zilongwang/ReadingBank huggingface dataset:
Post-marketing experience No descriptions of post marketing experience are yet available. A plan for acquisition of such data is described in the form of Clinical Protocol B2410. Safety issues with the potential for major regulatory impact Liver toxicity Clinically significant liver toxicity appears unlikely except for an unquantified possibility of this being a risk for patients with pre-existing hepatic impairment. Haematological toxicity No evidence of concern. Serious skin reactions No safety signals evident. Cardiovascular safety On currently available evidence and given the cautionary notes included in the PI regarding patients with existing risk factors, QT prolongation does not appear to be a major issue for pasireotide. Unwanted immunological events No safety signals evident. Other safety issues Safety in special populations Gender, age and race A subgroup evaluation of AE by CTC to look for any effect of gender, age or race was carried out for the dataset in pivotal Study B2305. The percentage of AE was similar between male and female patients. The numbers in the other subcategories were small, and it was difficult to draw any conclusions, particularly with regard to an effect of race as most of the subjects were in any case, Caucasian. Hepatically impaired patients In all of the summary documents, discussion regarding liver toxicity is completely focused on the possibility of hepatic adverse effects occurring in the general target population. There is no data or accompanying discussion on the possibility of this occurring in subjects with mild-to-moderate hepatic dysfunction, although the draft PI proposes that use be allowed in such individuals. Increased pasireotide exposure is seen in the presence of impaired hepatic function, and the sponsor has drawn a distinction between the level to which this occurs in moderately as opposed to severely impaired function based on a statistical test which obscures the observation that a functionally significant level of increased exposure was seen in both these groups, in contrast to those with mildly impaired function (Table 26 below). Furthermore, this distinction is made on the basis of a study which used single doses only, not allowing for the factor of accumulation, and in small numbers of subjects. It is noted that in the draft PI, the sponsor recommends that for patients with moderately impaired hepatic function, a starting dose of 300 µg bd be used and that the maximum dose be limited to 600 µg bd. While the concept of this dose limitation is correct, the quantum chosen appears to be empirical and no
- <0.001 Overall N=290 30 (25.1 ,35.6) N=145 3 (0.5, 6.4) CI: confidence interval; HR: hazard ratio; : Intent-to-treat; PFS: progression free survival. Figure 1 Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment for the Overall Population (Treatment-Naïve and Cytokine Pre-Treated Populations) Figure 2 Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment for the Treatment-Naïve Population
Hypothyroidism* Common Common Metabolic disorders Anorexia Very common Very common Weight decreased Common Very common Nervous System disorders Dizziness ♦ Very common Dysgeusia Common Very common Headache Very common Very common Ischaemic stroke* Uncommon Uncommon Transient ischaemic stroke* Common ♦ Cardiac Disorders Cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure)* Uncommon Common Bradycardia† Common Common Myocardial infarction* Uncommon Common Myocardial ischaemia Common ♦ QT prolongation* Common Common Torsade de pointes* Uncommon ♦ Vascular disorders Cerebral haemorrhage* Uncommon Uncommon Epistaxis Common Common Gastrointestinal haemorrhage* Uncommon Uncommon Haematuria Common Uncommon Hypertension* Very common Very common Pulmonary haemorrhage* Uncommon Common Venous thromboembolic events* Uncommon Common Respiratory, thoracic and mediastinal disorders
Cough ♦ Very common Dysphonia Common Common Dyspnoea ♦ Very common Pnuemothorax ♦ Common Gastrointestinal disorders Abdominal pain Very common Very common Diarrhoea Very common Very common Dyspepsia Common Common Gastrointestinal perforation* Uncommon ♦ Gastrointestinal fistula* Uncommon Uncommon Lipase elevations‡ Common ♦ Nausea Very common Very common Stomatitis ♦ Very common Vomiting Very common Very common Hepatobiliary disorders Alanine transferase increased Very common Common Aspartate amino transferase increased Very common Common Hepatic function abnormal Common ♦ Hyperbilirubinaemia Common Uncommon Skin and subcutaneous tissue disorders Alopecia Common Very common Dry Skin ♦ Common Exfoliative rash ♦ Very common Hair depigmentation Very common Very common Nail disorder ♦ Common Palmar-plantar erythrodysesthesia syndrome Common Very common Rash Common Uncommon Skin depigmentation Common Very common
