beta distribution with parameters a and b evaluated at x.(16) T (the thickness of the tranche in which the\nBIPRU 9.12.28G 01/04/2013 RP\n(1) When it is not practical for the firm to calculate the risk weighted exposure amounts for the securitised exposures as if they had not been securitised and the position does not qualify for the ABCP internal assessment approach, a firm may apply to the appropriate regulator for a variation of its IRB permission under which, on an exceptional basis, it may temporarily apply the method in (2) for the calculation of risk weighted exposure amounts for an unratedsecuritisation\n(1) For firms using the IRB approach set out in BIPRU 4, this paragraph applies in place of BIPRU 9.13.4 R.(2) For the purposes of this section, originators interest means the sum of:(a) the exposure value of that notional part of a pool of drawn amounts sold into a securitisation, the proportion of which in relation to the amount of the total pool sold into the structure determines the proportion of the cash-flows generated by principal and interest collections and other associated\nThis section applies to credit risk mitigation in relation to a securitisation position for a firm calculating risk weighted exposure amounts using the IRB approach.[Note:BCD Annex IX Part 4 point 37 (part)]\nBIPRU 9.9.4R 01/01/2007 RP\nSubject to BIPRU 9.9.5 R,(1) where a firm calculates risk weighted exposure amounts under the standardised approach to securitisations outlined in BIPRU 9.11, the exposure value of an on-balance sheet securitisation position must be its balance sheet value;(2) where a firm calculates risk weighted exposure amounts under the IRB approach to securitisations outlined in BIPRU 9.12, the exposure value of an on-balance sheet securitisation position must be measured gross of value adjustments;(3)\nWhen the conditions in this paragraph have been met, and in order to determine its exposure value, a conversion figure of 50% may be applied to the nominal amount of a liquidity facility. The risk weight to be applied is the highest risk weight that would be applied to any of the securitised exposures under the standardised approach by a firm holding the exposures. Those conditions are as follows:11(1) the liquidity facility documentation must clearly identify and limit the circumstances\n(1) In calculating risk weighted exposure amounts for the securitised exposures, where the conditions in BIPRU 9.5.1 R are met, the originator of a synthetic securitisation must, subject to the treatment of maturity mismatches set out in BIPRU 9.5.6 R-BIPRU 9.5.8 R, use the relevant calculation methodologies set out in BIPRU 9.9-BIPRU 9.14and not those set out in BIPRU 3 (Standardised credit risk) or BIPRU 4 (IRB approach).(2) For firms calculating risk weighted exposure amounts\nThe maturity of the securitised exposures must be taken to be the longest maturity of any of those exposures subject to a maximum of five years. The maturity of the credit protection must be determined in accordance with BIPRU 5 (Credit risk mitigation) and, so far as relevant, BIPRU 4.10 (Credit risk mitigation under the IRB approach).[Note:BCD Annex IX Part 2 point 6]\nThe following must be calculated in accordance with BIPRU 9 (Securitisation):(1) risk-weighted exposure amounts for securitisedexposures and for exposures belonging to the IRB exposure class referred to in BIPRU 4.3.2 R (6) (securitisation positions); and(2) the expected loss amounts for securitisedexposures.[Note: BCD Article 87(10) and Article 88(3)]\n(1) Where a firm uses the standardised approach set out in BIPRU 3 (Standardised approach to credit risk) for the calculation of risk weighted exposure amount for the standardised credit risk exposure class to which the securitised exposures would otherwise be assigned under BIPRU 3, then it must calculate the risk weighted exposure amount for a securitisation position in accordance with the standardised approach to securitisations set out in BIPRU 9.9, BIPRU 9.10, BIPRU 9.11"

"a BIPRU firm which meets any of the criteria in (2) on an individual basis, or in (3) on a consolidated basis.\nit has assets or liabilities of at least £2 billion (or the equivalent amount in foreign currency).\nSubject to (4), where all of the BIPRU firms within the same UK consolidation group or non-EEA sub-group, taken together, as if they were one firm, meet any of the criteria in (2), SYSC 20 applies to each of those BIPRU firms as if it individually met the criteria in (2).\nAny BIPRU firm which is included within the scope of SYSC 20 in accordance with (2) or (3) in any given year will continue to be subject to SYSC 20 for the following two years, irrespective of whether or not it continues to meet the inclusion criteria in any of those subsequent years.\nThis chapter amplifies Principle 2, under which a firm must conduct its business with due skill, care and diligence, and Principle 3, under which a firm must take reasonable care to organise and control its affairs responsibly and effectively, with adequate risk management systems.\nThis chapter contains rules on reverse stress testing, which require a firm to identify and assess events and circumstances that would cause its business model to become unviable. This chapter also requires the firm's senior management or governing body to review and approve the results of the reverse stress testing exercise. This should help the firm's senior management to identify the firm's vulnerabilities and design a strategy to prevent or mitigate the risk of business failure.\n7The reverse stress testing requirements are an integral component of a firm's6 business planning and risk management under SYSC. For IFPRU investment firms as referred to in SYSC 20.1.1AR (1)(a)65, this chapter amplifies SYSC 7.1.1 G to SYSC 7.1.8 G on risk control."

"Related provisions for REC 3.14.1\n1 - 6 of 6 items.\nRecognised investment exchanges (6)\nRecognised auction platforms (6)\nSpecified investments (3)\nNon United Kingdom (2)\nMiFID 2 (2)\nShareholder (2)\nRecognised clearing houses (1)\nAppointed representatives (1)\nAuthorised persons (1)\nREC 3.14.3R 01/04/2013 RP\nWhere a UK recognised body proposes to provide (or to cease to provide) clearing facilitation services3 in respect of:3(1) a specified investment (other than a security or an option in relation to a security); or (2) a type of security or a type of option in relation to a security;it must give the FCA3notice of that event and the information specified for the purposes of this rule in REC 3.14.6 R, at the same time as that proposal is first formally communicated to its members\nWhere a UK recognised body proposes to make (or to cease to make) arrangements for the safeguarding and administration of assets belonging to any other person (other than an undertaking in the same group), that recognised body must give the FCA3notice of that event, and the information specified for the purposes of this rule in REC 3.14.9 R, at the same time as that proposal is first formally communicated to its members or shareholders (or any group or class of them).3\nWhere a UK recognised body has taken any disciplinary action against any member or any employee of a member, in respect of a breach of a rule relating to the carrying on by the UK recognised body of any of its regulatory functions, that body must immediately notify the FCA1of that event, and give:1(1) the name of the person concerned;(2) details of the disciplinary action taken by the UK recognised body; and(3) the UK recognised body's reasons for taking that disciplinary act"

"§ 87 Regulatory fines provisions\nAnlage 1 (zu § 2 Abs. 1a)\nAnlage 2 (zu § 2 Absatz 3)\n§ 78 Persons obligated to effect registration\n§ 79 Penalty payments\n§ 82 False representation\n§ 84 Breach of duty to give notification of losses\n§ 85 Breach of confidentiality\n§ 86 Breach of duties in respect of statutory audits\n§ 88 Notifications to audit oversight body\n(1) Whoever, in their capacity as member of a supervisory board or member of an audit committee of a company which is a public-interest entity within the meaning of section 316a sentence 2 no. 1 or no. 2 of the Commercial Code,\n1. does not monitor the independence of the statutory auditor or of the audit firm in accordance with the provisions of Article 4 (3) subparagraph (2) of Article 5 (4) subparagraph (1) sentence 1 or of Article 6 (2) of Regulation EU No 537/2014 of the European Parliament and of the Council of 16 April 2014 on specific requirements regarding statutory audit of public-interest entities and repealing Commission Decision 2005/909/EU (OJ L 158, 27.5.2014, p. 77, L 170, 11.6.2014, p. 66) or\n2. makes a recommendation regarding the appointment of a statutory auditor or of an audit firm which does not comply with the requirements under Article 16 (2) subparagraph (2) or subparagraph (3) of Regulation (EU) No 537/2014 or was not preceded by a selection procedure in accordance with Article 16 (3) subparagraph (1) of Regulation (EU) No 537/2014\nis deemed to have committed a regulatory offence.\n(2) Whoever, in their capacity as member of a supervisory board which has not appointed an audit committee, submits a proposal to the shareholders of a company which is a public-interest entity within the meaning of section 316a sentence 2 no. 1 or no. 2 of the Commercial Code regarding the appointment of a statutory auditor or of an audit firm and which does not comply with the requirements under Article 16 (5) subparagraph (1) of Regulation (EU) No 537/2014 is deemed to have committed a regulatory offence.\n(3) Whoever, in their capacity as member of a supervisory board which has appointed an audit committee, submits a proposal to the shareholders of one of the companies referred to in subsection (2) regarding the appointment of a statutory auditor or of an audit firm and which does not comply with the requirements under Article 16 (5) subparagraph (1) or subparagraph (2) sentence 1 or sentence 2 of Regulation (EU) No 537/2014 is deemed to have committed a regulatory offence.\n(4) A fine of no more than 500,000 euros may be imposed for a regulatory offence.\n(5) The administrative authority within the meaning of section 36 (1) no. 1 of the Act on Regulatory Offences (Ordnungswidrigkeitengesetz) is, in the case of a company which is a public-interest entity within the meaning of section 316a sentence 2 no. 2 of the Commercial Code, the Federal Financial Supervisory Authority, in all other cases the Federal Office of Justice."

"Related provisions for EG 13.12.2\nAuthorised persons (15)\nEuropean Economic Area (7)\nAppointed representatives (6)\nSkills, knowledge and expertise (4)\nUnauthorised business (4)\nGroup companies (4)\nNon United Kingdom (4)\nSenior managers (4)\nEG 13.12.3 01/03/2016 RP\n1If the insolvent person is an authorised person and the sender of the information or documents knows that the insolvent person's supervisory contact operates from Edinburgh, information or documents should, in the first instance, be sent to the Financial Conduct Authority, Quayside House, 127 Fountainbridge, Edinburgh EH3 8DJ.\nSUP 10A.17.2G 01/04/2013 RP\nIf the firm or its advisers have further questions, they should contact the FCA's Contact Centre (see SUP 10A.12.6 G).\nGEN 2.2.25G 26/01/2017 RP\nAn example of a rule20 being interpreted as cut back by GEN 2.2.23R is SYSC 6.1.1R, which requires a firm to maintain adequate policies and procedures to ensure compliance with its obligations under the regulatory system; SYSC 6.1.1R should be interpreted as applied by the FCA in respect of a PRA-authorised person's compliance with regulatory obligations that are the responsibility of the FCA (for example, in respect of a bank maintaining policies and procedures to ensure compliance\nFIT 2.1.3G 10/12/2018 RP\nThe matters referred to in FIT 2.1.1 G to which the FCA5 will have regard, and to which an SMCR firm6 should also have regard, 5include, but are not limited to:55(1) whether the person has been convicted of any criminal offence; this must include, where provided for by the Rehabilitation Exceptions Orders4to2 the Rehabilitation of Offenders Act 1974 or the Rehabilitation of Offenders (Northern Ireland) Order 1978 (as applicable)4, any spent convictions2; particular consideration\nExamples of the kind of particular considerations to which the FCA may have regard when assessing whether a firm will satisfy, and continue to satisfy, this threshold condition include, but are not limited to, whether:1515(1) the firm has been open and co-operative in all its dealings with the FCA15and any other regulatory body (see Principle 11 (Relations with regulators)) and is ready, willing and organised to comply with the requirements and standards under the regulatory system\nEG 13.4.2 01/03/2016 RP\n1In determining whether it is appropriate to seek an insolvency order on this basis, the FCA will consider the facts of each case including, where relevant: (1) whether the company or partnership has taken or is taking steps to deal with its insolvency, including petitioning for its own administration, placing itself in voluntary winding up or proposing to enter into a company voluntary arrangement, and the effectiveness of those steps; (2) whether any consumer or other creditor\n1The FCA is given power to receive the same information as creditors are entitled to receive in the winding up, administration, receivership or voluntary arrangement of an authorised person, of appointed representatives and of persons who have carried out a regulated activity while unauthorised. The FCA is also entitled to attend and make representation at any creditors' meeting or (where relevant) creditors' committee meeting taking place in those regimes. When it decides whether\n2In deciding whether to exercise its powers to seek or require restitution under sections 382, 383 or 384 of the Act, the FCA will consider all the circumstances of the case. The factors which the FCA will consider may include, but are not limited to, those set out below. (1) Are the profits quantifiable? The FCA will consider whether quantifiable profits have been made which are owed to identifiable persons. In certain circumstances it may be difficult to prove that the conduct"

"Itron Expands Smart Grid Capabilities with Choice Collaboration\nCompanies' integrated solution to help identify non technical losses\nLIBERTY LAKE, Wash.—May 14, 2013—Itron, Inc. (NASDAQ: ITRI) announced today a strategic alliance with Choice, a Brazilian technology company, to integrate and jointly market a non-technical loss (NTL) solution to utilities around the world, with a strong focus in Brazil. The joint solution will help utilities quickly identify areas of non-technical loss in their service territory, delivering a high return on investment.\nItron is a global technology company that helps utilities measure, manage and analyze energy and water, and Choice is a leading NTL solution provider serving Brazil and other areas of Latin America. Itron's comprehensive smart metering and data management solutions integrated with Choice's Revenue Intelligence technology will provide utilities with a solution that more quickly and effectively identifies and recovers electricity losses. The solution will optimize both companies' ability to create, collect, measure, store and analyze meter information.\n\"Several utilities in Brazil and Latin America experience high non-technical electrical losses. By collaborating with Choice, we are bringing together two industry leaders to create a solution that addresses one of Brazilian utilities' greatest needs,\" said Gadner Vieira, general manager of Itron's electricity business line in Latin America. \"Itron is committed to helping utilities more efficiently manage energy resources. This solution will help utilities do just that by recovering lost electricity.\"\n\"Choice's extensive experience in the Brazilian market combined with Itron's global leadership in advanced AMI and MDM solutions will deliver a best-in-class NTL solution to the electricity market.\" said Denis Maia, CEO of Choice. \"Our joint goal is to help utilities optimize their NTL investments to recover losses and increase profits.\""

"Our meetings are held on the 3rd Tuesday of every month at 1830 hours. For the month of October 2015, we will be meeting at Don Carlos Restaurant, 29669 Hwy 181, Daphne, AL 36526​ Scuttlebut starts at 1800, meeting starts at 1830.\nLew Thomas, Eagle Scout Coord.\nKenya Thomas, Toys 4 Tots Coord.\nOur mission is to help those who served."

"That was a tough season to pull off! Thanks to everyone for their patience while we finished up the year with 4 races in 7 weeks! 2015 Banquet will be Saturday 1/23 at Coushatte Recreational Ranch at 6pm. Please email Jackie@torcsracing.com if you will be attending. $15 per person, we will be serving BBQ. Weather permitting we will have a ride day Sunday 1/24."

"Description \"25 [age] ; Black [race] ; carpenter ; Texas [place of birth].\"\nSource Includes data from the 1880 Census Population Schedules, Town of Beaumont, ED 40, Jefferson County, Texas, Series: T9, Roll: 1313, p. 183 (stamped), entry 250.\nArtisan or Artist Jones, David."

"Description \"25 [age] ; Harness Maker ; 300 [value of personal estate] ; Indiana [place of birth].\"\nSource Includes data from the 1870 Census Population Schedules, Ward No. 3, City of Jefferson, Marion County, Texas, Series: M593, Roll: 1597, p. 437, (stamped), entry 47.\nArtisan or Artist Troxler, John."

"Description \"37 [age] ; Blacksmith ; Baden [place of birth].\"\nSource Includes data from the 1880 Census Population Schedules, Precinct 3, ED 86, Marion County, Texas, Series: T9, Roll: 1318, p. 397 (stamped), entry 347.\nArtisan or Artist Bender, Gustav."

"With over 30k inhabitants, Marion is home to 12K households and 9040 families. General Francis Marion of South Carolina was the man after whom the county was named. Hamilton is the both the largest city and county seat. A great racial diversity of Whites, Black or African American, Native American, Asian, Pacific Islander forms the census portrait of the county.\nMarion County public guide is a massive and reliable repository that proves to be an effective tool for the new and budding records searchers. With the emergence of this site now accessing information has become extremely easy and effective over this site. Here, you can access variety of public and vital records in the most effective and comfortable manner. So, start searching and find valuable clues to resolve you personal and legal issues right away."