Skin hypopigmentation 27 (11) 0 0 0 0 0 Skin disorder 26 (11) 4 (2) 0 1 (<1) 0 0 Stomatitis 26 (11) 1 (<1) 0 4 (3) 0 0 Alopecia 25 (10) 0 0 1 (<1) 0 0 Musculoskeletal pain 23 (10) 1 (<1) 0 3 (2) 0 0 Table 6 presents laboratory abnormalities occurring in ≥ 15 % of patients who received VOTRIENT in the pivotal RCC studies. Grades are based on the NCI CTCAE. Table 6. Selected Laboratory Abnormalities in ≥ 15 % of Patients who Received VOTRIENT and More Commonly than Placebo Arm (VEG105192) VOTRIENT (N = 290) Placebo (N = 145) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Parameters % % % % % % Haematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose increased 41 <1 0 33 1 0
INEC Independent Neurology Evaluation Committee ITT intent-to-treat IXRS Interactive Voice/Web Response System kDa kiloDalton MDRD Modification of Diet in Renal Disease MIU million international MRI magnetic resonance imaging mRNA messenger ribonucleic acid MS multiple sclerosis MSIS Multiple Sclerosis Impact Scale MSFC MS Functional Composite N/A not applicable NAb neutralising antibody NC not calculated NCA non-compartmental analysis OAS, OAS 2’,5’ oligoadenylate synthetase PASAT Paced Auditory Serial Addition Test PD pharmacodynamic PEG polyethylene glycol PFP prefilled pen PFS prefilled syringe PI Product Information PK pharmacokinetic PP per-protocol PPMS primary progressive multiple sclerosis
E2007-A001-040 * Bioequivalence - Multi-dose n/a Bioavailability - Single dose E2007-E044-017 E2007-E044-028 * * Food effect – Single dose E2007-E044-003 * * PK in special populations Target population - Single dose n/a PK in special populations - Multi-dose E2007-E049-203 § Hepatic impairment E2007-E044-015 * Renal impairment n/a Paediatrics and adolescents n/a Elderly – Single dose E2007-E044-007 * Poly-substance users E2007-A001-023 E2007-A001-024 * * PK Males versus females E2007-E044-003 * PK interactions Ketoconazole E2007-E044-005 * PK interactions Carbamazepine E2007-E044-006 * Midazolam E2007-A001-014 * Oral contraceptives E2007-E044-019 E2007-E044-029 * * Levodopa E2007-E044-025 * Population PK analyses Healthy subjects * Population PK analyses Target population Adults (Phase II) EMFFR2008/06/00b CPMS-E2007-2011-003c § § Gender-
. AEs for Psychiatric Disorders by Decreasing Frequency Multiple Dose Studies in Healthy Subjects A TEAE is generally defined as an adverse event that begins within 30 days after dosing with perampanel/placebo or an ongoing event that increases in severity after dosing with perampanel/placebo. Full details are given in the SAP. For each row category, a subject with two or more adverse events in the category is counted only once. N=number of subjects receiving the dose at anytime in the study (a) Actual dose at onset of the first occurrence of the TEAE within each dose group. (b) MedDRA preferred terms are sorted in descending order of frequency in the total column.
300 1807.4 2.5 Dog Beagle (7 days) 1 days 550.0 337.0 112.0 75.0 0.0 0.2 3 188.0 261.0 65.0 85.0 0.0 0.1 10 534.0 512.0 133.0 131.0 0.0 0.2 S00010 (4 0.3 28 days 158.1 98.0 57.8 42.8 0.0 0.1 1 221.8 343.4 75.7 106.0 0.0 0.1 10 1222.5 3266.4 303.8 485.0 0.2 0.4 S01009 (13 0.1 91 days 21.6 49.3 9.0 13.5 0.0 0.0 1 281.4 264.4 49.1 60.0 0.0 0.1 10 905.5 913.1 148.8 122.9 0.1 0.2 Monkey Cynomolgus (2 weeks) 0.5 14 days 1581.0 1848.5 154.9 193.3 0.1 0.2 1 4197.9 2821.5 389.7 332.9 0.2 0.5 (4 weeks) 0.1 28 days 520.1 286.0 41.2 39.4 0.0 0.1 0.3 1177.3 1116.4 108.8 118.8 0.1 0.2 1 4526.4 3901.3 433.0 425.3 0.3 0.6 (39 weeks) 1 378 days 6286.8 5821.5 415.6 435.4 0.4 0.6 1→2→4→8 13666.8 8108.4 870.8 663.7 0.6 1.2 1→2→4→8 12089.7 12431.1 791.9 1098.3 0.9 1.1 0.1 364 days 446.9 429.0 43.4 41.1 0.0 0.1 1 3 2 6 1 1 1 5 6 5 0 5 1.
Bioequivalence - Single dose E2007-A001-008 E2007-E044-016 E2007-A001-039 * * * * * Bioequivalence - Multi-dose n/a Bioavailability - Single dose E2007-E044-028 * * Food effect – Single dose E2007-E044-003 * * PK in special populations Target population - Single dose n/a - E2007-J081-231 § Hepatic impairment E2007-E044-015 * Renal impairment n/a Paediatrics and adolescents n/a Elderly – Single dose E2007-E044-007 E2007-E044-004 * Poly-substance users E2007-A001-023 E2007-A001-024 * * Gender-related PK Males versus females E2007-E044-003 * PK interactions Ketoconazole * Carbamazepine E2007-E044-006 * Midazolam E2007-A001-014 * Oral contraceptives E2007-E044-019 E2007-E044-029 * * Levodopa E2007-E044-025 * Healthy subjects *
930037771) F 7.28 56.6 60/30 M 61.6 191 F 92.2 192 Monkey 1 month Asunaprevir and Daclatasvir 930035546) Daclatasvir - 72/15 M 4.57 4.78 F 7.77 5.43 M 73.9 36.8 F 60.2 35.2 Monkey 3 months Asunaprevir and Daclatasvir 930039780) Daclatasvir - 45/15 M 2.8 4.19 F 2.87 3.69 80/50 M 31.7 29.4 8 2. 9. 2. 3. 5. 7.
F: 22-35 days (DN08069) Pregnant mice 10-day oral DRF (DN08014/DCN 930068598) 60 57.8 15.7 125 603 163 250 1810 491 500 2380 645 Mouse Oral EFD, 10 days GD15 (DN08022) 10 0.851 0.2 50 19.1 5.2 250 737 200 500 1740 472 Nonpregnant Rabbits 5 days oral Exploratory (DN08015/DCN 930068281) 50 0.707 0.2 150 2.55 300 5.52 1.5 Nonpregnant Rabbits days oral Exploratory (DN09022/DCN 930068775) 250 3.06 0.8 500 4.11 1.1 750 5.61 1.5 1000 12.3 3.3 Pregnant Rabbits 13-Day oral DRF, GD19 (DN08021/DCN 930068624) 50 0.76 0.2 100 2.11 0.6 200 5.02 1.4 400 10.6 2.9 Rabbit Oral EFD, 13 days (DN08056/DCN 930043164) 50 1.17 0.3 100 2.79 0.8 200 4.4 1.2 Rat Oral pre/postnatal development GD 6-LD 20, (DN11186) 40 26.8 7.3 125 282 76 400 711 193
data lock point 15 November 2014) + Australia Specific Annex (version 2, dated 29 December 2014). A summary of the changes made are shown in Table 18. Table 18: Summary of key changes made to CCRMP and ASA Summary of key changes between CCRMP (v 1)/ASA (v 1) and CCRMP (v 2)/ASA(v 2) Safety specification New important identified risk: ‘Drug-drug interactions’ New important potential risk: ‘Increased risk of hepatic adverse events in patients with severe impairment not receiving hemodialysis’ New missing information: ‘Patients who failed prior treatment with NS3 protease inhibitors’ Amended missing information: ‘Use in liver transplant patients’ has been changed to ‘Use in pre-, peri-, and post-liver transplant patients’. activities Routine pharmacovigilance is proposed for the newly added risks. Risk minimisation activities Routine risk minimisation (ie product labelling statements) is proposed for the newly added risks. ASA Changes have been made to the PI text proposed for Australia in response to TGA evaluation reports. Suggested wording for conditions of registration RMP Any changes to which the sponsor agreed become part of the risk management system, whether they are included in the currently available version of the RMP document or not included inadvertently or otherwise. The suggesting wording is: Implement Asunaprevir Company Core RMP (version 2, dated 22 December 2014, data lock point 15 November 2014) with Australia Specific Annex (version 2, dated 29 December 2014) and any future updates as a condition of registration. VI. Overall conclusion and risk/benefit assessment The submission was summarised in the following Delegate’s overview and recommendations: Quality Registration of the proposed ‘Sunvepra’ asunaprevir 100mg soft gelatin capsules is recommended with respect to quality and biopharmaceutic aspects. All issues raised during the initial evaluation of this application have been satisfactorily resolved. Nonclinical There are nonclinical objections to the registration of asunaprevir.
subjects and patients with IPF or pulmonary fibrosis, including 1098 patients assigned to receive pirfenidone at doses of 2,403 mg/day or higher. Due to its availability in other markets, postmarketing experience for pirfenidone is based on cumulative exposure of over 15,000 patient-years. Pirfenidone has been an approved drug for the treatment of IPF in other countries such as Japan since 2008. Pirfenidone has been available on a namedpatient basis on the SAS. Guidance There is no specific EMA guidance for the investigation of drugs for IPF. The FDA gave advice on the design of the additional Study PIPF-016. Contents of the clinical dossier The submission included the following clinical information: 6 clinical pharmacology studies, including 5 that provided pharmacokinetic data and a pharmacodynamics study on ECG effects: 1 population pharmacokinetic analysis 3 pivotal efficacy/safety studies: (PIPF004, PIPF006 and PIPF016) 2 ongoing long-term safety studies Pooled analyses, Post-Marketing Safety Update Reports (PSUR), Integrated Summary of Efficacy, and Integrated Summary of Safety. In addition the sponsor also provided: Clinical summaries of efficacy, safety and other clinical literature EMA and Canadian regulatory reports Evaluator’s comments on clinical data Overall the development program was comprehensively documented and the dossier well presented, although links to some data were not functional. The clinical evaluation was based on the submitted information from the sponsor. Other agency reports were also viewed for additional information. Paediatric data The submission did not include paediatric data as IPF occurs only in the adult population. Good clinical practice The study reports for the each study submitted addressed the principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice and in accordance with any other applicable regulatory requirements. Pharmacokinetics Studies providing pharmacokinetic data Summaries of the pharmacokinetic studies were provided. Table 4 shows the studies relating to each pharmacokinetic topic.