"Last modified 163 days ago (Aug. 19, 2021)\nCounty shrinks, but Marion area grows\nBy ERIC MEYER\nMarion County's population declined 6.6%, compared to a statewide increase of 3.0%, according to new every-10-years census data released last week.\nOnly one of four tracts in the county — the east-central one, including Marion — showed increased population, rising 0.2% to 2,799.\nThe tract also includes the unincorporated communities of Aulne, Eastshore, and Marion County Park and Lake, all of which have Marion mailing addresses.\nOther tracts in the county recorded sharp population declines.\nA tract covering the county's northern two tiers of townships, including the cities of Durham, Lincolnville, Lost Springs, Ramona, and Tampa, declined 6.1% to 1,514.\nThe county's west-central tract, covering Hillsboro, Lehigh, and surrounding areas, declined 5.6% to 3,808.\nThe county's final and largest tract, covering its southern tier of townships, including the cities of Burns, Florence, Goessel, and Peabody, declined 8.1% to 3,702.\nFinal totals for incorporated cities have not yet been released. Only estimates are available for populations within city limits.\nWhile the county's population decreased from 12,660 to 11,823 between 2010 and 2020, its diversity — though not extensive — increased.\nWhite non-Hispanics and non-Latinos now account for 88.5% of the population, down from 93.7% a decade ago.\nCensus data indicate the county now has 442 Hispanics or Latinos (up 49.3%), 122 African Americans (up 17.3%), 54 American Indians (down 22.9%), 46 Asian or Pacific Islanders (up 35.3%, and 619 who identify themselves as being multiracial or of some other race or ethnicity (up 131.9%).\nThe county also is getting older. Population younger than 18 declined at a faster pace — by 9.8%.\nAmong the county's 2,586 residents younger than 18, several categories of diversity decreased.\nAfrican Americans were down 19.4% to 25, and American Indians were down 16.7% to 15. On the other hand, Hispanics and Latinos were up 133.9% to 442, and those listing themselves as multiracial or of other racial groups increased 84.6% to 251.\nThe census found 4.6% fewer housing units in the county than it did 10 years ago. Of the housing units, 4,786 were occupied, and 885 were vacant — roughly the same occupancy rate as 10 years earlier.\nOf the county's 11,823 residents, 217 were reported to be nominally living in nursing homes, 376 in student housing, and 11 in other group quarters.\nCensus figures such as these are the basis on which congressional, legislative, and other election districts are redrawn every 10 years and strongly influence such things as the availability of state and federal grants and aid programs.\nMost surrounding counties also lost population. Harvey was down 1.9%, Saline was down 2.3%, Dickinson was down 6.8%, Chase was down 7.8%, and Morris was down 9.1%.\nOnly Butler (up 2.3%) and McPherson (up 3.6%) grew. Sedgwick, in comparison, grew by 5.1%.\nThe state's fastest growing counties were Johnson in the Kansas City suburbs (up 12.1%) and Pottawatomie, including Wamego, Westmoreland, and area northeast of Manhattan (up 17.3%).\nAlthough not official or final, here are estimated population figures as of the census day in 2020 along with the percentage change from the 2010 census.\nCities 2020 Change\nBurns 205 –10.1%\nDurham 107 –4.5%\nFlorence 427 –8.2%\nGoessel 490 –9.1%\nHillsboro 2,769 –7.5%\nLehigh 168 –4.0%\nLincolnville 191 –5.9%\nLost Springs 66 –5.7%\nMarion 1,745 –9.4%\nPeabody 1,082 –10.6%\nRamona 174 –7.0%\nTampa 99 –11.6%\nLast modified Aug. 19, 2021"

"Priest in the diocese of Sandomierz, Poland. Taught theology at the Sandomierz seminary. Founded the Daughters of the Seraphic Saint Francis. Arrested by the Gestapo and deported to the Dachau concentration camp as part of the Nazi persecutions of Catholics. One of the 108 Polish Martyrs of World War II."

"The Chief Administrative Officer is responsible to Council for the efficient management of the municipal workforce, and for seeing that Council's directions and policies are carried out. The CAO provides leadership to the Town of Gibsons and coordinates the departments in the discharge of their responsibilities.\nThe Corporate Administration Department is the communications link between Council and other departments and the general public, providing assistance and advice to citizens with respect to Council/Committee processes, reporting procedures and decisions.\ncompose bylaws, legal notices etc."

"The Cass County Soil Conservation District is a legal subdivision of the State of North Dakota. Cass County was originally organized into four Soil Conservation Districts authorized by the North Dakota Soil Conservation District Law enacted in 1937 and as later amended.\nInitially, four conservation districts were organized to divide the County; the Southeast Cass District, Rush River District, Northwest Cass District, and Maple River District. Later, the Maple River and Northwest Cass Districts were combined to form the West Cass District and the Southeast Cass and Rush River District were combined to form the East Cass District. In 1974, these two districts were combined to form one county entity forming the present Cass County Soil Conservation District.\nThe Cass County Soil Conservation District is responsible for carrying out programs of soil and water conservation on all lands within the District boundaries. This provides a means for all interested parties to work together in the conservation of natural resources."

"Hanna. . HD Wallpaper and background images in the maldosas série de televisão club tagged: hanna pretty little liars.\nThis maldosas série de televisão wallpaper might contain retrato, headshot, close up, and closeup."

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"wallpaper. . HD Wallpaper and background images in the once upon a time club tagged: season 2 cast.\nThis once upon a time wallpaper might contain baterista, instrumento de percussão, instrumento percussivo, show, and concerto."

"Once Upon A Time. . HD Wallpaper and background images in the Once Upon A Time club tagged: once upon a time season 2 regina.\nThis Once Upon A Time wallpaper contains feu. There might also be feu, flammes, enfer, inferno, cheminée, poêle, foyer, and cheminée à foyer ouverte."

"Outlaw Queen dancing tango. Please give credit if آپ use it یا post it somewhere else!. HD Wallpaper and background images in the Once Upon A Time club tagged: photo once upon a time outlaw queen robin hood regina mills the evil queen evil queen lana parrilla sean maguire ouat fan art eqdesign eq design oncebg.\nThis Once Upon A Time wallpaper might contain اچھے کپڑے پہنے شخص, سوٹ, پتلون سوٹ, pantsuit, اچھی طرح کپڑے پہنے ہوئے شخص, پنٹساٹ, کاروبار سوٹ, and بزنس سوٹ."

"Let's take it as read that you believe in email marketing. That you want to send a regular email newsletter, implement some automated email nurtures. You still need an email list to send messages to. You don't have one. Not even an old list you can clean up.\nHow are you going to start building your email list from scratch?\nThe obvious email list-building options focus on your website. Have a subscription form on every page. (Sidebars are good here.) Offer premium content – something useful to your target market which you offer in exchange for an email. And then there's popups. You can set them up to appear when people are about to click away. When they scroll down. When they spend more than a certain amount of time on your site. There are plenty of options to investigate and test.\nBut there's more to email list-building than your website.\nIt's a simple place to start.\nHow many emails do you send every day? Radicati estimate the average business person sends over 120! Every day! How many opportunities does that give for some gentle promotion?\nNow, when you're sending an email to someone, you have their address already – but you may not have permission to add them to your mailing list. You may not feel comfortable asking for that permission. An email signature can help.\nPersonally, I prefer the second one. Even if no one signs up and it doesn't work for email list building, you've shared a positioning statement which helps people understand what you do.\nBut either is better than nothing.\nWhat about people you meet in general business activity and networking? Who can you add to your mailing list? The Spam Act says you must have 'implied consent', but it's not always clear what that means in practice.\nFor example, I'm in a business group where we all help and support each other. Some people have added me to their mailing list without asking. Other people have never added me to a mailing list. Other people have asked if they can add me to their mailing list.\nMost people will say yes, simply because you're being polite and they want to be polite back. Many of them may unsubscribe at a later date, but how is that different from other subscribers? As long as you're not pushy, you won't offend anyone – but you will have some extra opportunities to promote your expertise and even sell something.\nThe same kind of principle applies to one-off contacts. Those people you meet at networking events.\nThen give the cards to your PA to do the admin part of your email list building!\nIt may feel like it sometimes. Especially when you're starting out and you only have a few contacts on your list.\nBut there's no point in having lots of emails on your list if none of them are serious prospects. On the other hand, I've seen positive results from lists of fewer than 50 names.\nAnd there's no point in having any list if you don't use it!\nIf you don't mail them, you know you won't get anything. If you do mail them, you might. And if you include a 'please forward to anyone who might find this useful' comment, you may even get more contacts.\nSo what are you waiting for? Start your email list building and marketing now."

"When I started my business, one of the ideas I had was a monthly newsletter to keep my clients informed, offer specials etc. I started collecting my client's emails on my paperwork, with a little tickbox for \"yes, send me the awesome!\", or something like that.\nYesterday I finally got it set up.\nToday, I'm offering you a limited time, special discount, comes with a free chef knife (no it doesn't) offer to sign up.\nWhat's the benefit? Well, I'm glad you asked. You see. Um.\nYou get to read what I write, every once in a while?\nWell. This is easier. Here are some things that won't happen as a result of you signing up.\nYou will not see pictures of me clubbing baby seals. That's just not on.\nSo, what are the benefits? For serious.\nYou will get first chance at special offers, made only to my email list – like discounts on sessions etc.\nI will do at least one, maybe more, giveaways or contests. Available only to email subscribers – and you won't have to go through a complicated entry process every time – just signing up once is enough.\nYou may find that in 24 hours after signing up, visible signs of aging have decreased. Then again, this isn't face cream, so that may not happen.\nI hope you want to read what I write, and get whatever awesomeness I can think of. I'm always willing to listen to suggestions, so feel free to email me with what you think an occasional email newsletter should include. I won't promise to obey you, but I'll at least think about it.\nGo ahead and click it. I'll wait.\nAnd I'll see you in your inbox later. It's a date.\nI know well that not many people visit here, except possibly to research information. At least, that's what my page analysis tells me.\nHowever, in order to make this page both more appealing visually, and content wise, I will be performing some updates.\nThe page style has been changed to something more modern and clean. I'll be putting up a price list so that people can research price without resorting to emailing me, or worse, posting on Facebook. Facebook is great for many things, but I have lost at least three major shoots to having notifications of new messages not sent to me, and not getting back to people in a reasonable time frame because of it.\nI used to subscribe to the idea that it was better to start building a rapport with every potential customer by having them contact me for prices, that way I could begin selling them my service right from the beginning. However, as I am not a natural salesperson, this is not working well. I think it better to provide the information and just get the customer contact that has already looked at my price list, had a slight heart attack, and decided that they like my work enough to pay my prices.\nI'll not promise to continue to update this content constantly, but while I work on the site and getting it better, there will be a few more posts generated.\nI will be doing a couple of \"marathon\" shoots this autumn. The first of these is coming up in just 3 weeks!\nBook now to get portrait sessions done on Saturday, October 8th. I will be booking 15 Minute mini-sessions for only $45.00 each.\nEach mini session will come with a full set of digital copies in medium resolution – with a printing release included. These are great for printing up to 5×7, and possibly higher, depending on the image.\nThese are great sessions to replace or accentuate school photos, seasonal cards and can even fit quick family sessions. Feel free to book multiple sessions on this day if you think you need just a little more time.\nGive me a call, or email me and I will get you booked. I'm expecting times to fill up fast.\nI've shot three weddings over the last three weekends. My mother got married, after 26 years of being single after my father died. It was wonderful, and I love the man she married. But still, it's my mom. She's never been married in basically all of my remembering life.\nSo, when I wanted to go to school in town, I had to stay somewhere with bus service, so I stayed with friends where I only had to ride a bus for an hour and a quarter each way, twice a day. What a relaxing life! We even had electricity. So, after 16 years, they got married too. And I photographed their wedding.\nThen the next weekend, my sister got married. So I got to shoot that wedding too. Very elegant. Very Formal. Very – Jen. It was my sister to a \"T\". Beautiful and trendy. So, I have some more wedding portfolio stock now. I'm thinking next summer will be my first summer of real wedding bookings.\nWe also got our new exchange student. Moise. He is from Paris, and he is a great kid. He's super kind, helpful and has a great positive outlook on life. I'm already sad that he will be leaving us next summer – exchange student hosting is hard for that reason. Moise is so kind and eager and great with the kids – he brought them beautiful gifts and really enjoys playing silly games with them. He even offered to spoon feed the toddler today! Wow – what a young man!\nI also saw the first colourful leaves of fall today – falling down from their treetop homes to carpet the roads. Soon it will be time for beautiful fall family photos – and with school starting, some great outdoor shots of the kids might be nice to complement the standard school packages. Give me a call, or email me.\nContact info can be found in the navigation bar above.\nThose are my updates – how have you been? Let me know in the comments.\nIt's \"quiet season\" in Quesnel right now. Dead of winter, and we're getting the coldest temperatures that we've had all winter so far.\nI've been out shooting a little bit, but mostly indoors. Some great still life pictures of flowers and whatnot, as well as some family pictures from some recent winter events here in Quesnel, like our Quesnel Winter Carnival. It was a fantastic event, with free snowshoeing, cross-country skiing, pond skating, and some other fun events for the children. The girls had a great time roasting bannock over an open fire, sculpting snow castles, painting snow with dye in spray bottles and jumping in a bouncy castle.\nI had a great time talking with a couple fellow photographers about their passion – bird photography. I got to play with some cool lenses that are outside my normal purview. Really, a great day. I have some great photographs from the day that I'll be putting up as soon as I have them edited.\nWinter is coming! I know lots of you have been putting off getting fall photos done for a multitude of reasons. This November 11th I'll be having a special \"last minute\" fall sale!\nShot outdoors on location at my beautiful acreage, I'll be booking 20 minute sessions for the low price of 45.00 each. You will receive a CD with the edited images in medium resolution (excellent for prints up to 5×7) and a printing release.\nDigital copies will be ready on Saturday the 20th of November – leaving lots of time for Christmas cards etc. Print orders placed on the 20th will also receive a 50% discount.\nI am booking sessions from 10AM until 4PM. Call, Email or Message me right away to reserve your spot or spots.\nI'm messing around on the back end a bit today. Page colours and whatnot may change sporadically. If you see something you like, post a comment or something to let me know, but also let know what it is – cause I might change it again later on.\nOh, and if it's all broken, likely can't read this anyway, so don't worry."

"Inspired-Search is looking for a Logistics Manager, responsible for the day-to-day (warehousing) operations with 5 FTE direct and 75 FTE indirect reports. You are a result-oriented people-manager. Some keywords: family owned international trading company, cultural change, SAP implementation, paperless picking, >5 years logistics leadership experience, minimum Bachelor-degree. You need to speak Dutch and English. Work location: Rotterdam Area."

"Was launched with the Palmach's infiltrating a platoon into Safed thus reinforcing the Jewish positions. Eventually the goal of the operation was to capture the northern Galilee. By May 17th, most of the Galilee from Rosh Pina to Acre were in Jewish hands."

"LEXUS FLAGSHIP TAKES SAFETY TECHNOLOGIES TO A HIGHER LEVEL\nLexus has introduced even more sophisticated driving assistance and advanced pre-collision support for its all-new Lexus LS flagship sedan.\nThe additional features, now standard for LS 500 and LS 500h Sports Luxury grades, provide safer and more secure driving in a wider range of situations.\nThey include world-first technology that can pinpoint the location of a pedestrian and automatically control the car's steering and braking.\nOther new features are designed to help the car stay in its correct lane and to warn the driver of the possibility of collisions with vehicles approaching diagonally or from either side at intersections.\nThe new features expand the capabilities of the standard Lexus LS pre-collision system that uses a radar and camera to detect pedestrians and vehicles ahead.\nThe existing system provides an alert, pre-collision brake assist and autonomous emergency braking to help prevent or mitigate damage from a collision.\nIn addition, two more safety features have been introduced across the LS range to form part of a broader Lexus System System+ suite of technologies -lane-tracing assist and road-sign assist.\nThe new pedestrian alert operates if there is a possibility of the vehicle colliding with a pedestrian ahead. The position of the pedestrian is shown in an animated graphic on the vehicle's head-up display, aiding the driver's intuitive recognition of the situation.\nActive steering assist is designed to determine when there is a high possibility of collision with a pedestrian in the lane of travel or with some continuous structures, such as a guardrail.\nIf it calculates that brake control alone will be insufficient to avoid a collision, the system can provide steering assistance in addition to activating an alert and applying the brakes.\nWhen active steering assist is deployed, the car will only move within a clearly marked lane. The system automatically checks for any vehicles in the car's blind spots, including motorcycles.\nLateral side radar pre-collision is designed to detect vehicles approaching diagonally at up to 50 metres in front of the Lexus LS. It alerts the driver through the head-up display and can trigger brake assist.\nFront cross-traffic alert (Sports Luxury grade) is designed to help prevent collisions at intersections by using side-scanning radars. It can detect vehicles or bicycles approaching from either the left or the right at up to 7 metres from the front of the Lexus and travelling between 10 and 60 km/h. In a world first, the Lexus driver is alerted via the head-up display.\nLane-tracing assist operates with the vehicle's standard all-speed radar active cruise control. It can significantly reduce the burden on the driver by providing seamless lane-keeping support on roads with many bends, or in traffic jams.\nAs well as camera detection of lane markings, the system will trace the path of the vehicle ahead to enable assistance even when lines cannot be recognised, for example when driving in low-speed congestion with little space between vehicles.\nThe system is co-ordinated with the head-up and multi-information displays to give the driver clear notification of the status of the support being provided.\nLane-tracing assist builds on the existing lane departure alert with steering assist, technology that can warn the driver when the vehicle might depart from its lane and provide steering assistance to help keep the vehicle in its lane.\nRoad-sign assist uses a camera to acquire speed-limit information, which it presents on the vehicle's head-up and multi-information displays, encouraging safe driving and reducing the risk of the driver failing to recognise signs.\nOther safety system in the Lexus LS include adaptive high-beam system for the LED headlamps, blind-spot monitor, rear cross-traffic alert, pop-up bonnet and tyre pressure monitoring system.\nMinimal price adjustments result in the LS 500 being priced from $190,500 and the LS 500h from $190,750*.\nThe fifth-generation LS is based on a new rear-drive platform and features a bold design with a coupe-like silhouette.\nTwo powertrains are offered, including the first turbocharged petrol engine offered in the LS and the first 10-speed transmission in the segment.\nThe powertrains are 310kW twin-turbo V6 LS 500 and multi-stage hybrid system LS 500h (combining V6 petrol and electric power for a maximum 264kW).\nLexus has taken its renowned customer care to the next level with an unconditional 10-year complimentary roadside assistance program, making ownership even easier and more beneficial.\n* Recommended retail price provided for general media release purposes only. Excludes dealer delivery, statutory charges and metallic paint. Optional extras at additional cost.\nThe striking flagship sedan that delivers the pinnacle of elegance, comfort and safety.\nExplore Lexus LS"