TP protein TPn Normalised protein VEGF Vascular Endothelial Growth Factor V1 Distribution volume for central compartment of free drug V2 Distribution volume for peripheral compartment of free drug V3 Distribution volume of bound drug (Vb) Vb Volume of distribution of bound drug Vmax Maximum binding capacity Vp Central volume of distribution of free drug (L), Vt Peripheral volume of distribution of free drug Vs Versus VSS Steady state volume of distribution WAM Wald’s approximation method WRES Weighted residuals WT Weight ε Residual random effect η Inter-individual random effect θ Population mean value of the parameter κ Inter-occasion random effect σ2 Variance of ε φ2 Variance of κ Clinical rationale Bristol-Myers Squibb (BMS) Australia Pty Ltd wishes to vary the dosing recommendations for the use of Reyataz (atazanavir) in HIV-infected paediatric patients. In essence the proposal is: To lower the age range from 8 years to 6 years For patients in the weight 15 to 20 kg, to add the new dose of atazanavir/ritonavir (ATV/RTV) 150/100 mg trial
For each subsequent drop below < 0.5 x 109/L Interrupt treatment Return to ≥ 1 x 109/L Resume treatment at 1 mg less than previous dose ANC – Absolute Neutrophil Count; CBC – Complete Blood Count; G-CSF – Granulocyte- Colony Stimulating Factor For other Grade 3/4 adverse reactions judged to be related to pomalidomide, stop treatment and restart treatment at 1 mg less than the previous dose when an adverse reaction has resolved to ≤ Grade 2 at the physician’s discretion. If toxicities occur after dose reductions to 1 mg, then the medicine should be discontinued. 11. Overdosage Pomalidomide doses as high as 50 mg as a single dose in healthy volunteers and 10 mg as once-daily multiple doses in multiple myeloma patients have been studied without reported serious adverse events related to overdose. No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable. In the event of overdose, supportive care is advised. In Australia, contact the Poisons Advisory Centre on 13 11 26 for advice on management. In New Zealand, contact the National Poison Centre on 0800 POISON or 0800 764 766 for advice on management. 12. Presentation and storage conditions 12.1 Presentation Pomalyst is available as 1 mg, 2 mg, 3 mg and 4 mg capsules in blister packs containing 21 capsules each. Pomalyst 1 mg capsules: dark blue/yellow size 4 gelatin capsules marked “POML” in white ink and “1 mg” in black ink. Each 1 mg capsule contains 1 mg of pomalidomide. Pomalyst 2 mg capsules: dark blue/orange size 2 gelatin capsules marked “POML 2 mg” in ink. Each 2 mg capsule contains 2 mg of pomalidomide. Pomalyst 3 mg capsules: dark blue/green size 2 gelatin capsules marked “POML 3 mg” in white ink. Each 3 mg capsule contains 3 mg of pomalidomide. Pomalyst 4 mg capsules: dark blue/blue size 2 gelatin capsules marked “POML 4 mg” in white ink. Each 4 mg capsule contains 4 mg of pomalidomide. 12.2 Composition Active Pomalidomide Excipients See section 2-Description, for a list of the excipients.
function. CC-4047-MM-008 Protocol available subjects with RRMM and impaired renal function. A Phase I, open-label, two-part study to evaluate the pharmacokinetics of pomalidomide (cc-4047) in hepatically impaired male subjects. CC-4047-CP-009. Protocol available. Use in patients with hepatic impairment Primary Objectives: Part 1: To evaluate the effect of severe hepatic impairment on the pharmacokinetics (PK) of a single oral dose of pomalidomide in male subjects. Part 2: To evaluate the effect of moderate and mild hepatic impairment on the PK of a single oral dose of pomalidomide in male subjects. Secondary Objectives: To evaluate the effect of hepatic impairment on the safety of a single oral dose of pomalidomide in male subjects. Q1 2016 (Final report) In assessment of pomalidomide as an inhibitor of P-glycoprotein using Caco-2 cells. CC-4047-DMPK-1586 Final report available Interactions with drugs affecting and metabolised by CYP1A2, 3A4/5 and Conclusion: The efflux ratio of digoxin was not reduced in the presence of pomalidomide indicating it is not an inhibitor of P-gp in vitro. Q3 2013 (Final Report) trial
CC-4047: Substrate potential in OATP1B1 and OATP1B3 expressing HEK293 cells. CC-4047-DMPK-1653 Protocol synopsis available None assigned. To determine if a clinical drug-drug interaction study evaluating pomalidomide as a substrate of OATP1B1 or OATP1B3 may be necessary. Q4 2013 Report) Population pharmacokinetics and exposure response analysis plan of pomalidomide. Protocol available Use in patients with renal impairment Use in patients with hepatic impairment Use in patients of different racial origin Pharmacokinetic data from completed studies in healthy subjects and MM patients will be included in a population pharmacokinetic analysis The covariates to be included in the analysis will include, but not be limited to, disease state, dose, formulation, fed state, age, weight, race, gender, creatinine clearance (mL/min) and markers of hepatic function, as available. End of 2013 (Final Report) Q=quarter