"A former consultant to PharmacyChecker.com was, unfortunately, swept up in this indictment for an action having nothing to do with his work with PharmacyChecker.com (see our posting about the indictment) [UPDATE: The charges against this individual were dismissed on October 20].\nBut even though PharmacyChecker, nor any of its executives or employees, are the subject of the recent indictment or even mentioned in it, ASOP and LegitScript, who we see as sharks for Big Pharma and Big Pharmacy, could not resist throwing a public relations party, which we believe is aimed at manipulating the media and reporters, government, and worse – consumers! It appears that they spent a lot of money on a PR firm, ECI Communications, to put together and disseminate lies about PharmacyChecker.com and misleading information about international online pharmacies.\nWant proof? After reading ASOP and LegitScript's deceitfully misleading news release, a writer at the publication Medicine Marketing & Media was apparently duped into writing on Wednesday that PharmacyChecker was being indicted! After we contacted that publication about the inaccuracy, we were swiftly given an apology, the article was corrected, and the following statement posted: \"CORRECTION: An earlier version of this story incorrectly listed PharmacyChecker.com as a defendant. PharmacyChecker.com is not a defendant in the case.\nA renowned expert in First Amendment Law considers the news release \"libelous\" and ASOP, LegitScript, and ECI have been asked to take it down. PR Newswire has also been asked to remove it, as it appears to violate PR Newswire's own guidelines regarding libelous content and this certainly doesn't help their existing reputation for distributing \"low quality content.\" However, perhaps due to the enormous funding behind these groups, they have yet to make any attempt to correct the situation. We'll see how much they care about the truth by their actions.\nIt's important to keep in mind who these groups are. ASOP's members and funders include large pharmaceutical companies and the National Association of Chain Drugstores. To protect their bottom lines, these companies and ASOP lobby congress and federal agencies, such as the FDA, to try to curtail your access to much more affordable and safe medication from outside the U.S. In fact, ASOP is actually located in the offices of the government relations and communications consulting firm FraegreBD, where ASOPs executive director, also happens to be a Vice President. And ECI Communications is a PR firm which does extensive business for U.S. pharmaceutical companies. Of course LegitScript.com happens to be a founding member of ASOP. Can we trust LegitScript.com or ASOP? Well, you already know who ASOP works for, right? On the other hand, much of LegitScript.com's income is from a contract with the FDA for $5.2 million. That's not bad in and of itself but, if that money is being used to spread misinformation to U.S. consumers and lobby congress and maybe even the FDA itself, then that stinks.\nASOP's and LegitScript's vision of \"legitimacy\" is a nightmare for Americans! Thirty-five million Americans don't fill a script each year because of cost. A safe online pharmacy is not safe for a consumer who can't afford the medications it sells. ASOP, LegitScript, the NABP, FDA, etc., can't wish away the fact that safe international online pharmacies are a lifeline for many American consumers. Scaring these Americans away from safe pharmacy options with misleading and false information means that more Americans will go without their prescribed medications. There is nothing \"safe\" or \"legit\" about that."

"Q: Let's start where we stopped Is this phrase idiomatic? \n\n\"Let's start where we stopped\" \n\nIf it isn't then what is the right phrase?\n\nA: I can't really imagine many people using OP's example. The most common thing would probably be...\n\nLet's pick up where we left off\n\nThat's definition 7 in macmillandictionary\n\nto pick up - to start something again, from the point where you stopped (italics mine)\n Example: He seems to think that we can get back together and just pick up where we left off.\n\n...plus this definition from Cambridge Dictionary...\n\nto leave off (sth/doing sth) - to stop, or to stop doing something\n Example: This novel begins where the other one leaves off.\n\n"

"Home > Health & Wellness > Publications > Gundersen Magazine > Fall 2019 Issue > 'Changing the picture of addiction'\nGundersen Magazine\n'Changing the picture of addiction'\nThe young woman had already overdosed three times the week Sandy Brekke met her and heard her story. She had experienced abuse, family addiction, homelessness and abandonment. And after hip surgery in her 20s, she found relief with opioids, drugs that eased her physical pain, along with the emotional pain she had been carrying.\nWhen her prescription stopped, she turned to the street for drugs. She tried unsuccessfully to quit using on her own. She desperately did not want to be addicted.\n\"Nobody grows up and says, 'I want to be an addict.' When she was hurting, opioids were the thing that took the pain away,\" Sandy remembers.\nWhile this woman continues to struggle with addiction, Sandy, a senior consultant with the Gundersen Health System Office of Population Health, and more than 100 community members in the Alliance to HEAL (Halting the Effects of Addiction Locally) are working to cut the supply of drugs in the area and show people that life is better without drugs.\nHealth systems, small non-profits, private businesses, law enforcement, school districts, local elected officials and many more are part of the Alliance to HEAL. The Alliance is focused on four goals: 1) decreasing the supply of opioids; 2) increasing the number of people in treatment; 3) decreasing the fatal overdose rate; and 4) decreasing the non-fatal overdose rate.\nEarly success is encouraging:\nLa Crosse County reported two fatal overdose deaths in 2018, down from 19 in 2016.\nThe Alliance has a goal to cut the time it takes to get someone into a treatment program from 30 days or more to 24 hours\n\"This issue affects all of us on some level,\" Sandy says. \"Changing the picture of addiction is the call for the community to raise awareness and help people struggling with addiction.\"\nProgress at Gundersen\n\"As clinicians and as a system, we feel a sense of responsibility because, for better or worse, we contributed to this opioid epidemic by virtue of things that happened in the 1990s,\" says Marilu Bintz, MD, MBA, Chief Population Health Officer, Gundersen Health System. \"Pain was classified as a vital sign and, frankly, patients were being judged or evaluated based on how well they were relieved of pain. That really contributed to the opioid epidemic.\"\nThis epidemic impacts patients of all ages and from all walks of life. Gundersen clinicians and frontline clinical staff are staying updated on internal and external pain management guidelines and best practices. Their efforts are making an impact. The number of opioids prescribed system wide at Gundersen dropped 31 percent in 2018; pills per prescription decreased 26 percent.\n\"The data that we've created is not just for folks on the Gundersen La Crosse Campus. It's data for the prescribers across our entire system,\" Dr. Bintz says. \"Our regional clinics are taking up the banner of decreasing their opioid prescribing habits as well. We're helping prescribers understand how their prescribing habits compare to a partner's prescribing habits and whether there is there an opportunity for education where alternatives to opioids might be used to diminish the likelihood of substance use disorder in patients. This is a system wide effort.\"\nAlliance to HEAL in Action\nDuring conversations, huge gaps in treatment were identified by Alliance to HEAL members. 100 people who had gone through treatment locally were surveyed, and it was found the average length of time to get into treatment was 30 days.\n\"Research shows you have to have someone in treatment within 24 hours for it to be effective,\" Brekke says. \"There is a group within the Alliance to HEAL that is working on how to get people into treatment more rapidly, and how standardized patient assessments across all community stakeholders can help reach the goal.\"\nOther work in The Alliance is examining the distance some patients have to travel to receive treatment.\n\"We're currently sending some people two hours away to get treatment,\" Brekke says. \"Alliance to HEAL members are creating a business plan for a local treatment facility that will address initial treatment through follow up treatment five to 10 years in the future. In the meantime, how do we fill the gaps? Who can treat patients? This is what the Alliance to HEAL is trying to figure out.\"\nThe Alliance to HEAL is also implementing innovative practices created from community stakeholder conversations and connections.\n\"We have nine work groups working to change how everything is done in the community,\" Brekke says. \"One of our work groups is now having police officers and social workers go along on mobile meals rounds to collect unused prescription drugs. There have been massive amounts of medications collected from these homes, and this work is now being replicated across Wisconsin. This happened because we had everyone at the table talking about solutions.\"\nWatch the WXOW \"Hooked to Heal\" half-hour special.\nSubscribe to our Health & Wellness e-Newsletter\nMore e-Newsletters\nJoin GundersenENGAGE\nGundersen News\nIntegrated care brings together physical and mental healthcare May 9, 2018\nGundersen welcomes new counselor to Sparta and Tomah April 5, 2018\nGundersen to build new clinic in Tomah November 16, 2017\nNew Gundersen therapist seeing patients in Sparta and Tomah November 7, 2017\nGundersen Viroqua Clinic welcomes two seasoned behavioral health counselors June 13, 2017\nLatest Healthy Living articles\nSay goodbye to dry eyes January 10, 2022\nMeeting your vitamin D needs in the wintertime January 7, 2022\n4 tips for a healthy holiday season December 6, 2021\nHoliday gift guide: Top beauty products December 1, 2021\n7 tips for staying healthy this winter November 19, 2021\nTrending Healthy Living articles\nHow to support a partner with anxiety June 22, 2021\n5 signs your body is saying 'See an orthopedic surgeon' May 12, 2021\nHeel pain: You can't just 'walk it off' March 24, 2021\n6 natural ways to prevent diabetes before it starts September 9, 2020\nActivities for kids during quarantine March 25, 2020"

"Urgent care centers and walk in clinics are relatively new health care choices. In the last 10 years many new clinics have opened across the country and in Nashville, however, determining when to visit an urgent care clinic or walk in medical center can be confusing, especially if you have a primary care doctor. Read more to learn about the differences between urgent care and primary care as well as how to make the right health care choice for your needs.\nThese are things you are certain don't require a visit to the emergency room, but that don't need to wait days or weeks for your primary care provider to schedule you. Unsure if your injury or illness requires an urgent care or emergency room visit? Visit the emergency room for life or limb-threatening events such as chest pain, strokes, seizures, suspected poisoning, displaced or open wound fractures, uncontrollable bleeding, shortness of breath, mental status change or head injury. For more information, check out Dr. Mickiewicz's blog post on this topic.\nThese are conditions that need to be monitored over time, and the attention of a long-term provider is most necessary.\nUrgent care should be the choice if you need quick, same day care, don't require a trip to the emergency room and don't have a primary care provider. If you do have a primary care doctor, the decision to visit an urgent care or walk in clinic can be more difficult. Your primary care physician knows you and your medical history, however many internal medicine and family medicine practices stay booked and cannot see you when you have an urgent illness or injury. Most primary care clinics also do not have weekend or evening hours which limits when they can see you for urgent after-hours concerns. Some primary care offices don't have onsite X-Ray or complete procedures such as stitches, so an urgent care visit may be the most efficient option for certain injuries and illnesses. If you have an injury or illness and your primary care clinic can't fit you into their schedule, a visit to an urgent care or walk-in clinic is appropriate.\nA primary care clinic visit is most appropriate for managing your long-term medical health as well as same-day treatment of illnesses and some injuries when your provider is available. Your PCP knows your medical history and can help steer a long-term plan especially if your illness or injury is connected to other medical conditions. If you think you need a medication change, a visit to your primary care provider is the best decision because they know how you have responded to medications in the past. Your primary care provider should conduct your annual physical as well as steer recommendations for specialists. While urgent care clinics can provide prescription refills and help during a chronic disease crisis, urgent care is not a replacement for primary care.\nOur West Nashville health clinic opened in 2017 simply as an urgent care/walk in clinic. However as our patients expressed needs that we couldn't meet as a walk in clinic, we designed a more complete care model and Complete Health Partners was born. Now offering urgent care, primary care and sports medicine, we are a medical home for our West Nashville community. Our urgent care clinic is open 9am to 7pm, 7 days a week, so you know we are always here everyday if you need us. There is no need to check a schedule or call ahead, as long as it isn't a major holiday, you can walk in any time and be seen the same day. Because we know not everyone has insurance, we believe in transparent healthcare pricing – our urgent care visit pricing is listed right here on our website.\nWe found that many patients we saw in the urgent care required primary care followup but didn't have a primary care physician. Patients told us the wait to establish care with some primary care clinics in town was 6-12 months! So we started our own. Now, if you need primary care followup and don't have a primary care provider, we can set you up with one of our excellent & highly trained PCPs. We also added a Board Certified Sports Medicine physician to manage joint pain and orthopedic injuries that don't require surgery. With our sports medicine clinic, we can treat many sprains, strains and fractures from start to finish – including casting!\nBecause our urgent care clinic is directed by Board Certified Emergency Medicine Physicians, we can see a larger variety of illnesses & injuries than the typical walk in clinic. We have onsite X-Ray, lab testing, and can do stitches and other small medical procedures such as incision & drainage (I&D) and splinting. With ER doctors as our leaders, we prioritize quick, efficient visits and keeping unnecessary injuries and illnesses out of the ER. Many of our patients expressed a need to schedule appointments around their work and life schedule, so we added our simple online scheduling feature on the front page of our website. We also added a patient portal for patients to have access to their medical records right at their fingertips. Our clinic is now essentially paperless – we make less waste and save time by completing registration on tablets rather than clipboards.\nAt our Nashville primary care clinic, we believe that the primary care relationship is very personal and crucial to your long-term health – that's why we schedule extra time for our primary care patient visits. We want to get to know you, your medical history and your unique medical needs. With this extra time and attention, we can make the most informed decisions and recommendations regarding your medical care.\nThe primary care clinic should be your medical home. We recommend everyone have a primary care provider, even if they chose to go elsewhere for their primary care management. We believe that you are part of your healthcare team, and we take your concerns seriously.\nOur walk in clinic doors are open everyday to our Nashville community who needs prompt care & easy online scheduling is available to establish care with one of our primary care providers. Complete Health Partners Urgent Care/Walk in Clinic is located at 6746 Charlotte Pike by the old log cabin and Costco, we offer urgent and walk in care 7 days a week from 9am-7pm. With our new online check in, you can select a time that works for you and get seen on your schedule. Our Nashville primary care & urgent care services serve patients from Belle Meade to Fairview and from downtown Nashville to Ashland City – we are Nashville's partner in complete health.\nComplete Health Partners Urgent Care. Primary Care. Sports Medicine.\nAddress: 6746 Charlotte Pike Nashville, TN 37209 Copyright 2018 Complete Health Partners. All Rights Reserved."

"Literacy & Girls' Education\nImpact & Reach\nTracking & Results\nOrganizational Funders\nBy continuing to use this site you consent to the use of cookies. Find out more.\nOur leaders represent the best attributes of the private and public sectors. We get things done. And we take risks that get results. Across functions, our global leaders have deep expertise in international education, business and finance. Our board is comprised of CEOs of major companies, leaders of industries, and regional influencers. These people push us, keep our eye on the prize, and help us achieve our bold goals. Their vision empowers us to provide millions of children in low-income communities with the lifelong gift of education.\nBoard of\nCommittees/Regional Boards\nDr. Geetha Murali\nHeather Simpson\nChief Program Officer\nLaurie McMahon\nChief Development and Communications Officer\nNicole Sayres\nShari Freedman\nDinesh Shrestha\nCo-Founder and Director of Field Operations\nErin Ganju\nJohn Wood\nChristie Scott\nVice President, Program Operations\nDeepak Dogra\nDirector, Asia Program Operations\nNorkham Souphanouvong\nCountry Director, Laos\nNuong Nguyen\nCountry Director, Vietnam\nPaul Kilambya\nDirector, Africa Program Operations\nPeter Mwakabwale\nCountry Director, Tanzania\nRakhi Sarkar\nCountry Director, Bangladesh and Acting Country Director, Nepal\nShevanthi Jayasuriya\nCountry Director, Sri Lanka\nSourav Banerjee\nCountry Director, India\nVanessa Francis\nCountry Director, South Africa\nVantha Chea\nCountry Director, Cambodia\nJohn Ridding, Board Chair\nJohn Ridding is the chief executive officer of the Financial Times and FT.com. He was formerly editor and publisher of the Financial Times, Asia, as well as chairman of Pearson in Asia. John led the launch of the Asia edition of the FT in 2003. It won the award for the best newspaper from the Society of Publishers in Asia in its launch year and received top awards for business reporting, scoops and newspaper design at the same ceremony in 2006. He graduated from Oxford University with a first-class honors degree in philosophy, politics and economics.\nYusuf Alireza\nYusuf Alireza is the CEO and Co-CIO, ARP Global Capital Limited. Formerly CEO of Noble Group, Yusuf is also a retired management committee member, partner, and co-president of non-Japan Asia at the Goldman Sachs Group. Yusuf holds a joint bachelor's and master's degree from Georgetown University's School of Foreign Service.\nAndrew Balls\nAndrew Balls is PIMCO's Chief Investment Officer for Global Fixed Income. Based in London, he oversees PIMCO's European, Asia-Pacific, emerging markets and global investment teams. He manages global portfolios and is a member of PIMCO's investment committee. Before joining PIMCO in 2006 he was an economics correspondent and columnist for the Financial Times in London, New York and Washington, DC. He holds a bachelor's degree from Oxford, a master's degree from Harvard and was a lecturer in economics at Keble College, Oxford.\nMary Byron\nMary Byron is retired from Goldman Sachs, most recently as the global head of corporate technology including Finance, Risk, Operations and Human Resources at Goldman Sachs. She served on the Technology Division Executive, Operating and Risk Committees. Prior to this role, Mary was based in Tokyo as CIO for Asia Pacific businesses and co-chair of the Asia Pacific Diversity Committee. She joined Goldman Sachs in 1989 and has held various roles within technology, including managing the firm's global networks and computing infrastructure. Mary was named managing director in 1999 and partner in 2006. She serves on the Board of Directors for the Maureen and Mike Mansfield Foundation and the Auburn Theological Seminary. Mary earned her bachelor's degree from Marquette University in 1986.\nMike Cannon-Brookes is the co-founder and co-chief executive officer of Atlassian, a leading provider of team collaboration and productivity software. Sydney-based Atlassian currently has over 20,000 customers globally, including industry-leaders such as Microsoft, Facebook, Cisco, Oracle, Proctor & Gamble, Exxon, BMW and NASA. Mike has received international recognition for his work and was named \"Australian IT Professional of the Year\" in 2004 and \"Australian Entrepreneur of the Year\" in 2006. He was honored by the World Economic Forum as a Young Global Leader in 2009 and is currently a member of The Forum of Young Global Leaders.\nSabine Chalmers\nSabine Chalmers is General Counsel of BT Group Plc, formerly known as British Telecom. Previously, she served as Chief Legal & Corporate Affairs Officer and Secretary to the Board of Directors at AB InBev. She is qualified as a solicitor in England and is a member of the New York State Bar. Sabine is a member of the Board of Directors of Grupo Modelo. She also serves on several professional councils and not-for-profit boards, including the Association of Corporate Counsel and Legal Momentum, the United States' oldest legal defense and an education fund dedicated to advancing the rights of women and girls. Sabine's education reflects her global background. She spent her formative years as a student in the Philippines at the International School Manila, went on to graduate from London School of Economics, and received her Solicitor distinction at London's College of Law. She is on the Board of Advisers at Harvard Law School's Center for the Legal Profession, where she also received its Legal Profession Award for Excellence in 2016.\nDr. Luis Crouch\nDr. Luis Crouch is the Senior Economist of RTI's International Development Group and is a recognized international leader in providing high-level advice to governments involved in complex educational systems change. In this role, Luis leads work in key strategic areas, addressing important challenges in global health and youth issues, and in particular, measurement and finance issues regarding these two sectors. Prior to this, Luis was Coordinator for the Global Good Practice group with the Global Partnership for Education. Luis has worked on all aspects of policy analysis research and implementation, from field surveys to quantitative and qualitative analysis to policy dialogue presentations. Luis has experience in many countries in the developing world. In particular, he was a high-level technical advisor to the governments of South Africa in the period after the end of apartheid and Egypt during the current drive to decentralization. Luis received a bachelor's degree in anthropology from the University of California, Santa Barbara, as well as a master's degree and doctorate in agricultural economics from the University of California, Berkeley.\nCarl Huttenlocher\nCarl Huttenlocher is Managing Partner and Chief Investment Officer for Myriad Asset Management. Myriad is a multi strategy hedge fund investing across equities and fixed income with a focus on the Asia Pacific region and the global technology sector. Prior to founding Myriad in 2011, Carl was a Managing Director of Highbridge Capital Management, Senior Portfolio Manager for the Highbridge Asia Opportunities Fund and a member of the Global Investment Committee for Highbridge Capital Corporation. Before joining Highbridge in 2002, Carl worked at Citadel Investment Group and Long Term Capital Management. He also founded Intelligent Markets—a venture capital-backed financial software company—and served as chief executive officer from 1999 to 2001. Carl earned his bachelor's degree in mathematics from Massachusetts Institute of Technology. Carl is married to Tami Lippit. They live in Hong Kong and have four children.\nScott Kapnick\nScott Kapnick is Chief Executive Officer of HPS Investment Partners, LLC (\"HPS\") which he founded in 2007. HPS is a leading global investment platform with a focus on non-investment grade credit and has over $38bn of assets under management. HPS has approximately 100 investment professionals and over 200 employees globally, and is headquartered in New York with ten offices worldwide. HPS was originally formed as a unit of Highbridge Capital Management, LLC, a subsidiary of J.P. Morgan Asset Management. In March 2016, the principals of HPS acquired the firm from J.P. Morgan, which retained Highbridge and the hedge fund strategies. From 2013-2016, Mr. Kapnick also served as Chief Executive Officer and Chairman of the Executive Committee of Highbridge Capital Management, and currently serves as Non-Executive Chairman and Senior Advisor. Before founding HPS, Mr. Kapnick was a Management Committee Member, Partner, and Co-Head of Global Investment Banking at Goldman Sachs, positions he held from 2001 to 2006. He also served as Co-Chief Executive Officer of Goldman Sachs International from 2005 to 2006 and spent 12 out of his 21 years at the firm in Europe (London and Frankfurt). Mr. Kapnick was named Partner in 1994. Mr. Kapnick is a graduate of Williams College and holds a combined JD/MBA from the University of Chicago. He also studied at the London School of Economics & Political Science. Mr. Kapnick is a member of the Council on Foreign Relations, Chairman of the Boards of Directors of Room to Read and Aileron Therapeutics, and serves on the Board of Directors of the Naples Botanical Garden.\nDr. Elizabeth M. King\nElizabeth is currently Non-resident Senior Fellow at the Brookings Institution, Commissioner of 3ie, Technical Adviser to the RISE Project of Oxford University, and co-Editor of Comparative Education Review. She was Director of Education from 2009 and Acting Vice President for Human Development in 2014 before retiring from the World Bank, Washington, DC, in September 2014. In these positions, she was the World Bank's senior spokesperson and professional head for global policy and strategic issues related to education and human development. She has published on topics such as household investments in human capital and the link between these investments and poverty and economic development; gender issues in development; education finance, and the impact of decentralization reforms. She has worked on countries as diverse as Bangladesh, Colombia, Ghana, Indonesia, Nicaragua, Pakistan, and the Philippines, among others, contributing to public expenditure reviews, country economic assessments, policy analyses of the human development sectors, and impact evaluations of policies and programs. Ms. King has a Ph.D. in Economics from Yale University and a Masters and BA (Economics) degrees from the University of the Philippines.\nJohn Lindfors\nJohn Lindfors is the Managing Partner of DST Investment Management, the investment adviser of DST Global funds. Over the last several years, DST Global has invested in companies such as Facebook, Alibaba, JD.com, Didi, AirBnB, Spotify, Xiaomi, WhatsApp, etc. and currently has more than $10 billion of assets under management. John joined DST in 2010 and has been based in Hong Kong since 2011. Prior to joining DST, John was the Partner in charge of the European Technology and Media Investment Banking department for Goldman Sachs. He joined Goldman Sachs in 1993 and worked in London and New York during his 17 years at the firm. John earned a M.Sc. (Econ.) from the Swedish School of Economics in Helsinki in 1993.\nDr. Geetha Murali is the Chief Executive Officer of Room to Read. As Chief Executive Officer, Geetha oversees Room to Read's global operations, which include programmatic work in 15 low-income countries, a global network of investors and volunteer chapters, and a worldwide staff of more than 1,600 employees. In her most recent role as Chief Development and Communications Officer, Geetha oversaw Room to Read's global resource development department with staff across nine locations. In that role, she was responsible for global fundraising, marketing, public relations, and communications, while working directly with the organization's largest investors. Under her leadership, Room to Read embarked on several key initiatives, including the development of major institutional and cause-marketing partnerships, as well as the launch of legacy giving and multi-currency crowdfunding programs. Dr. Murali was instrumental in helping Room to Read scale its impact by building innovative public and private partnerships.\nGeetha has nearly 20 years of diverse experience across the corporate and non-profit sectors. This includes working as a statistician for multinational companies and with large-scale technology programs such as the Digital Equalizer Program (American India Foundation) and Adobe Youth Voices (Adobe Systems Incorporated). Geetha received her master's degree in biostatistics from the University of North Carolina at Chapel Hill and her master's and doctorate degrees in South Asian Politics from the University of California at Berkeley.\nStasia Obremskey\nStasia Obremskey is the strategy director for Contraceptive Technology Development at Rhia Ventures, a social impact investing firm focused on women's health. She has more than twenty-five years of experience providing financial and strategic planning consulting to organizations in the U.S. and Asia. She began her consulting career as a management consultant with Bain & Company. Previously, she worked in investment banking for Morgan Stanley & Co. She holds a bachelor's degree in Business Administration with a concentration in finance, from the University of Notre Dame and an MBA from the Harvard Graduate School of Business. In addition to her consulting work, she has extensive experience as a member of several non-profit boards where she has held a number of leadership positions.\nFrank van Veenendaal\nMr. Frank van Veenendaal retired from Salesforce in 2015 after almost 14 years with the company in multiple leadership roles including Vice Chairman, President of Worldwide Sales and Services, President of Worldwide Sales and Chief Sales Officer, President of North American Operations and Global Corporate Sales, President of Worldwide Corporate Sales and Services and Senior Vice President of North America Sales at Salesforce.com. He was instrumental in growing Salesforce from $5M to $5B+. Mr. van Veenendaal has over 30 years of technology sales and executive management experience. Previously Mr. van Veenendaal held various sales and sales management positions for companies such as Actuate, Interleaf, Integrated Solutions, Pyramid, and Harris Corporation. Mr. van Veenendaal also serves on the board of directors of Coupa, NewVoiceMedia and Vlocity.\nSusan Wojcicki is CEO of YouTube, the world's most popular digital video platform used by a billion people across the globe to access information, share video, and shape culture. An early champion of online video who was instrumental in Google's 2006 acquisition of YouTube, Susan now oversees YouTube's content and business operations, engineering, and product development. Prior to joining YouTube in February 2014, Susan was Senior Vice President of Advertising & Commerce at Google, where she oversaw the design and engineering of AdWords, AdSense, DoubleClick, and Google Analytics. She joined Google in 1999 as the company's first marketing manager and led the initial development of several key consumer products including Google Images and Google Books. In 2002, Susan began working on Google's advertising products and over the next 12 years she led teams that helped define the vision and direction of Google's monetization platforms. Before joining Google, Susan worked at Intel, Bain & Company, and a number of start-ups. She graduated with honors from Harvard University, holds a master's in economics from UC Santa Cruz, and an MBA from UCLA.\nJohn Wood is the founder of Room to Read. He started Room to Read after a fast-paced and distinguished career with Microsoft from 1991 to 1999, during which he served as director of business development for the Greater China region and as director of marketing for the Asia-Pacific region. John continues to bring Room to Read a vision for a scalable solution to developing global educational problems with an intense focus on results and an ability to attract a world-class group of employees, volunteers, and funders. Today, John focuses full-time on long-term strategy, capital acquisition, public speaking, and media opportunities for the organization. John holds a master's degree in business administration from the Kellogg Graduate School of Management at Northwestern University, a bachelor's degree in finance from the University of Colorado, and has four honorary doctorates including from McGill University and the University of San Francisco. He also serves on the advisory board of the Clinton Global Initiative and New Story. John is a frequent lecturer at Harvard Business School and at NYU's Wagner School of Public Policy.\nEmeritus Board\nHilary Valentine: Chair\nHilary is a board member of the Lucile Packard Foundation for Children's Health and a member of Part the Cloud whose mission is to fund Alzheimer's research with the highest probability of slowing, stopping or ultimately curing Alzheimer's disease. Hilary serves on the Board of Directors of the Valentine Family Foundation and the Canary Foundation. She also serves on the Emeritus Board of Breast Cancer Connections. Her primary focus has been to evangelize the Room to Read mission in front of high net-worth donors in the technology world. The Valentine Family Foundation provided the initial multi-year seed funding for Room to Read's Girls' Education program. Hilary served on the Room to Read Board of Directors from 2003 to 2012 and was Co-Chair of the Board of Directors from 2005 to 2008 and was Chair of the Board of Directors from 2008 to 2010. Hilary graduated with a BS in Psychology from St. Lawrence University.\nChristopher S. Beer\nChristopher Beer is the managing member of Ironmark Law Group, PLLC, a firm providing strategic business and intellectual property services to individuals, companies and other lawyers both in the U.S. and worldwide. Chris received his bachelor's degree from Pacific Lutheran University, a Juris Doctor from the University of Washington and master's degree from the Henry M. Jackson School of International Studies, University of Washington. Chris served on the Room to Read Board of Directors from 2004 to 2013.\nCraig Bruya\nCraig Bruya is retired from Microsoft Corporation, most recently as chief financial officer of Microsoft Business Solutions. During a three-year sabbatical, he taught accounting and management classes to M.B.A. students at Seattle University and the University of Washington. Prior to this, he spent 12 years at Microsoft in executive finance positions primarily in Microsoft International as well as nine years with the audit division of Arthur Andersen & Company in Seattle, Brussels, Belgium and Athens, Greece.\nJerry del Missier\nJerry del Missier is former COO of Barclays Bank Plc and former Co-Chief Executive of Corporate and Investment Banking. Before joining Barclays in 1997, Jerry was the Senior Managing Director of Derivative Products at Bankers Trust, responsible for European Business. Jerry is a former Chairman of the Board of the Securities Industry and Financial Markets Association and has served on the Boards of the Global Financial Markets Association, the International Swaps and Derivatives Association, and the Markets Management Group of the International Institute of Finance. He served on the Board of Trustees of Queen's University in Kingston, Ontario and is currently on the Advisory Board of the Queen's School of Business. Jerry received his bachelor's degree in chemical engineering and an MBA from Queen's University, Ontario.\nErin Ganju is a Co-founder, former CEO, and former COO of Room to Read. From the early start-up days, Erin was instrumental in the design and implementation of the organization's scalable, replicable model for improving the quality of education around the world. In 2009, Erin became Chief Executive Officer of Room to Read. As CEO, Erin oversaw Room to Read's global operations across 15 countries; a technical assistance unit called Room to Read Accelerator; fundraising teams in North America, Europe, Australia and the Asia Pacific region; and a worldwide staff of more than 1,500 employees. Erin has been selected as one of the World Economic Forum's Schwab Foundation Social Entrepreneurs for 2014 and in 2012 was one of Fast Company's Extraordinary Women. Before founding Room to Read, Erin worked at Unilever, Goldman, Sachs & Co. and a couple of technology start-ups. She has spent extensive time working and living in Asia, where she saw firsthand the need to enhance developing countries' educational systems. Erin holds a combined bachelor's and master's degree in international relations and economics from The Johns Hopkins University in Washington, D.C.\nPeter T. Grauer\nPeter T. Grauer is Chairman of Bloomberg L.P., the global financial media company. He has been a member of the Bloomberg Board since October 1996 and was named Chairman of the Board in March 2001 succeeding Michael R. Bloomberg. Mr. Grauer joined Bloomberg full time in his executive capacities in March 2002. Prior to this, he was a Managing Director of Donaldson, Lufkin & Jenrette from 1992 to 2000 when DLJ was acquired by Credit Suisse First Boston and then Managing Director and Senior Partner of CSFB Private Equity until March 2002. Mr. Grauer serves as lead director of Davita, Inc., as well as the Boards of The University of North Carolina at Chapel Hill, the Inner City Scholarship Fund in New York City, Rockefeller University and the Prostate Cancer Foundation. He is a graduate of the University of North Carolina and the Harvard University Graduate School of Business, Program for Management Development.