‘routine pharmacovigilance system in Australia’ in the ASA: Activities are carried out according to the TGA guidelines ‘Australian requirements and recommendations for pharmacovigilance responsibilities of sponsors of medicines’, version 1.1, dated Dec-2012 (see section 8.2). guidelines ‘Australian requirements and recommendations for pharmacovigilance responsibilities of sponsors of medicines’, version 1.2, dated 8 August 2013 (see section 8.2). evaluator’s request in an updated ASA is considered acceptable. 3.d) The sponsor describes in this table that additional activities are conducted for Ischemic cardiac events, Ischemic cerebrovascular events and Ischemic peripheral vascular events. However, the activities listed are additional risk minimisation activities, not additional pharmacovigilance activities. Consequently, these activities should be deleted from this table in an updated version of the ASA (see section 8.2). The sponsor regrets the oversight and agrees to delete the additional risk minimization activities from the of pharmacovigilance activities in next update to the ASA. These activities have also been deleted from the corresponding table of the EU RMP version 9.0. This is considered acceptable. 3.e) The sponsor describes that the potential risk of teratogenicity is addressed by an additional pharmacovigilance This study is an ‘in vivo interaction study of the effect of ponatinib on oral contraceptives’. It appears that this study will evaluate the interaction of ponatinib and oral contraceptives and therefore, does not provide any information on the teratogenic potential of ponatinib. Consequently, it is recommended that this table be amended and reference of this study be removed from the potential risk of ‘teratogenicity’. In addition, the sponsor should add ‘Interaction of ponatinib with oral contraceptives’ as missing information in the table of ongoing safety concerns, and assign the study to this missing information (see section 8.2). The sponsor acknowledges the error and will remove reference to this study from the potential risk of teratogenicity in the next update to the ASA. The sponsor’s commitment to implement the RMP evaluator’s request in an updated RMP is considered acceptable. Please also to point 2.9 in this table.
Blood and lymphatic system disorders Very common anaemia, platelet count decreased, neutrophil count decreased Common pancytopenia, febrile neutropenia, white blood cell count decreased Metabolism and nutrition disorders Very common decreased appetite Common dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, weight decreased Uncommon tumour syndrome Psychiatric disorders Very common insomnia Nervous system disorders Very common headache, dizziness Common cerebrovascular accident, cerebral infarction, neuropathy peripheral, lethargy, migraine, hyperaesthesia, hypoaesthesia, paraesthesia, transient ischaemic attack Uncommon cerebral artery stenosis Eye disorders Common vision blurred, dry eye, periorbital oedema, eyelid oedema Uncommon retinal vein thrombosis, retinal vein occlusion, retinal artery occlusion, visual impairment Cardiac disorders Common cardiac failure, myocardial infarction, cardiac failure congestive, coronary artery disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased Uncommon myocardial ischemia, coronary syndrome, cardiac discomfort, ischemic cardiomyopathy, arteriospasm coronary, left ventricular dysfunction, atrial flutter Vascular Disorders Very common hypertension
Common peripheral arterial occlusive disease, peripheral ischaemia, peripheral artery stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing Uncommon poor peripheral circulation, splenic infarction, embolism venous, venous thrombosis Respiratory, thoracic and mediastinal disorders Very common dyspnoea, Common pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension Gastrointestinal disorders Very common abdominal pain, diarrhoea, vomiting, constipation, nausea, lipase increased Common pancreatitis, blood amylase increased, gastrooesophageal reflux disease, stomatitis, dyspepsia, abdominal distension, abdominal discomfort, dry mouth Uncommon gastric haemorrhage Hepatobiliary disorders Very common alanine aminotransferase increased, aspartate aminotransferase increased Common blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased Uncommon hepatotoxicity, jaundice Skin and subcutaneous tissue disorders Very common rash, dry skin Common rash pruritic, exfoliative rash, erythema, alopecia, pruritis, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, pain of skin, dermatitis exfoliative Musculoskeletal and connective tissue disorders Very common bone pain, arthralgia, myalgia, pain in extremity, back pain, muscle spasms Common musculoskeletal pain, neck pain, musculoskeletal chest pain Reproductive system and breast disorders Common erectile dysfunction
Discontinuation due to adverse events Pivotal studies See Table 14. Table 14: Discontinuations due to adverse events reported in sponsor initiated trials. Trial Number of patients treated Duration of due to AE in treated patients (1985) HRT 200mg daily on days of cycle 29 1 year 9 Kleinstein (2002) Luteal Support 600mg daily 218 10 1 Lorain (1994) HRT 200mg on days 14-28 of cycle 20 13 months Unknown (1988) Menstrual 200mg and 300mg daily 39 19 200mg 20 300mg 10 days 0 (1988) Luteal support Up to 600mg daily 22 60 days Unknown Moyer (1987) HRT 200mg or 300mg daily on days of cycle 157 131 200mg 26 300mg >5 79 for ‘personal reasons’ studies These were meta-analyses which were not evaluable for withdrawals due to adverse events.