\nTim Koogle\nTim Koogle is a private venture capitalist, entrepreneur and business leader, and philanthropist. He has had a long career in starting and growing businesses of scale. From 1995 to 2001 he served as Yahoo! founding Chief Executive Officer and Chairman of the Board of Directors. Currently, Tim is on the board of a number of private early stage companies in which he is a venture capital investor. Additionally, he serves on the board of directors of Thomas Weisel Partners, a publicly held investment bank; is the founder and CEO of Serendipity Land Holdings; chairman of the board of Method Home Products, Inc.; and managing director of the Koogle Foundation, a nonprofit foundation focused on the education of underprivileged and high risk young people in the United States, Asia, and Latin America. Tim holds a BS degree in mechanical engineering from the University of Virginia and an MS and EngrD in engineering from Stanford University.\nAlastair Mactaggart is President of Emerald Fund Inc., a San Francisco residential real estate developer. Since 1998 Emerald has developed in excess of US$2 billion of real estate, including over 1,500 units of new housing, and 1,900 units of condominium conversions. Alastair serves on the board of Sutter West Bay Hospitals, which includes San Francisco's California Pacific Medical Center. Alastair received a BA from Harvard College and an MBA from Harvard Business School. He lives in San Francisco, CA. Alastair served on Room to Read's Board of Directors from 2005 to 2009.\nKim Anstatt Morton\nKim Anstatt Morton worked almost a decade on Wall Street as an equity research analyst at UBS and Hambrecht and Quist in New York City. She later joined Montgomery Securities in San Francisco where she covered emerging growth and big cap biotech companies. Kim is passionate about literacy, education and the arts. She enthusiastically serves on the advisory board of 10x10, a global movement for girls' education through a film and social action campaign (and a partner of Room to Read). She is a member of San Francisco's Edgewood Arts Advisory Board, has trained as a docent for middle school children with SFMOMA, and is active on their Artist's Circle Donor Development Committee. Kim has worked with the Department of Health and Human Services in San Francisco with abused and neglected children and has tutored a special literacy program for sixth through eighth grade students struggling with reading at Francisco Middle School in San Francisco. Kim received her bachelor's degree from Dartmouth College, and fine art and graduate painting degrees at the San Francisco Art Institute. Kim travels extensively in the developing world and lives in San Francisco with her husband Ian and son Baker.\nDr. Fernando Reimers\nFernando Reimers is the Ford Foundation Professor of International Education and Director of Global Education and of International Education Policy at Harvard University. Prior to joining the faculty at the Harvard Graduate School of Education, Fernando was a senior education specialist at the World Bank. He has extensive experience in the area of international development assistance with the United States Agency for International Development, the World Bank, the Inter-American Development Bank and other development organizations. Fernando is best known for his theory of informed dialogue, an approach to bridge scientific research and education policy through the mapping and mobilization of social networks. Fernando is a member of the Council of Foreign Relations, a fellow of the International Academy of Education, a member of the Advisory Board of the Division of Behavioral and Social Sciences and Education, National Academy of Sciences, and a member of the World Economic Forum's Global Agenda Council on Education. Fernando earned doctoral and master's degrees in education from Harvard University and obtained a Licenciatura en Psicologia at the Universidad Central de Venezuela. He was also awarded an honorary doctorate in humane letters by Emerson College for his work advancing global education.\nMuneer A. Satter\nMuneer Satter manages Satter Investment Management (SIM), a Chicago-based private investment firm, and the Satter Foundation, a private family foundation. SIM has significant investments in several life sciences and medical technology companies. Muneer retired in 2012 after sixteen years as a partner at Goldman Sachs in the Merchant Banking Division. As Global Head of Goldman Sachs Mezzanine Group, Muneer raised and managed more than $30 billion of investments. He is Vice Chairman of the Board of the Goldman Sachs Foundation and he is on the Board of the Nature Conservancy where he is Chairman of the Finance Committee. Muneer received a B.A. from Northwestern University, and a JD/MBA from Harvard Law School and Harvard Business School. Muneer served on the Room to Read Board of Directors from 2004 to 2010 and was Co-Chair from 2005 to 2008.\nMark Bedingham\nMark is President and CEO, Singapore Myanmar Investco Ltd, a company listed on the Singapore Stock Exchange focused on investing and in managing businesses in Myanmar. He has held this position since 2015 and is responsible for the Group's corporate plans, policies and business development as well as the general management of the Group's operations. Mark also serves as Chairman of the Board, Ce La Vi; Advisor and Consultant, Access Myanmar Distribution Co Ltd, Myanmar; Non-Executive Director of the Scotch Malt Whisky (Holdings) Limited; and Advisor and Director of the Board, Crystal Jade Culinary Concepts Holding.\nFrom 1995 to 2014 Mark was Regional Managing Director, Moet Hennessy Asia Pacific. He joined Moet Hennessy following 8 years as President of Jardine Wines and Spirits (Now known as Moet Hennesy Diageo Japan). Mark began his career in 1977 as a member of the \"cadre\" of Jardine Matheson. Mark graduated with a Master's degree in Agricultural and Forest Sciences from the School of Biological Sciences of Oxford University.\nIsabelle and Antoine Decitre\nAntoine is the Co-Founder and Director of Velcan (ALVEL FP), a listed investment holding company, operating as an independent power producer in emerging countries and managing a global portfolio of financial assets. Antoine led the IPO in 2005 and the subsequent fund raising totalling Eur 150 million between 2005 and 2007.\nAntoine started his career at Price Waterhouse in 1993. Prior to founding Velcan, he cofounded one of the first technology incubators in Paris and was the co-founder or first investor in 23 IT startups between 1999 and 2002. These were successfully sold to the likes of IBM Corp and Cisco.\nIsabelle is the Founder and CEO of ID Capital, a venture capital investment & advisory company headquartered in Singapore. The company focuses on supporting startups which are bringing sustainable technology solutions to address the challenge of the food value chain, like the latent of shortage of sustainable proteins, water- and input-saving technologies for agriculture, or crop biocontrol. Supported by the Singapore Economic Development Board since its inception, the Future Food Asia platform operated by ID Capital has rapidly gained traction across the Asia-Pacific region. Prior to moving to Asia in 2012 Isabelle has worked for 20 years in the luxury industry (for Louis Vuitton, Cartier, Dunhill, Boucheron), in various executive positions and lastly as the CMO for Hennessy (LVMH Group).\nAntoine and Isabelle are both trained engineers and graduated from Ecole Polytechnique in 1993. Isabelle holds a degree in Chinese language and civilization.\nThey live with their three children in Singapore.\nAntony Ng and Koh Toh Tzu\nAntony Ng is the co-founder and CEO of D'Crypt Pte Ltd. Prior to this, Antony was a Distinguished member of Technical Staff at DSO National Laboratories, where he was also the winner of 1998's Defence Technology Prize. He was also an Adjunct Lecturer at NUS, where he helped to start the Computational Science Programme in the Faculty of Science.\nAntony obtained his Ph.D. in Electrical Engineering and Computer Science from the University of California, Berkeley in 1991.\nAntony is active in promoting Innovation and Entrepreneurship in the local business community. He was an alumnus of the BMW Herbert Quandt Foundation's Europe-Asia Young Leaders Forum and was a speaker at the 13th Principal's Forum, a closed-door session for all school principals in Singapore. Away from work, Antony currently serves on the management committee of a shelter for people living with HIV/AIDS.\nMarried for 27 years to Koh Toh Tzu, he's the proud father of Ruth and Anne.\nWith a librarian and Chinese scholar for a father and a secondary school principal for a mother, Koh Toh Tzu hails from a family heavily steeped in Singapore education. A graduate of the Singapore school system, she blends a traditionally Chinese upbringing with her 1st Class Honours in Computer Science from Queens University in Ontario Canada in 1986. Initially a Software Engineer at the Institute of System Science, NUS, she moved into corporate management in 1991, rising through various appointments to be the General Manager and Chief Operating Officer of J.M. Sassoon, a large local stockbroker in Singapore.\nThe person behind some of the earliest Internet stock trading systems in Singapore, Toh Tzu was featured in SmartInvestor magazine as one of the select group of women to succeed in a predominantly male enclave. Toh Tzu is now a full time homemaker, wife and mother.\nHelman and Ria Sitohang\nHelman Sitohang has been the Chief Executive Officer for Credit Suisse Asia Pacific since 2014. In 2015, he was appointed to the Executive Board of Credit Suisse Group AG and Credit Suisse AG. He is the first Indonesian to sit on the Executive Board of a global bank.\nUnder his leadership, Credit Suisse has won among the most prestigious house, country and deal awards in Asia Pacific including, most recently Best Investment Bank by Global Capital, Asia's Best Bank for Wealth Management and Asia's Best Bank for Financing in Euromoney's Awards for Excellence, and was ranked as having Asia's top Equity Sales and Trading house in a poll by Institutional Investor. Credit Suisse was also named House of the Year by AsiaRisk and Best Private Bank by Asian Private Banker in 2016. In 2015, Mr. Sitohang was awarded the Outstanding Achievement Award by FinanceAsia. In 2009, Mr. Sitohang was named as an inaugural member of Finance Asia's \"Club\" of the 50 most influential people in Asia's financial markets.\nMr. Sitohang joined Credit Suisse in 1998 from Bankers Trust, where he worked in the derivatives group. Upon joining Credit Suisse, Mr. Sitohang worked as part of the Indonesian coverage team and rose to become head of the team. He continued to take on additional responsibilities across Southeast Asia, until in 2009 he became the Co-Head of the Investment Banking Department (the corporate advisory business, covering M&A and Capital Markets) for Asia Pacific. In 2012 he was appointed as Head of the Investment Bank in Asia Pacific, responsible for all Credit Suisse's Fixed Income, Equity and Investment Banking Department activities across the region.\nRia A. Sitohang is the co-founder of Ars86care Foundation, a highly acclaimed charity based in Indonesia, whose vision and mission is to promote and create high quality child friendly living spaces in order to achieve a better quality of life for children and build public awareness on the importance of child friendly living spaces. She is a highly committed and active philanthropist and has been instrumental in driving a strong culture of giving and volunteering for Indonesian causes. In 2017, Room to Read honored Helman and Ria with the Friends of Global Literacy Award, after they launched the Room to Read Accelerator program, which harnessed the skills and resources of foundations, corporations and individuals to support and kick-start a two-year project aimed at setting up school libraries and publishing children's books in Bahasa. The initiative was undertaken in cooperation with five local NGOs and two private sector publishers. As a result, 24 libraries have been established across 3 districts and 15 book titles published. The innovative Accelerator model of enhancing the skillbase of incumbent NGOs has now been rolled out by Room to Read across eight countries to date, benefiting over 1.5 million children, with more than 720,000 books have been distributed to approximately 9,600 project sites. In 2014, Ria Sitohang was named by Tatler Indonesia as one of just seven \"Heroes of Philanthropy\" for her work in education.\nMichael and Lynne Taylor\nMichael is a Managing Director for HarbourVest Partners, a global private equity firm. He joined HarbourVest in 1998 after several years with Morgan Stanley's technology investment banking division. Michael is an experienced private equity investor with a focus on partnership investing. In 2014, Michael relocated from Boston to Tokyo to complement HarbourVest's local Asia offices and act as a member of the global leadership team. Michael is the senior partner in Asia and has served on various Firm committees including, Executive, Investment (Asia), Audit and Compensation Committees. Michael served as a Lieutenant Commander with the United States Navy, as a Naval Aviator and still maintains his commercial pilot ratings. He received a BS (with distinction) from the United States Naval Academy in 1986 and an MBA in Finance from the Wharton School at the University of Pennsylvania in 1995.\nLynne received her BA from Mount Holyoke college in 1989 where she focused on history and language studies. She worked in publishing at Condé Nast publications, including GQ Magazine and book publishing at Random House. Lynne was Director of Communications at a private school in New York City and with the move to Boston, she worked on strategic planning and public relations in the technology sector. Lynne spends her time consulting with several organizations which have included, Year-Up and Women Working for the Oceans, The New England Aquarium. She is passionate about her charity work and spends her time helping charities based in Phnom Penh, Cambodia. Working with children is very important to Lynne. Lynne and Michael have four boys of their own and live in Singapore.\nJustin Teo\nJustin Teo is Head of Corporate Finance and Strategy at TCIL, a Hong Kong listed corporation operating in eleven countries across Asia, spanning automotive retail and distribution, transportation and logistics, manufacturing, real estate and hospitality. Justin manages corporate strategy and business planning, mergers and acquisitions, fund raising and strategic partnerships. He is concurrently Managing Director and executive board member of TC Zero, a transportation and logistics joint venture with Japan listed Zero Co Ltd. Justin also serves as a Management Committee member of the Motor Image Group. Prior to TCIL, Justin held investment and corporate finance roles at Magnetar Capital, Ardmore Park Capital and UBS in New York, Singapore and Tokyo. Justin is a member of the UBS 20/20 Impact Circle and was involved in microfinance and social enterprise projects in Africa and South East Asia. Justin holds a bachelor degree in economics from Cornell University.\nYusuf Alireza and Dina Khreino-Alireza\nYusuf Alireza is the CEO and Co-CIO, ARP Global Capital Limited. Previously, he served as CEO of Noble Group and Co-President of Asia (excluding Japan) for Goldman Sachs and a member of that firm's Global Management Committee. He joined Goldman Sachs in 1992 in New York and moved to London in 1997, where his last position was head of sales for Europe, the Middle East and Africa. In 2008 Yusuf moved to Hong Kong to lead Goldman Sachs' Asia Pacific securities division. He also serves on Room to Read's Global Board of Directors. Yusuf has a joint undergraduate and graduate degree from Georgetown University's School of Foreign Service. He and his wife, Dina Khreino-Alireza, relocated to Dubai in 2017 and have 3 children.\nDina Khreino-Alireza received her bachelor's degree in International Affairs from L'Universite Americaine de Paris, and completed her post-graduate studies at the University of London, where she obtained a master's degree in Middle Eastern politics. She has worked as a researcher and writer of International Law and Politics and has been published in the Washington Report on Middle East Affairs and the Herald Tribune. She is the founder and chief executive officer of INVU Media, a post production company specializing in family motion picture entertainment. She lives with her husband and three young children in Dubai.\nDamien and Rebecca Brosnan\nDamien Brosnan is Portfolio Manager at Maven Investment Partners. Previously he was Co-Head of Equity Capital Markets at UBS Asia. Before joining UBS in 2012 as Head of Equity Syndicate & Equity-linked Origination for Asia, he worked for Morgan Stanley in New York. A Physics graduate from the Massachusetts Institute of Technology, Brosnan is a keen runner. In 2015, he ran the New York marathon to raise money for Room to Read. He and his wife, Rebecca Brosnan, live in Hong Kong.\nRebecca Brosnan is currently the COO at Mother's Choice. Until February 2016, Rebecca served as Managing Director at HKEx in variety of roles including Head of Product Development, responsible for the design of new products to be listed on HKFE, and Head of Asia Commodities, responsible for growing LME's business in the Asia-Pacific region. Prior to these roles, Rebecca was responsible for corporate strategy and business development running the deal team which successfully acquire the London Metals Exchange, the world's leading industrial metals trading venue. While at HKEx, Rebecca founded and co-chaired the Women's Exchange at Hong Kong Exchange. Prior to joining HKEx in 2010, Rebecca worked in the Investment Banking Division of Merrill Lynch in HK from 2005 to 2008 and served as a Legal Assistant at Skadden, Arps in both the Washington, D.C. and HK offices. In 2016, China Daily and the Asia News Network awarded Rebecca the \"Asian Women's Leadership Award\". Rebecca holds a bachelor's degree in Economics from Trinity College, and master's degree in the History of International Relations from the London School of Economics and completed the General Management Program at Harvard Business School.\nJohn and Camilla Lindfors\nJohn Lindfors is the Managing Partner of DST Investment Management, the investment adviser of DST Global. DST was founded by Yuri Milner to back exceptional category-leading internet companies led by visionary founders. Over the last several years, DST has invested more than $5 billion in companies such as Facebook, Alibaba, JD.com, Xiaomi, AirBnB, Spotify, Lending Club, Flipkart, etc. Prior to joining DST in 2010, John was the Partner in charge of the European Technology and Media Investment Banking department for Goldman Sachs. He joined Goldman Sachs in 1993 and worked in London and New York during his 17 years at the firm. John earned a M.Sc. (Econ.) from the Swedish School of Economics in Helsinki in 1993.\nCamilla Lindfors received a M.Sc. (Econ.) from the Swedish School of Economics in Helsinki in 1993 and worked for the leading global paper company UPM Kymmene following her graduation. She received diplomas from the Inchbald School of Design in London in 1998 and the New York School of Interior Design in 1999 after which she launched a successful interior design business taking on projects in different parts of the world.\nJohn and Camilla reside in Hong Kong with their three children.\nCarl Huttenlocher and Tamiko M. Lippit\nCarl Huttenlocher is managing partner and chief investment officer for Myriad Asset Management. Prior to founding Myriad in 2011, Carl was managing director of Highbridge Capital Management, senior portfolio manager for the Highbridge Asia Opportunities Fund and a member of the Global Investment Committee for Highbridge Capital Corporation. Before joining Highbridge in 2002, Carl was the portfolio manager for Asian Convertibles and Equity Derivatives at Long Term Capital Management. Carl began his career at Citadel Investment Group where he traded European and Latin American Convertible Bonds. He also founded Intelligent Markets—a venture capital-backed financial software company—and served as chief executive officer from 1999 to 2001. Carl earned his bachelor's degree in mathematics from Massachusetts Institute of Technology.\nTamiko M. Lippit received her bachelor's degree, magna cum laude, in history and literature from Harvard College and her J.D. from Columbia Law School. She has practiced law at Hughes, Hubbard & Reed, LLP in New York City and at Venture Law Group in Menlo Park, California, where she advised start-up companies on a broad array of legal issues. She currently lives in Hong Kong with her family.\nChris and Valeria Mancini\nChris is the CEO of Savills Asia Pacific, excluding Greater China. He assumed this role in 2016. Prior to that, Chris was CEO of North East Asia, as well as the Representative Director and CEO of both Korea and Japan. He is responsible for the implementation of the organization's strategic objectives and works closely with other Savills offices across the world. He remains actively involved in Investment Sales, Asset Management and Client Relations with the firm's multinational client base, both in Japan and in the broader Asia Pacific region.\nChris has been with Savills since its inception in Japan in 2004. He established the Savills Japan Investment and Valuation Division. Chris has been the CEO of Savills Japan since 2007 and has more than doubled the firm's annual revenue during that time. In 2012, Chris became director of Savills Asset Advisory, a wholly-owned Asset Management subsidiary of Savills. Prior to Savills, he worked with GMAC Commercial Mortgage Japan, RTKL Associates, and Takenaka Corporation. He has spent his entire professional life in Japan and has almost 20 years of experience working with real estate in various roles in the architecture, construction, real estate investment and asset management industries.\nKimberley Stafford and Ryan Korinke\nMs. Stafford is a managing director and head of PIMCO Asia-Pacific. Based in Hong Kong, she is responsible for setting strategic direction for the region and leading a team of PIMCO professionals to deliver investment solutions and service to Asia-Pacific clients. Ms. Stafford is also a member of the firm's Executive Committee. She joined PIMCO in 2000 and has held several positions, including global head of consultant relations, head of U.S. institutional sales and alternatives marketing teams and global head of human resources and talent management. Prior to these roles, Ms. Stafford was a member of PIMCO's executive office, contributing to firmwide strategic, financial and operational initiatives; head of global sustainability initiatives, overseeing the firm's environmental, social and governance efforts; an account manager in the consultant relations group; and an analyst in PIMCO's trade compliance group. She has 18 years of investment experience and holds an MBA from the Marshall School of Business at the University of Southern California. She earned her undergraduate degree at the University of Redlands.\nMr. Korinke is an executive vice president in the Hong Kong office and head of hedge fund and quantitative strategies. In this role, he leads a team of product strategists covering discretionary and systematic absolute return-oriented strategies. He previously served as an account manager with institutional client servicing responsibility and as the product manager for the Total Return and Unconstrained Bond strategies. Prior to joining PIMCO in 2005, Mr. Korinke was with The Concord Group, a real estate investment advisory firm. He has 17 years of investment experience and holds an MBA from the Marshall School of Business at the University of Southern California. He received an undergraduate degree from Harvard University.\nDieter Turowski and Laura Howard\nDieter Turowski is co-head of the Asia Pacific investment banking division and member of Asia Pacific Executive Committee of Morgan Stanley since early 2013, based in Hong Kong. Prior to his current role, Dieter was co-head of the global natural resources group within investment banking division, which includes energy, metals & mining, chemicals, cement and forest products. For most of his career, Dieter was in the merger and acquisitions department, including a period as head of European mergers and acquisitions, based in London. Dieter joined Morgan Stanley in 1988 and has worked in Toronto, New York, London, Frankfurt and Hong Kong. Dieter graduated from the University of Waterloo with a B.A.Sc. in Systems Design Engineering and has an M.B.A. from Harvard University where he was both a Baker Scholar and a Loeb Fellow. Dieter is a Canadian and British citizen. He and his wife, Laura Howard, live in Hong Kong and have two children.\nLaura Howard is a senior advisor within the Asia Pacific investment banking division at Morgan Stanley. Prior to this she was the co-head of the European healthcare group at Morgan Stanley based in London where she worked from 1997 to 2013. Laura also worked in the mergers & acquisitions department at Goldman Sachs in New York from 1990 to 1992 and The MAC Group / Gemini Consulting in both New York and London from 1992 to 1997. Laura received her bachelor's degree magna cum laude in economics from Haverford College where she currently serves on the International Council. Laura is also a member of the Board of Chelsea & Westminster Healthcare Trust. Laura lives in Hong Kong with her husband Dieter Turowski and twin boys.\nBassam Aflak and Rita Azar\nBassam and Rita were raised in Sydney by migrant parents who believe in the value of education, faith and giving.\nBassam Aflak is founder and director of Ecove Group, a boutique property development firm, specialising in large-scale, mixed-use developments across various property classes.\nRita Azar went from university to the corporate world to work for a cutting-edge online training company. Since then she became an active presence in her son's school being recruited as the parent advisor for the school's mental health program, has been part of staff recruitment panels, has mentored students in the area of literacy and volunteers in social justice initiatives.\nMike and Annie Cannon-Brookes\nMike Cannon-Brookes is the co-founder and co-chief executive officer of Atlassian, an award-winning enterprise software company. Sydney-based Atlassian currently has over 20,000 customers globally, including industry-leaders such as Microsoft, Facebook, Cisco, Oracle, Proctor & Gamble, Exxon, BMW and NASA. Mike has received international recognition for his work, and was named \"Australian IT Professional of the Year\" in 2004 and \"Australian Entrepreneur of the Year\" in 2006. He was honored by the World Economic Forum as a Young Global Leader in 2009 and is currently a member of The Forum of Young Global Leaders.\nBrett and Zahra Godfrey\nBrett Godfrey is a non-executive director on the boards of WestJet, Green Cross Australia, Auckland Airport and Tourism Australia. In 2010, Brett stepped down from the position of chief executive officer for Australia's second largest air carrier, Virgin Blue Airlines Group, a position he had held since launching the company in August 2000. Prior to establishing Virgin Blue, Brett worked for 12 years in aviation and finance, which included appointments as chief financial officer of Virgin Express in Brussels and finance positions for London-based Virgin Atlantic. Brett has been awarded the Centenary Medal for his service to Tourism and Aviation, was recognized as the \"Australian Chief Executive of the Year\" by the Institute Of Customer Service and an \"Outstanding Chartered Accountant in Business\" by the Institute of Chartered Accountants.\nZahra Godfrey was raised in Calgary and earned her degree in law from Queen's University in Ontario. She was admitted to the Bar in 1988 and worked for the Ontario Human Rights Commission before moving to Australia with her husband, Brett. She has worked with a number of charities in addition to raising the couple's two sons.\nCharles and Alison Gorman\nCharles and Alison Gorman live in Sydney with their two teenage sons Samuel and Will. Charles Gorman is the head of the Financial Markets Business at Investec Australia, having joined the firm in late 2013. He has spent the last 20 years in various senior Banking roles. Charles was previously Managing Director and Co-Head of FICC Sales at Goldman Sachs Australia, where he had primary responsibility for the Foreign Exchange, Futures and Institutional Rates business. Prior to joining GS in 2003 he was Head of Foreign Exchange Sales for Credit Suisse in Australia. He began his career at the Australian Wheat Board in Melbourne.\nAlison Gorman teaches creative writing to primary and secondary students at the Kuringai Arts centre and volunteers at the Sydney story factory. She completed a masters of creative writing at the University of Sydney and her poetry has been published in a number of Australian literary journals. Alison completed her bachelor's degree in Speech Pathology at La Trobe university in Melbourne and worked in brain injury rehabilitation for 12 years.\nJason Karas and Anna Baillie-Karas\nJason Karas is the co-founder and global leader of Lipman Karas, an international law firm specialising in financial dispute resolution, based in Hong Kong, Australia and London. In more than 25 years working as a lawyer, Jason has led some of the most significant corporate litigation and cross-border fraud investigation projects in the Asia Pacific region and internationally. Jason has also been at the forefront of the development of the international litigation financing industry over the last 20 years. He is a recognised industry speaker including in the areas of litigation finance, multijurisdictional disputes and cross-border investigations. Jason graduated from the University of Adelaide with a bachelor's degree in Economics and an honours degree in Law. He was appointed one of the first Solicitor Advocates in Hong Kong in 2013. Jason splits his professional time principally between Hong Kong, London and Australia and is a keen amateur tennis player and competitive runner.\nAnna Baillie-Karas is the founder and co-host of the \"Books On The Go\" podcast. Formerly a commercial litigation lawyer, Anna has also worked as a secondary school teacher specialising in economics, law and English. She holds Bachelor's degrees in Economics, Law and Teaching from the University of Adelaide and a Certificate in Teaching English to Speakers of Other Languages from Cambridge University. Anna currently serves on the Chairman's Circle Committee for the Adelaide Festival of Arts. She lives with her husband Jason and their children Zoe and George in Adelaide, with part of their time spent in Hong Kong and London.\nDavid Torrible and Donna Yip\nDavid Torrible and Donna Yip are currently living in Sydney, Australia with their four young boys. David relocated to Sydney in 2012 following a 19 year career in Asian investment banking. He has lived in Hong Kong, Indonesia and New York, but always followed Asian Equity markets. He is a retired partner of Goldman Sachs and was responsible for their Asian Equity sales team up until his departure from Hong Kong in 2012. David is a citizen of Canada, the UK, and Hong Kong. He graduated from Queen's university with a BA (Hons) in History in 1993. David is currently a member of the Janchor Partners Management Board.\nDonna is Australian and a chartered accountant by background, but has held jobs in marketing, adventure travel and media. She graduated from Sydney University in 1992 with a Bachelor of Economics. She is currently studying to design and build furniture.\nSusan Breyer\nSusan Z. Breyer is a Woodside, California painter of abstract and impressionist landscapes. In her work, she endeavors to reflect her reverence for the mystery, power and vulnerability of nature. Susan is a graduate of Stanford University and subsequently worked in strategy and marketing for the advertising agencies Benton & Bowles in New York, HBM/Creamer in Boston and Hal Riney in San Francisco. After graduating from Harvard Business School, Susan served as Director of Marketing for First Republic Bank. In moving from the corporate world to art, Susan studied for seven years with Bay Area master painter and former SF Academy of Art teacher, Ning Hou. Susan has worked to increase her community's awareness of and investment in Room to Read since 2012. She currently serves on the Leadership Council of NARAL Pro-Choice America and in the Leadership Circle of WANDA (Women's Advancement Network and Development Alliance,) of Silicon Valley.\nErin and Jitendra Ganju\nErin Ganju is currently the Managing Director of Echidna Giving, a private funder that will grant over $500 million over the next 40 years to advancing girls' education in countries with limited resources. She is a Co-founder, former CEO, and former COO of Room to Read. From the early start-up days, Erin was instrumental in the design and implementation of the organization's scalable, replicable model for improving the quality of education around the world. In 2009, Erin became Chief Executive Officer of Room to Read. As CEO, Erin oversaw Room to Read's global operations across 15 countries; a technical assistance unit called Room to Read Accelerator; fundraising teams in North America, Europe, Australia and the Asia Pacific region; and a worldwide staff of more than 1,500 employees. Erin captured her experiences and insights as co-author of Scaling Global change: A Social Entrepreneur's Guide to Surviving the Start-up Phase and Driving Impact. Erin has been selected as one of the World Economic Forum's Schwab Foundation Social Entrepreneurs for 2014 and in 2012 was one of Fast Company's Extraordinary Women. Before founding Room to Read, Erin worked at Unilever, Goldman, Sachs & Co. and a couple of technology start-ups. She has spent extensive time working and living in Asia, where she saw firsthand the need to enhance developing countries' educational systems. Erin holds a combined bachelor's and master's degree in international relations and economics from The Johns Hopkins University in Washington, D.C.\nJitendra (Jeetu) Ganju, Ph.D. is a clinical trials consultant trained in statistics with over 20 years experience in the pharmaceuticals and biotech industry. His prior employment includes tenures as the VP of Biometrics at Global Blood Therapeutics and Hyperion Therapeutics and Senior Director at Gilead Sciences. Therapeutic areas include hematology, diabetes, pulmonology, cardiovascular, inflammation, vaccines. Areas of interest include speeding up Phase 1-3 development, statistics representative at FDA / EMA meetings, collaborations on regulatory documents, clinical development plans with attention to mitigating risk, endpoint selection, competitive analysis. Jeetu has been published in peer-reviewed journals on non-inferiority trials, improving operational efficiency, methods to increase power.\nAngel Mehta\nAngel Mehta is an early stage investor in technology companies with a particular interest in artificial intelligence, enterprise software, bio-hacking/longevity, blockchain, and meat-alternative food companies. He also serves as an advisor to entrepreneurs, coaching them on human capital/recruitment, automation, and outsourcing.\nBetween 1998 and 2018, Angel served as Chief Executive Officer of Sterling-Hoffman Management Consultants, a global executive-search firm with over 300 employees worldwide and offices in 5 countries.\nAngel is an active member of several CEO mastermind groups, including Young President's Organization (YPO), and Tiger 21. His philanthropic interests are focused on girl's education, human trafficking, fact-based journalism, and animal rights. Mr. Mehta Holds a BA degree from York University in Toronto.\nIn his spare time, Angel enjoys weight lifting, ice hockey, and learning magic.\nHe can be reached on Twitter: @angelmehta99\nMythili Sankaran and Shekar Ayyar\nMythili is the Principal at Stratalens. She previously served as Director of West Coast Operations at U.S.-India Business Council (USIBC). Mythili joined USIBC from the business world of the Silicon Valley. She has a wealth of experience in IT and venture capital. Earlier, she served as Chief Executive Officer of a Telecom/Web startup, Koollage. Prior to this, she was an Executive at the American India Foundation. She has degrees in physics and electrical engineering and an executive management certificate offered jointly by AT&T and the Wharton School of Business.\nShekar Ayyar joined VMware in June 2007 and serves as the company's strategy and corporate development efforts as well as general manager of VMware's Telco Network Functions Virtualization (NFV) group, which is designed to help communications service providers accelerate innovation and launch new services faster, easier and with less expense through virtualization of telecommunications core networks and network functions. In his Strategy and Corporate Development role, Shekar is responsible for aligning strategy and long-term planning across VMware businesses as well as managing the company's mergers and acquisitions, and strategic investments. Under his leadership the company has executed on several acquisitions including Nicira and Airwatch.\nShekar brings more than 15 years of senior leadership experience in enterprise software, communications and semiconductors. Prior to joining VMware, Shekar held senior roles at BindView, Instantis and Lucent, spanning product management, marketing, and business development, and was also a consultant with McKinsey. Ayyar earned his Ph.D. in electrical engineering from the Johns Hopkins University and MBA from the Wharton School where he graduated as a Palmer Scholar. He earned his bachelor's degree in electrical engineering from the Indian Institute of Technology, Mumbai. Ayyar serves on the Board of the VMware Foundation.\nHilary Valentine\nFrank and Leslie van Veenendaal\nMr. Frank van Veenendaal retired from Salesforce in 2015 after almost 14 years with the company in multiple leadership roles including Vice Chairman, President of Worldwide Sales and Services, President of Worldwide Sales and Chief Sales Officer, President of North American Operations and Global Corporate Sales, President of Worldwide Corporate Sales and Services and Senior Vice President of North America Sales at Salesforce.com. He was instrumental in growing Salesforce from $5M to $5B+. Mr. van Veenendaal has over 30 years of technology sales and executive management experience. Previously Mr. van Veenendaal held various sales and sales management positions for companies such as Actuate, Interleaf, Integrated Solutions, Pyramid, and Harris Corporation. Mr. van Veenendaal also serves on the board of directors of Coupa, NewVoiceMedia and Vlocity. Leslie van Veenendaal was a Certified Travel Consultant for 20 years.\nGaurav Dalmia\nGaurav Dalmia is the Chairman of Dalmia Group Holdings, a holding company for business and financial assets. It invests in private equity, real estate, public markets, structured debt and fixed income.\nHe is an early investor in and a Board member of True North (formerly India Value Fund), a leading Indian private equity fund, which manages approximately $3.5billion. He is also the founder and Chairman of Landmark Holdings, a real estate investment firm, which has invested in more than 40 housing projects. He co founded GTI, a long term investment vehicle for India focused investments.\nHe is a Board member of Brookings India. He was selected as a Global Leader for Tomorrow by the World Economic Forum in 2000. Gaurav Dalmia received an MBA with Beta Gamma Sigma honors from Columbia Business School.\nMickey Doshi\nMihir J. (\"Mickey\") Doshi is Managing Director and Country CEO of Credit Suisse, India. He joined Credit Suisse in April 2006 and is based in Mumbai. He is a member of the Asia Pacific Management Committee and the Emerging Markets Council.\nMickey has been instrumental in establishing Credit Suisse's India franchise, which today is active across Private Banking, and Investment Banking. He has been deeply involved in strengthening the overall business profile of the Bank in India and in providing its strategic direction. Under his leadership, Credit Suisse has been awarded a banking license by the Reserve Bank of India and established a bank branch in Mumbai in 2011.\nMickey is involved in Credit Suisse's human capital and corporate responsibility initiatives and is a member of the Asia Pacific Philanthropy Committee. He also serves on the Board of United Way, Mumbai, Board of JSW Foundation, and the Board of Asia Society. In addition, he is a Trustee of Save The Children India and a member of the UN Women's Business Sector Advisory Council.\nBefore joining Credit Suisse, Mickey spent 22 years at Morgan Stanley in various capacities, primarily in New York, Tokyo and Mumbai. His last position was Managing Director and CEO of JM Morgan Stanley Securities Pvt. Ltd. and he is credited with building Morgan Stanley's presence in India.\nMickey holds a Bachelor of Science (Honors) from New York University and a C. P. A. from New York State, which he gained while working with Deloitte Haskins and Sells, New York.\nKhozem Merchant\nKhozem has more than three decades' experience in the media and business sectors as a journalist with the Financial Times and management with Pearson. He launched and leads Brunswick's India practice, specialising in Indian macro and public affairs. Most recently, Khozem served as President, Pearson India and was instrumental in shaping and rolling out Pearson's education services strategy across the country. Prior to this, he was for two decades a journalist with the Financial Times, including six years as the FT's Mumbai correspondent, before taking on a management role as director of businesses development.\nNandini Piramal\nNandini Piramal is Executive Director of Piramal Enterprises Limited, leading the Over-The-Counter (OTC) business of the company. She heads the Human Resources function at Piramal Group and the Quality & Risk functions at Piramal Enterprises.\nUnder Nandini's leadership, the OTC business is one of the fastest growing Indian OTC companies and all its brands are either No.1 or No.2 in their respective categories. She is leading a five-year transformation agenda across the Piramal Group for top talent identification and development process across levels. She has been instrumental in setting up the Risk Function with Jaideep Sen (Chief Risk Officer).\nIn 2014, World Economic Forum recognised Nandini as a 'Young Global Leader.'\nNandini is passionately involved with Piramal Foundation (the philanthropic arm of the Piramal Group), Piramal Foundation Education Leadership programs, Piramal Sarvajal and Piramal Swasthya. She graduated with BA (Hons) Politics, Philosophy, and Economics from Oxford University, followed by an MBA from Stanford Graduate School of Business.\nRavi C. and Sumati Raheja\nAn Entrepreneur, and an MBA from the London Business School, Ravi has almost 25 years of experience across real estate, retail and hospitality. He plays a key role in guiding the teams of finance, corporate strategy and planning for the retail and hospitality divisions of the Company.\nRavi has been involved in growing the business from a family owned business into a professionally managed one. A respected name in Indian corporate community, Ravi has been a supporter of the green building cause in the country, as an active contributor to premier forums such as Indian Green Building Council, where he served as the Chairman (Mumbai chapter), the WEF (World Economic Forum) and FICCI (Federation of Indian Chamber of Commerce & Industry).