Tmax Time after administration when maximum plasma concentration is reached UC Urothelial cancer UIP Usual interstitial pneumonia ULN Upper limit of normal VEGF Vascular endothelial growth factor VEGFR Vascular endothelial growth factor receptor V1 Central volume of distribution V2 Peripheral volume of distribution Vss Volume of distribution at steady state
Information on the number of doses to be released in Australia with accompanying expiry dates for the product and diluents (if included). Evidence of the maintenance of registered storage conditions during transport to Australia. Five vials of each batch for testing by the TGA Laboratories Branch together with any necessary standards, impurities and active pharmaceutical ingredients (with their Certificates of Analysis) required for method development and validation. Attachment 1. Product Information The PI for Tecentriq approved with the submission is described in this AusPAR is at Attachment 1. For the most recent PI, please refer to the TGA website at <>. Attachment 2. Extract from the Clinical Evaluation Report
6: Incidence of adverse drug reactions (≥10%) reported in patients treated with STIVARGA and reported more commonly than in patients receiving placebo (GRID) System Organ Class/Preferred Term STIVARGA plus BSC§ (N=132) Placebo plus BSC§ (N=66) Grade Grade All % ≥3 % All % ≥3 % General disorders and administration site conditions Asthenia/Fatigue Mucosal inflammation Pain Fever 52 17 24 21 4 2 2 0 39 2 21 11 2 0 5 2 Metabolism and nutrition disorders Decreased appetite and food intake Hypothyroidism 31 13 <1 0 21 3 3 0 Skin and subcutaneous tissue disorders HFSR/PPE Rash Alopecia 67 30 24 22 7 2 15 3 2 2 0 0 Gastrointestinal disorders Diarrhoea Stomatitis Nausea Vomiting 47 25 20 17 8 0 2 <1 9 6 12 8 0 2 2 0 Investigations Weight loss 14 0 8 0 Infections and infestations Infection 32 5 5 0 Vascular disorders Hypertension Haemorrhage* 59 11 28 4 27 3 5 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Nervous system disorders Headache 16 0 9 0 Musculoskeletal and connective tissue disorders Musculoskeletal 14 0 3 0
statistical significance due to low study power shows despite clinically relevant large effect sizes in the paediatric subpopulation. Advice from the ACPM is requested. Proposed action Given the above findings and my comments, the Delegate is of the view that the current submission has demonstrable deficiencies in all areas – that is, Quality, Toxicology and Clinical – and thus its efficacy and safety were not satisfactorily shown based on the data in the submitted dossier. The Delegate accepts the drug will be used in highly specialised units by highly trained physicians. However, this in itself is not an alternative to reliable evidence of effectiveness for general marketing authorisation. Please also note that remestemcel-L (ex vivo hMSCs), as product derived from blood, is an unscheduled substance under the Poisons Schedule, that is, it has not been classified as prescription only medicine. However, given the expected use of this drug only in specialised circumstances this is not considered an issue. Please also note that such submissions now fall the new Biologicals regulatory framework whereby an orphan designation is no longer available which may be relevant to any future submission for this product. The Delegate thanks the Committee for considering this submission and providing advice to the TGA. Outcome On 18 November 2012, Delpharm Consultants Pty Limited wrote to the TGA, asking for the application for Prochymal to be withdrawn before it was presented for consideration by the Advisory Committee on Prescription Medicines. Attachment 1. Extract from the Clinical Evaluation Report
LABA Long acting beta-agonist LAMA Long acting muscarinic antagonist LS Least squares LTRA Leukotriene receptor antagonist mAb Monoclonal antibody MedDRA Medical Dictionary for Regulatory Activities MMRM Mixed effect model for repeated measures NB Negative binomial NIH National Institute of Health OCS Oral corticosteroid PEFR Peak expiratory flow rate PFT Pulmonary function tests PI Product Information PIP Paediatric investigation plan PCS Potentially clinically significant PD Pharmacodynamic PK Pharmacokinetic % predicted FEV1 Actual FEV1 divided by standard predicted FEV1 times 100% PopPK Population pharmacokinetic PP Per protocol PT Preferred Term RMP Risk Management Plan RR Rate ratio
Table 1: Complete Summary of Studies – Design and Methodology Table 1 continued: Complete Summary of Studies – Design and Methodology Table 1 continued: Complete Summary of Studies – Design and Methodology 1 continued: Complete Summary of Studies – Design and Methodology Table 1 continued: Complete Summary of Studies – Design and Methodology BD – a day, CSR – clinical study report, F – female, ITTC – intent-to-treat clinical population, M – male, MRSA – methicillin-resistant S. aureus, PK – pharmacokinetic(s), SID –secondarily infected dermatoses, SIRS – skin infection rating scale, SITL, secondarily infected traumatic lesions, TID – three times a day
Table 5. Repeat dose toxicity studies; exposure relative to hepatically impaired patients Species Study duration (weeks) Dose Cmax ng/mL (m/f) Cmax ratioa AUC0-24 h ng.h/mL (m/f) AUC Exposure ratioa Repeat dose toxicity studies Mouse 28 days 250 0.5/0.7 95.9/117 0.7/0.9 1000 0.5/0.6 69.9/176 0.5/1.3 2000 0.6/1.2 88.4/215 0.7/1.6 Rat Day 1 of 26 5 14.21 0.7 50.65 0.4 week study 150 20.83 1.0 92.35 0.7 300 25.04 1.2 126.7 1.0 Dog 39 week 100 16.97 0.8 61.35 0.5 300 21.82 1.0 75.45 0.6 1000 21.88 1.0 105.7 0.8 Dog 4 week 1000 7/10 0.3/0.5 80/113 0.6/0.9 300 (amorp.) 91/68 67/71 1000 (amorp.) 95/55 a Exposure based on human study with hepatically impaired patients (550 mg twice daily: Cmax 21.1 ng/mL; AUCtau 130 ng.h/mL (Study no. RFHE 3002PK). Table 6. Embryofetal development; exposure relative to healthy volunteers Species Study Dose PO (gavage) Cmax Cmax ratioa AUC 0-24 ng·h/ml AUC Exposure ratioa Rabbit toxicity 62.5 ND - ND - 250 1.7 0.5 8.3 0.7 trial
Creatinine clearance mL/min Median Interquartile range 68 42-99 88 50-121 75 46-110 BVAS (RITUXVAS) BVAS/WG (RAVE) median Interquartile range 8 6-10 7 5-10 8 6-10 19 14-24 18 12-25 Dialysis required N (%) 0 0 8* (24%) 1* (9%) 8 Use of plasma exchange N(%) 0 0 8 (24%) 3 (27%) Deaths 2 2 6 3*** 9 * The glomerular filtration rate was 0 ml per minute among patients who underwent dialysis. ** RB et al Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis. N Engl J Med 2010, 363:211-20 *** Jones RB et al Verbal presentation of abstract 2010a Three deaths occurred during the first 6 months of treatment. Two patients in the CYC arm died of infections. One patient in the RTX arm died of multi-organ failure. One more death occurred in the RTX arm subsequently by the two year follow-up (Table 10). Table 10. Summary of deaths in RAVE Age (yrs) Creatinine at Entry Died months from entry Cause RTX unrelated 65 157 μmol/L no dialysis 2 Multi-organ failure; considered associated with the patient’s underlying disease by the investigator RTX unrelated 78 16 Respiratory failure; investigator considers alveolar haemorrhage due to disease flare being life threatening, fatal, and unrelated to study medication, but rather related to a lack of efficacy. CYC Possibly 68 no dialysis 4 Pneumonia (multi-organ system failure with sepsis, due to
600 Rat (SD) 26 weeks / 100 300 1000 Dog (Beagle, ♂) 9 10 5850 10 30 41 60 127 (healthy ♂ volunteers) 200 mg 4113 – M4 (active metabolite) Rat (SD) 300 – – 70 7 trial 7
evaluations performed in this study. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the PI be updated to include the following statement ‘Use in the elderly’ as men >70 years remains missing information: ‘Data on patients older than 70 years are limited’. (As in the EU SmPC) The sponsor notes the comment. Any proposed changes will be made to the PI after the Delegates overview. The evaluator has noted the sponsor’s response. The recommendation on the PI document remains, for consideration by the Delegate. Summary of recommendations It is considered that the sponsor’s response to the TGA has adequately addressed most of the issues identified in the RMP evaluation report. Additional recommendations are detailed below. Outstanding issues Issues in relation to the RMP The recommendation on the draft Product Information remains, awaiting consideration by the Delegate. Additional recommendations The evaluator supports the clinical evaluator’s comments. The sponsor has provided a justification as to why QT interval prolongation is not considered a safety concern for avanafil (see sponsor’s response to Recommendation 4 under section 4 ‘Reconciliation of issues outlined in the RMP Evaluation Report (Round 1)’). The RMP evaluator agrees with the clinical evaluator that patients with risk factors for cardiac disease could be more sensitive to the effects of an increased dose of avanafil. The sponsor should add ‘QT interval prolongation’ as a potential risk to the ASA and undertake to give specific consideration to arrhythmia events in the PSURs. In the EU-RMP, the sponsor acknowledges the possibility of recreational use and misuse of PDE5 inhibitors, including the use of PDE5 inhibitor with other illicit drugs including ketamine and amyl nitrate which may lead to serious hypotension. The evaluator has noted that concomitant use of avanafil and nitrates is listed under ‘Contraindication’. This routine risk minimisation measure is considered adequate. The sponsor should undertake to report all the serious adverse events related to recreational use and off-label use in the PSURs. Advice from the Advisory Committee on the Safety of Medicines (ACSOM) ACSOM advice was not sought for this submission.