\nRavi plays a key role in the group's philanthropic initiatives through K. Raheja Foundation, Sadhana Education Society and S. L. Raheja Hospital. He actively supports various educational initiatives with a focus on the girl child and empowering marginalized children with better future through quality education.\nSumati was a student of the Roedean School in Brighton, England and went on to pursue her LLB at King's College, London.\nShe currently serves on the board of her family's company and actively manages investments. She is a firm believer in education and also a strong supporter of Emancipaction, an organization which helps rehabilitate child sex workers.\nJitu Virwani\nJitu Virwani is the Chairman & Managing Director of Embassy Group, India's leading property developer. Over the last three decades, Embassy together with its promoters has developed over 55 million sq ft. of commercial, residential, industrial & warehousing, retail, education and hospitality spaces in India and overseas. Being at the helm of affairs since 1993, Jitu has led Embassy Group through the most challenging and exciting periods in the history of the real estate industry. He has not only spread the company's operations across Bangalore, Chennai, Hyderabad, Pune and Coimbatore, but also spearheaded its international operations at Serbia in Eastern Europe and completed projects in Malaysia.\nJitu's Future First Vision and his diversified interest has set trends and given rise to many successful enterprises. With several contributions to social causes, Jitu is committed to improving the standards of education and employment. In 2008, Jitu founded the Stonehill International school which is the only Institution in South India to offer three International Baccalaureate programs, with a faculty and students from over 35 nationalities and world class infrastructure.\nJitu is a member of the Young Presidents Organization and a member of the Equestrian Federation of India. He is a dedicated equestrian and owns and maintains a state of the art International Riding Academy in Bangalore. Embassy International Riding School has produced exemplary riders that have made the Indian equestrian fraternity proud at the Asian Games and other International events across the world.\nBen and Asami Ferguson\nBen is co-head of Asia Pacific Equities Distribution. Ben joined Goldman Sachs in 1998 as a financial analyst in Tokyo. He was named managing director in 2005 and partner in 2008. He earned a BS in Finance and a BA in Economics from Pepperdine University in 1998 and graduated from Sophia University's Japanese Language Institute in 1995.\nAsami started her career as a model for global brands like Adidas and Uniqlo while attending Senzoku University. She spent 6 years with Miss Universe Japan (MUJ) to recruit, develop and manage finalists in addition to working in public relations and event planning. After leaving MUJ, Asami worked with a number of brands including Red Bull's F1 team in public relations and event planning in Japan. Later she worked with Valentino as a brand consultant. Asami has leveraged her event planning background to work with charities like the Pink Ball/Run for the Cure in Tokyo and Special Olympics Japan. Asami loves sport and is an avid tennis player, wake-boarder, swimmer and snowboarder.\nEric and Ayako Golden\nEric Golden is a Managing Director of Fortress Investment Group Japan focused on real estate private equity in Japan and Asia. Prior to joining Fortress in 2008, Mr. Golden worked at Credit Suisse / Donaldson, Lufkin, & Jenrette for nine years investing in real estate in the US, Japan, and China. Eric graduated from Brown University in 1999 with a B.A. in Mathematical Economics. Ayako Golden owns and runs Beaute Absolue in Tokyo and previously worked at Animal Refugee Kansai. Ayako graduated from Mejiro University. Ayako is also very involved in her children's school programs and taking care of Eric's and Ayako's son and daughter.\nTomoya and Yuri Masanao\nYuri Masanao received an MA in linguistics from University of London (SOAS) and has worked as an interpreter for executives around the world. Inspired by an international social entrepreneur who she helped as an interpreter, Yuri decided to devote herself to humanitarian aid activities which she had been dreaming about since her school days in The International School of Kuala Lumpur in Malaysia. She is engaged with philanthropic activities of the Italian Royal House of Savoy and is bestowed a Dame from the order of Saints Maurice and Lazarus. Yuri also holds a BA majored in comparative culture from Sophia University and was associated with Nomura Securities. She currently lives in Tokyo and Southern California. She plays Jazz piano and performs with her band.\nTomoya Masanao is a managing director in the Tokyo office and co-head of Asia-Pacific portfolio management of PIMCO. He co-oversees the portfolio management teams in the region and manages clients' assets. He is also a core member of the PIMCO's Asia-Pacific Portfolio Committee. His interests in philanthropic activities grew as he traveled in the emerging Asia. Prior to joining PIMCO in 2001 in the Newport Beach office in California, Tomoya was an executive director and senior portfolio manager at Goldman Sachs Asset Management in London. He was also with The Sumitomo Bank in Osaka, Tokyo and London. He holds an MBA from Boston University, and a master's degree and an undergraduate degree, both in engineering, from Osaka University.\nTheo and Susan Seltzer\nTheo and Susan Seltzer have called Tokyo home for the last 17 years. Theo is a partner at Morrison & Foerster LLP, where his practice focuses on real estate and finance, including the representation of U.S., Japanese, and other global institutional investors in the acquisition, financing and disposition of real estate, including cross-border equity and debt financing, fund formations, distressed loan portfolios, joint ventures and development projects. Theo and Susan have been supporters Room to Read in various capacities from the early days of Room to Read Japan, such as, working with the Morrison & Foerster team in the establishment of Room to Read's legal entity in Japan, and assisting with fundraising and its annual galas. Theo and Susan have two sons who attend the American School in Japan, where Susan serves on the Parent Teacher Association and Board of Trustees. Theo has a B.A. from Columbia College, and J.D. and LL.M. from the Georgetown University Law Center. Susan has a B.A. in journalism and has written for various publications in New York.\nFred Towfigh\nFred Towfigh is an advisory director to the Goldman Sachs Group, a retired partner and former president of Goldman Sachs (Singapore) Pte. Fred joined Goldman Sachs in 1995 holding various roles in Hong Kong, Tokyo and Singapore. Fred headed the Asia Pacific Prime Brokerage, Futures and Electronic Trading businesses before assuming responsibility for firm's Equities and FICC franchise in Southeast Asia until his retirement in 2017. Fred earned a BA from the University of California, Irvine and an MBA from Georgetown University.\nSamantha Barry\nSamantha Barry is the editor-in-chief of Glamour. She oversees content development, production and consumer experiences for Glamour's digital, social, video and print platforms.\nShe joins Glamour from CNN Worldwide, where she served as executive producer for social and emerging media. Under Barry's leadership at CNN, the network became the most followed and fanned news organization in the world. She led her team and the organization at large with compelling work for social audiences on an array of platforms including Facebook, Snapchat, Twitter, Instagram, Line, Kik and other emerging media. While at CNN, Barry spearheaded CNN's 2016 Election coverage across social platforms, which received the first ever Edward R. Murrow Award for excellence in social media and a Webby Award recognizing the same 2016 campaign work.\nBarry joined CNN from BBC World News in London, where she served as a social media producer and journalist, focusing on using social media as a tool for both news gathering and audience building.\nPreviously, Barry worked as reporter and producer for RTE and Newstalk in Ireland. She spent time in Papua New Guinea with the Australian Broadcasting Corporation (ABC) and has worked as a social media and technology trainer for the U.S. State Department, the United States Institute of Peace and Internews.\nBorn in Ireland, Barry has worked in more than 25 countries, reporting and training other journalists in broadcasting, technology and social media. Barry graduated from Dublin City University with a Masters in Journalism. She is a 2016 fellow of Columbia University School's Sulzberger executive program and is a guest lecturer at Yale.\nRichard and Sabine Chalmers\nRichard is a citizen of the US and UK and Sabine is a citizen of the US with German and Indian origin. They have been married for 25 years and have one 18-year-old daughter, Natasha. They have lived in London, Miami, Stamford, Brussels, and New York and believe strongly in the power of education to transform lives, which was their main inspiration for becoming friends of Room to Read.\nRichard received a degree in Business Studies from the University of Edinburgh before training to become a lawyer with Berwin Leighton in London. He practiced family and litigation law in England, Florida and Connecticut before dedicating himself wholly to raising Natasha and volunteering for various causes. He has served on parents' associations at Natasha's schools in Brussels and New York, coached rugby at the International School of Brussels for three years, and served as President of the United Nations International School Athletics Association. Richard also chairs the board of the apartment building where the family lives in New York. On a personal level, he enjoys sports, travel and photography.\nSabine was recently appointed General Counsel of BT Group Plc. Prior to this appointment, she served as Chief Legal & Corporate Affairs Officer and Secretary to the Board of Directors of Anheuser-Busch InBev, one of the world's top five consumer products companies and the leading global brewer. In addition to her more than a decade at Anheuser-Busch InBev, she served in a number of leadership positions, including General Counsel of the Latin American and U.S. Businesses at Diageo plc, the world's largest producer of spirits. Sabine also worked in private practice at the law firm of Lovell White Durrant and was a lecturer at University College, London. She holds a law degree from the London School of Economics and is qualified to practice in England and New York State. She also serves on the boards of the Royal National Theatre London and Coty, Inc., one of the world's largest consumer beauty companies.\nRichard and Sabine are members of both Room to Read's New York and UK Regional Development Boards.\nSara Eisen and Matthew Levine\nSara Eisen joined CNBC in December 2013 as a correspondent focusing on the global consumer. She is co-anchor of the 10AM ET hour of CNBC's \"Squawk on the Street\" (M-F, 9AM-11AM ET), broadcast from Post 9 at the New York Stock Exchange. In January 2016, Eisen was named co-anchor of CNBC's \"Worldwide Exchange\" (M-F, 5AM-6AM ET), which broadcasts from CNBC Global Headquarters in Englewood Cliffs, N.J. Previously, Eisen was co-anchor of \"Bloomberg Surveillance\" as well as a correspondent for Bloomberg Television, where she covered global macroeconomics, policy and business. During that time, she covered the European debt crisis, the tsunami aftermath and Fukushima nuclear crisis in Japan. Prior to Bloomberg Television, she hosted the Bloomberg Radio program, \"On the Economy.\" She is the editor of \"Currencies After the Crash: The Uncertain Future of the Global Paper-Based Currency System\" published by McGraw-Hill in Jan. 2013. Eisen holds a master's degree in broadcast journalism with a concentration in business reporting from the Medill School of Journalism at Northwestern University.\nMatthew Levine is the Head of U.S. Programming at Bloomberg Television, where he directs the network's editorial priorities. He has led numerous coverage initiatives, including Bloomberg's 2016 election night coverage, and acted as executive producer on a variety of special programs and documentaries. Previously, he served as Bloomberg Television's U.S.-based managing editor among other roles.\nBefore Bloomberg, Levine was senior editor at CNBC in Englewood Cliffs, NJ. During that time, he was nominated for a News & Documentary Emmy Award for producing \"Investing in America,\" a town hall with President Barack Obama. He was also acknowledged with a Scripps Howard National Journalism Award for the network's coverage of General Motors' public stock offering.\nLevine graduated cum laude from the University of Pennsylvania, where he majored in economics and political science. He holds a master's degree in international relations from the University of Sussex.\nCaryn Freiberger\nCaryn Freiberger is a Director on Citi's FX Sales Desk within Citi Global Markets. Caryn specializes in FX derivative solutions, developing relationships with the firm's largest institutional clients. In 2013 Caryn launched 'Citi's e for education' a groundbreaking corporate social responsibility program linked to volumes executed on Citi's electronic trading platform. Over the last 3 years the initiative has donated over $12MM to global education non-profits. Outside of Room to Read, Caryn serves on the NY Junior Board of EMpower. Caryn holds a BA in Economics from Brown University.\nPeter T. Grauer is chairman of Bloomberg L.P., the global financial media company. He has been a member of the Bloomberg board since October 1996 and was named chairman of the board in March 2001, succeeding Michael R. Bloomberg. Peter joined Bloomberg full time in his executive capacities in March 2002. Prior to this, he was a managing director of Donaldson, Lufkin & Jenrette from 1992 to 2000, when the company was acquired by Credit Suisse First Boston, and then managing director and senior partner of Credit Suisse First Boston Private Equity until March 2002. Peter serves as lead director of Davita, Inc., as well as on the boards of the University of North Carolina at Chapel Hill, the Inner City Scholarship Fund in New York City, Rockefeller University and the Prostate Cancer Foundation. He is a graduate of the University of North Carolina and the Harvard University Graduate School of Business.\nSonny Kalsi\nSonny Kalsi is a Founder of GreenOak Real Estate, an independent, partner-owned real estate principal investing and advisory firm. Formed in 2010, GreenOak Real Estate is a highly focused global platform with an experienced and cohesive senior team that possesses a long and successful track record. The firm has offices in New York, Los Angeles, London, Madrid, Tokyo and Seoul. Sonny was previously the Global Co-Head of Morgan Stanley's Real Estate Investing business and President of the MSREF funds until early 2009. At its peak, that platform had approximately $100 billion of AUM in 33 countries. Sonny was recently named by PERE as one of the 100 most influential people in private real estate from the past decade. He is a graduate of Georgetown University with a degree in Business Administration and has been a member of the Georgetown's Board of Regents. He also serves on the board of several organizations including: The Spence School, Teaching Matters, The Starfish Foundation, Room to Read and the Asia Society. Sonny is married and resides in New York City with his wife and two children.\nJaideep Khanna\nMr. Khanna is the President and co-founder of Artha Capital. He has successfully managed multibillion-dollar institutional portfolios for over 23 years at Artha Capital and Morgan Stanley. Mr. Khanna generously funds and supports several businesses and organizations in the US and India that are dedicated to educational initiatives focused on the underprivileged, the environment, and other socially responsible causes. He serves as an active board member for Pratham USA, Ashoka University India, and the Center for the Advanced Studies of India (CASI) at the University of Pennsylvania. Mr. Khanna received his MBA from the Fuqua School of Business at Duke University and a BA from Muskingum College.​\nArt Mbanefo\nArt Mbanefo is Head of Financial Resource Management for Barclays International. He is a member of the Barclays International Executive Committee and the Barclays International Risk Committee. During his time with Barclays, Art has held a number of other leadership roles in the Markets business, including Head of Markets in the Americas, Chief Operating Officer, Interim Head of Equities and Credit Products and Head of Structured and Financing Products. He also held the position of Head of Markets for EMEAPAC between July 2016 and June 2017, relocating to London. Art joined Barclays in 2009 from the buy-side where he served as Chief Investment Officer and Chief Executive Officer at two alternative investment firms, managing capital allocation and risk across multi-product and multi-entity balance sheets. Previously, Art served in a number of leadership roles at Credit Suisse after starting his banking career as a derivatives trader at JP Morgan. Art is also a member of the Provost's Board of Villanova University in Pennsylvania, USA.\nMarc Seidner\nMarc Seidner, CFA, is CIO, nontraditional strategies, a managing director, and head of portfolio management in the New York office of PIMCO. He is also a generalist portfolio manager and a member of the Investment Committee. He rejoined PIMCO in November 2014 after serving as head of fixed income at GMO LLC, and previously he was a PIMCO managing director, generalist portfolio manager, and a member of the Investment Committee until January 2014. Prior to joining PIMCO in 2009, he was a managing director and domestic fixed income portfolio manager at Harvard Management Company. Previously, Marc was director of active core strategies at Standish Mellon Asset Management and a senior portfolio manager at Fidelity Management and Research. He serves on several boards, including the Boston College Board of Regents and the Trustees of Donations to the Protestant Episcopal Church in addition to the Room to Read, New York, Regional Development Board. Marc has 30 years of investment experience and holds an undergraduate degree in economics from Boston College.\nJürgen Bauer\nJürgen is an Entrepreneur who brings with him more than 25 years of management consultant and business leadership experience, largely with multinational life science corporations on business transformation programs. Having spent 13 years as a partner at consulting firms PricewaterhouseCoopers and IBM, he co-founded in 2005 and built Lodestone Management Consultants, an international consulting firm in 18 countries. After selling Lodestone to Infosys in 2012, he acted as Managing Partner of Infosys Lodestone and CEO of Infosys Consulting until 2016. Since leaving Infosys Consulting, Jürgen has joined the board of directors of a number of healthcare and IT growth companies. In 2017, he founded and now chairs Tenthpin Management Consultants, a global management consulting firm with deep expertise in the life sciences sector and is a Co-Founder of Turos Capital AG in Zürich. He received a master's degree in Engineering and Management from the Munich University of Applied Sciences.\nJürgen and his wife Henriette live in Zürich and have 2 teenage daughters. The family are passionate skiers, love sports, traveling and reading.\nPatricia Horgan\nPatricia became an avid and engaged supporter of Room to Read in 2011 and in 2016 became Chairperson of the Development Board Switzerland. During her 38-year banking career Patricia headed large business units for major financial institutions, including Credit Suisse, UBS, and Deutsche Bank. After retiring from Credit Suisse at the end of 2016 Patricia has concentrated on supporting Room to Read as well as serving on the advisory boards of two other non-profit institutions. In 2018 Patricia joined the board of Goldman Sachs Bank AG as a non-executive director. A native of New Jersey, she holds both US and Swiss citizenship and has lived in Zurich for more than 30 years.\nIqbal Khan\nIqbal has been a very engaged supporter of Room to Read since 2015 and provides strong encouragement to increase the reach of Room to Read. Iqbal is a member of the Executive Board of Credit Suisse Group AG and the Chief Executive Officer of International Wealth Management, which comprises the businesses in EMEA and Latin America as well as global Asset Management. Iqbal was the Chief Financial Officer of Private Banking & Wealth Management from 2013 to 2015. Prior to joining Credit Suisse in June 2013, he was the Managing Partner of Assurance Financial Services Switzerland and a member of the Swiss Management Committee of Ernst & Young. He holds an Advanced Master of International Business Law (LLM) degree from the University of Zurich and is a Swiss Certified Trustee, Certified Accountant and Certified Financial Analyst. Iqbal, his wife and their two children live near Zurich. The family is passionate about children's education and creating equal opportunity. In their free time they enjoy the outdoors.\nSarah and Aydin Kurt-Elli\nBorn and raised in the UK, Sarah carried out her medical training in Edinburgh. She went on to work as a General Practitioner in the rural Scottish Borders in addition to her latter role as a GP Appraiser. She served as Chair of the Parent Council at the local primary school for several years. Sarah moved to Switzerland at the beginning of 2014 with her husband and three children. She has a keen interest in music and reading as well as a love of the great outdoors.\nHaving originally trained as a medical doctor in Edinburgh, Aydin's career took a turn towards technology when he founded his first Internet services business during university. This grew organically until acquisition by European PE fund Bridgepoint which resulted in an accelerated buy and build journey in the UK Internet and Datacentres market. Aydin has experience on a number of startup, midmarket and charitable boards across Europe, Middle East and the US.\nWhen time permits, Aydin is an early music fanatic, an avid skier, and loves flying both Flexwing microlights and fixed wing aero planes. Bookish by nature, supporting Room to Read is a natural fit for his owlish passions.\nMaria Vigil and Marco Pagliara\nMarco is an Italian national currently serving as General Manager for Goldman Sachs AG in Switzerland. He holds a degree in Economics from Bocconi University and an MBA from Columbia University. Maria is of dual American and Nicaraguan nationalities. She holds a BBA from the University of Texas at Austin and an MBA from Columbia University. They have lived in Zürich for seven years and are eager to share their passion and commitment to children's literacy with Room to Read.\nLaura and Robert Schmoll\nLaura and Rob are Swiss and US nationals who have lived in the Geneva area for thirty-five years. Rob worked for Citigroup for twenty-eight years, splitting his time between Zurich and Geneva. Before leaving in 2018, Rob was Citi's Head of Institutional Markets and Securities Services for Switzerland. Laura brings a valuable track record of involvement in various fundraising events in the Geneva area. Both are graduates of Bowdoin College, with Laura holding a BS degree in Economics and Rob holding a dual BS degree in Economics and French Literature. They have three sons living in the US and UK. The family are avid outdoor sports enthusiasts.\nTina Wüstemann\nTina advises Swiss and foreign private clients, family offices and executives regarding complex estate, succession and wealth planning matters as well as concerning the administration of international estates. She further represents private clients in contentious estate and trust disputes, advises charitable foundations and is active as board member of several charities. She publishes frequently and lectures regularly in Switzerland and abroad.\nTina graduated at the University in Zurich (1990 lic. iur.) and New York (1998 LL.M.). She is admitted to the Zurich Bar since 1994 and passed the New York Bar Exam in 1998. Since 2004 she is partner at Bär & Karrer and heads the private client team.\nTina is married with two children and lives in Zurich. Her family is very sportive, loves traveling and enjoys spending time with the wider family and friends.\nMarisa Drew\nMarisa is a direct report of Credit Suisse's Group CEO and is responsible for setting the strategy, directing, coordinating and facilitating activities across the bank in the field of Sustainable Finance and Impact Investing on behalf of the bank's private wealth, institutional and corporate clients. Prior to this role, from 2013 to 2017, she was the Co-Head of the EMEA Investment Banking and Capital Markets Division. A seasoned investment banker of over 30 years, Marisa joined Credit Suisse in 2003 and has held various other management roles at the bank, including Global Head of Global Market Solutions and Head of European Leveraged Finance Origination. At Credit Suisse, Marisa sits on the UK Conduct and Ethics Board, the Global Reputational Risk Committee and she is a Trustee of the CS Foundation. Prior to joining Credit Suisse, Marisa worked for Merrill Lynch for eleven years in Leveraged Finance and she spent time in the Private Equity industry. Marisa holds Advisory Board roles for The Wharton School and Lessons for Life Foundation. She is also a member of the Women's Leadership Board at Harvard, a member of the FCA's Markets Practitioner Panel and of several High Level Working Groups sponsored by the World Economic Forum.\nMarisa received a BA in Finance and Marketing with distinction from the University of Virginia's McIntire School of Commerce in 1986 and an MBA with distinction from the Wharton School in 1992.\nElio and Maria Leoni-Sceti\nElio is Italian and Maria is American and they have been married for 25 years, moved internationally 7 times and have 4 children - aged 13 to 24 – each born in a different country. They are firm believers in the power of education, and are friends of Room to Read from its early days.\nElio is the former CEO of Iglo Group (2013-2015) and previously of EMI (2008-2010). He is an independent Board Director at ABInBev and an early stage investor in media & technology. Elio is Chairman of LSG Holdings, an investment, advisory and corporate finance boutique in London and a counsellor at One Young World. He spent his earlier career in Proctor & Gamble and then Reckitt Benckiser, where he served his last roles as Exec Vice President and Global Head of Category & Innovation until 2006 and then as Head of Europe.\nMaria received her BA in Economics from Wake Forest University and her Master in International Management from Thunderbird. She speaks 4 languages and her first job was in Rome with Saatchi and Saatchi. While in Paris, Maria founded Global Access, a language school for corporate management, based on phone-conversation learning. After several years focusing on her family's growth and progress - and actively serving on committees in various schools and charities - Maria recently founded True Gem Properties, a high-end refurbishments and interior design boutique in London.\nBjörn Nilsson\nBjörn Nilsson is a private investor. Björn was previously a senior partner at Triton, a European investment firm, since the firm's inception. Over the 20 years at Triton, Björn held various roles within both private equity and credit investing and he was part of the investment committee of the firm. Prior to Triton, Björn was at Chase Manhattan Bank, both in New York and London, working mainly with leverage finance and high yield origination.\nBjörn is currently the vice chairman of Rederi AB Gotland, a Swedish based maritime transportation company.\nBjörn is also the chairman of Human Rights Watch's Stockholm Committee and a trustee of the Young Nilsson Foundation.\nBjörn was born and grew up in Sweden, went to high school and the Naval Academy in Stockholm, and then moved to New York. He holds a BA in Economics from Columbia University in New York. He currently lives in London with his wife Sandra and children Aliya, David and Alice.\nJohn Ridding\nJohn Ridding is the CEO of the Financial Times Group. He was appointed to the role in 2006, having been with the company for 20 years in both editorial and executive positions. Previously, John served as editor and publisher of the Financial Times Asia and chairman of Pearson in Asia. He led the launch of the Asia edition of the Financial Times in 2003 and led the development of the paper's Chinese-language website. In his Pearson role, John established a series of collaborative ventures between group companies, including a series of business publications, and launched a series of financial journalism training courses. He joined the Financial Times in 1987 and earned a degree in philosophy, politics and economics, with first class honors, from Oxford University.\nStuart and Joanna Riley\nStuart Riley is a founding Partner and Portfolio Manager at Rokos Capital Management, which was launched in September of 2015. Prior to this, he spent 16 years at Goldman Sachs in the Securities Division, most recently as Partner and Co-Head of Asia Macro Trading for the last three years in Hong Kong, where he was also a member of the Asia Pacific Risk Committee. Before moving to Hong Kong, Stuart was a Partner and co-head of European Interest Rates Product Trading in London. Stuart holds an MSc (1st Class Honours) in Physics from Imperial College London. He is also a keen tennis player and has played for both the Queen's Club in London and the LRC in Hong Kong.\nJoanna began her career at Accenture in New York in 1997 and then joined Goldman Sachs, where she worked until 2008. At Goldman Sachs in New York, Joanna worked in the eCommerce business with a focus on marketing the firm's electronic trading platforms. In London, she held both business management and marketing roles within the Securities division. Joanna received an A.B. in History from Princeton University, where she was also a member of the Women's Rowing team.\nJoanna and Stuart recently relocated from Hong Kong back to London with their three young boys.\nErica Wax and Andrew Balls\nErica Wax has a wide range of experience in politics, the private sector and non-profit organizations. She worked in international development and trade policy in Washington DC, as a Director at Fontheim International, an international trade consulting firm. She was a vice president in the Global Markets and Investment Banking group at Merrill Lynch in New York and London. She has worked on numerous political campaigns over the last 20 years. Erica was the co-founder of a New York-based non-profit organization called Girls Career Workshop, which targets at-risk high school girls. Erica has a Masters in Public Policy from Harvard's John F Kennedy School of Government and a BA in Politics from University of California, Santa Cruz.\nAndrew Balls is chief investment officer for global fixed income at PIMCO. He is a member of the firm's Investment Committee and Executive Committee and manages a range of global portfolios. Prior to joining PIMCO in 2006, Andrew spent eight years at the Financial Times as an economics correspondent and columnist in London, New York and Washington, DC. He holds a bachelor's degree from Oxford, a master's degree from Harvard, and was a lecturer in economics at Keble College, Oxford.\nRandy Work\nRandy Work is a managing director of Kitano Capital LLC, a privately-owned financial management company. He also sits on the board of several start-up companies. Previously, Randy worked for 12 years with Lone Star Funds, a global private equity investment fund, helping to establish and manage the fund's investment activities in Japan. Randy earned his bachelor's degree in international economics and an M.B.A. in finance from the University of California, Los Angeles.\nTechnology Advisory Committee\nJames Arnett, Capco\nJames Arnett is a Partner in the UK office, with a focus on complex business and technology transformations. He specializes in mobilizing and leading large change and regulatory remediation programs, and also leads a major global client account. James is a lateral thinker, dynamic and entrepreneurial program director with an extensive track record of business transformation (particularly back office) and change delivery across capital markets and banking. James is passionate about the development of BPO, ITO and utility style models and the benefits they can deliver to organizations. Prior to joining Capco, James worked for technology consultancies IBM and EDS, where he managed large scale transformation, bank migration, core banking replacement and delivering optimization through offshore delivery centers in Asia and Africa. James also worked at Capita, where he ran four large BPO deals, and previously designed and delivered internet banking start-ups.\nAlex Belous, Education Portfolio Manager, The Cisco Foundation\nAlex began his career as a first grade teacher. He then served as the Internet Technology Manager for the Arizona Department of Education. Joining Cisco in 1998, Alex served as one of the founders of the Cisco Network Academy. After 6 years he became the Educational Specialist within the Cisco Corporate Affairs group. Presently as the Cisco Foundation and Cisco Public Benefit Investments Education Portfolio Manager, he is responsible for grants with Cisco NGO partners that have helped millions of students and teachers. He also serves as co-chair of the STEM taskforce. Alex holds a BA Early Childhood Education and two Masters in Elementary Education/Reading Instruction and Counseling Psychology.\nChandra Elango, Head of IT, Go to Market Tech at Atlassian\nChandra has held various management and technical roles at Atlassian, VMware, Cisco, and Gallup. He is a hands-on leader with a passion towards building great teams. Chandra is presently the Head of IT, Go to Market at Atlassian. In this role, he heads a global team of product managers and engineers responsible for Commerce, Sales and Marketing Tech and Customer Support Tech.\nPreviously as Vice President, IT at VMware in the Business Applications group, Chandra was instrumental in delivering several large enterprise programs. He has led Enterprise Architecture, SaaS Subscription Billing, Engineering, Go to Market, Emerging technologies, Development, QA and Application Support organizations. Chandra led VMware IT's mobile and DevOps transformation initiatives. During his tenure at VMware, Chandra relocated to India to set up VMware IT in Bangalore from scratch and grew it into a key global delivery center.\nPrior to joining VMware, Chandra was a hands-on Engineer at Cisco responsible for Platform and Integration Architecture. He moved into a Project Management role to deliver Engineering Change Management and Compliance portfolio of applications. Prior to Cisco, he was a Software Engineer at Gallup.\nHe holds a Masters degree in Electrical Engineering from University of Washington, Seattle and an MBA from San Jose State University, San Jose.\nDustin Frazier, Independent Consultant\nDustin Frazier is an IT consultant focused on helping small- and medium-sized nonprofit organizations create usable, affordable, and sustainable information systems to maximize their long-term growth and impact. He has been heavily involved in Room to Read's efforts for more than 10 years, as a volunteer, webmaster, chapter leader, donor, and staff member. From 2007 to 2010, Dustin served as the organization's first IT Director and helped build a team of professionals tasked with modernizing and managing Room to Read's global IT infrastructure. Dustin has also consulted for Global Citizen Year, Philanthropix, and other Bay Area nonprofit organizations.\nDaniel Freeman, Chief Commercial Officer, Netlify\nDaniel has an extensive career as a GoToMarket Executive and Advisor for leading enterprise software and infrastructure companies. Currently, he is the Chief Commercial Officer of Netlify, an upstart internet infrastructure company funded by Andreesen Horowitz and Kleiner Perkins. In the past, he has held Product, Marketing and Sales leadership roles at leading companies, Atlassian, Cloudflare, Sumo Logic and Symantec. As an advisor, he has helped a wide range of companies including BrowserStack, Podium and Upguard. To start his career, Daniel held various Product Management roles for both Cobalt Networks and Brightmail. He holds a BA from Claremont Mckenna College (CMC) and a Masters in International Business from ESCP-EAP in Paris.\nMatthew Glotzbach, CEO, Quizlet\nMatthew is the CEO of Quizlet, a global education technology company whose mission is to harness the world's knowledge to allow anyone to unlock their learning potential. He has over 20 years of experience in consumer and enterprise technology, product strategy, product management, marketing and sales. Prior to joining Quizlet, Matthew was the vice president of product management at YouTube, responsible for YouTube's Subscription and Music business and a member of the YouTube executive leadership team. He formerly lead the global Creator product and technology direction and served as the Managing Director of YouTube in Europe, Middle East and Africa where he was responsible for the strategy, development and management of YouTube's business and product direction. In 2007 he launched Google Apps, Google's cloud computing suite for business. Matthew holds a bachelor's degree in mechanical engineering from Cornell University.\nMaggie Johnson, VP, Education and University Programs, Google\nMaggie Johnson is Vice President of Education and University Programs for Google. She manages all technical training, content development, and information management programs for Google engineers and operations staff, as well as Google's K12 educational programs in STEM and computer science. She also manages the University Relations area, building research partnerships with faculty and labs globally; and Google's strategic initiatives in online teaching and learning. Prior to Google, Maggie was teaching faculty and Director of Educational Affairs in the Department of Computer Science at Stanford University.\nAndrea Leszek, EVP & COO, Technology, Salesforce.com\nAndrea leads engineering operations and services for the Technology organization, focusing on the success of Salesforce's customers and the enablement of the engineering teams. Her team includes engineering functions responsible for site reliability, service management, release management, customer success engineering, and technology communications and documentation. Andrea's team also runs internal engineering enablement such as innovation programs, engineering training, employee recognition, diversity, technology marketing, and agile coaching. She is a founding member of Salesforce's Women in Technology network, and is passionate about increasing diversity in tech. She holds a B.S. and M.S. from the Massachusetts Institute of Technology.\nAmbarish Malpani, VP of Engineering, Edmodo\nAmbarish Malpani has over 20 years in software development and management. He was the CTO and VP Engineering at Cenzic, Inc. and co-founded ValiCert in 1996, which he helped take public in July 2000. Ambarish also has a wide range of experience in the software engineering and development area - from creating standards in IETF, to creating the first Windows version of Apache. Ambarsh has a M.S. in Computer Science from U.C.S.B. and a B.Tech in Computer Science from I.I.T. Bombay\nVibhu Mittal, CEO, Edmodo\nVibhu serves as the current CEO of Edmodo, a K-12 education resource network for teachers, students and parents. He came to Edmodo through the acquisition of Root-1, a mobile educational platform startup. Prior to Root-1, he worked in research at Google where he worked on a variety of products including Google Scholar and Google Translate. He was also responsible for helping set up the Google engineering offices in India. He has also worked at Xerox PARC, CMU/LTI, Pitt/LRDC, USC/ISI, Ohio State University and TIFR, Bombay.\nBrett Robson, IT Workplace Engineering Manager, Atlassian\nBrett Robson is the IT Workplace Engineering manager at Atlassian where he is responsible for office infrastructure and services. Brett has over fifteen years experiencing working across corporate and not-for-profit organizations, with a focus on IT infrastructure, service delivery and strategy. Prior to his time at Atlassian Brett spent time as the CIO for Relationships Australia as well as over ten years at Cochlear Ltd, holding senior positions in infrastructure management and architecture.\nTim Wood, Senior Program Manager, Bill & Melinda Gates Foundation\nTim specializes in applying information technology to address the problems of poverty and health in developing countries. After 12 years at Microsoft working on software development, Tim joined the Grameen Foundation's Technology Center in 2002 where he pioneered replication of the Grameen Village Phone program, launching sustainable initiatives in Uganda and Rwanda and co-authoring the Village Phone Replication Manual. Tim went on to implement mobile money pilot programs for microfinance institutions in the Philippines and Kenya and spent four years as the Director of Mobile Health Innovation at Grameen Foundation, creating the MOTECH platform to deliver multiple mobile-service initiatives at scale in India and Africa. Tim joined the Bill & Melinda Gates Foundation in 2013 and is working across a wide range of information technology initiatives.\nFrank Lucido, VP of Information Technology, Making Waves Foundation\nFrank is VP of Information Technology for Making Waves Foundation, A non-profit committed to advance educational opportunities for college-bound, career-minded, historically underrepresented, and underserved youth. This includes responsibility for internal and externally facing technologies related to programs and operations as well as the multiple real estate development, construction, and property management project currently in progress to expand Making Waves impact and reach. Frank was formerly the Director of IT at Room to Read, his leadership drove the back end business transformation and migration to the cloud that allows Room to Read to scale operations and innovate in a constantly changing world. With over 20 years of experience, with roles in the private sector ranging from software developer to CIO, he brings a broad but intimate understanding of and passion for Room to Read's mission, vision, and goals. Frank holds a B.A. in English Literature from the Dominican University.\nWorld Change Starts with Educated Children.®\nI understand that Room to Read will respect my privacy in accordance with its privacy policy."

"Sainte-Radegonde is een gemeente in het Franse departement Saône-et-Loire (regio Bourgogne-Franche-Comté) en telt 210 inwoners (1999). De plaats maakt deel uit van het arrondissement Autun.\n\nGeografie\nDe oppervlakte van Sainte-Radegonde bedraagt 22,3 km², de bevolkingsdichtheid is 9,4 inwoners per km².\n\nDemografie\nOnderstaande figuur toont het verloop van het inwonertal (bron: INSEE-tellingen).\n\nExterne links\n \n\nGemeente in Saône-et-Loire"