GCP Good Clinical Practice ICF Informed consent form ICH International Conference on Harmonisation IMP Investigational medicinal product IRB Institutional review board IRR Infusion-related reaction IV Intravenous IxRS Interactive and web response system LDH Lactate dehydrogenase MedDRA Medical Dictionary for Regulatory Activities MTX Methotrexate NCI National Cancer Institute NSAID Nonsteroidal anti-inflammatory drug RA Rheumatoid arthritis RBC Red blood cell RF Rheumatoid factor RTX Rituximab SAE Serious adverse event SBP Systolic blood pressure SIRR Serious infusion-related reaction SIE Serious infection event SSR SUSAR Report SUSAR Suspected unexpected serious adverse reaction TNF Tumor necrosis factor trial
The ADRs listed in Table 18 were all adverse events which occurred at an incidence of ≥ 5% in the MABTHERA-treated group. The safety profile from long-term use of MABTHERA to treat GPA/MPA has not been established. Table 18 Adverse Drug Reactions occurring in ≥ 5% of patients receiving MABTHERA, and at a higher frequency than cyclophosphamide, in the pivotal study at Adverse reactions MABTHERA n =99 CYC n 98 Blood and lymphatic system disorders Thrombocytopenia 7% 3% Gastrointestinal disorders Diarrhoea Dyspepsia Constipation 18% 6% 5% 12% 5% 1% General disorders and administration site conditions Peripheral oedema 16% 9% Immune system disorders Infusion related reactions 5% 2% Infections and infestations Urinary tract infection Bronchitis Herpes zoster Nasopharyngitis 7% 5% 5% 5% 3% 2% 2% 4% Investigations Decreased haemoglobin 6% 4% Metabolism and nutrition disorders Hypokalaemia 5% 2% Musculoskeletal and connective tissue disorders Muscle spasm Arthralgia Back pain Muscle weakness Musculoskeletal pain Pain in extremities 18% 15% 10% 5% 5% 5% 17% 10% 6% 4% 0% 3% Nervous system disorders Dizziness Tremor 10% 10% 9% 6% Psychiatric disorders Insomnia 14% 13% Respiratory, thoracic and mediastinal disorders Cough Dyspnoea Epistaxis Nasal congestion 12% 11% 11% 6% 11% 9% 6% 2%
Australian Public Assessment Report for Rituximab Proprietary Product Name: MabThera Sponsor: Roche Products Pty Ltd About the Therapeutic Goods Administration (TGA) The Therapeutic Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website <>. About AusPARs An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. AusPARs are prepared and published by the TGA. An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, variations, and extensions of indications. An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. trial
Infections and infestations bacterial infections, viral infections sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology Blood and the lymphatic system disorders neutropenia, leucopenia anaemia, thrombocytopenia coagulation disorders, transient aplastic anaemia, haemolytic anaemia, lymphadenopathy Immune system disorders angioedema hypersensitivity Metabolism and nutrition disorders hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia Psychiatric disorders depression, nervousness Nervous system disorders paresthesia, hypoesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety dysgeusia Eye disorders lacrimation disorder, conjunctivitis Ear and labyrinth disorders tinnitus, ear pain Cardiac disorders +myocardial infarction, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder +left ventricular failure, +supraventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia Vascular disorders hypertension, orthostatic hypotension, hypotension Respiratory, thoracic and mediastinal disorders bronchospasm, respiratory disease, pain, dyspnoea, cough, rhinitis asthma, bronchiolitis obliterans, lung disorder, hypoxia Gastrointestinal disorders nausea vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation dyspepsia, anorexia, throat irritation abdominal enlargement Skin and subcutaneous tissue disorders pruritis, rash urticaria, +alopecia, sweating, night sweats
Xarelto (10 mg od) N = 4657 Enoxaparin/Placebo (40 mg od) N = 4692 System Organ Clas Medical Entity / Preferred Term AE ADR AE ADR Anaemia (incl. respective lab parameters) 54 (1.16%) 55 (1.17%) Cardiac disorders Hypertension 77 (1.65%) 86 (1.83%) Hypotension 244 (5.24%) 238 (5.07%) Tachycardia 74 (1.59%) 71 (1.51%) Procedural hypotension 47 (1.01%) 34 (0.72%) Endocrine disorders Hyperglycaemia 43 (0.92%) 53 (1.13%) Gastrointestinal disorders Nausea 517 (11.10%) 69 (1.48%) 519 (11.06%) 86 (1.83%) Constipation 318 (6.83%) 335 (7.14%) Diarrhoea 106 (2.28%) 137 (2.92%) Dyspepsia 42 (0.90%) 51 (1.09%) GI and abdominal pain 89 (1.91%) 93 (1.98%) Vomiting 452 (9.71%) 482 (10.27%) Feeling unwell 92 (1.98%) 81 (1.73%) Fever 430 (9.23%) 444 (9.46%) Headache 108 (2.32%) 108 (2.30%) Peripheral Oedema 202 (4.34%) 168 (3.58%) Unspecific pain 285 (6.12%) 295 (6.29%) Urinary tract infection 82 (1.76%) 90 (1.92%) Injury, Poisoning and Procedural Complications Arthralgia 65 (1.40%) 81 (1.73%) Post procedural haemorrhage (incl. postoperative anaemia and wound haemorrhage) 292 (6.27%) 123 (2.64%) 279 (5.95%) 109 (2.32%) Wound healing complications 199 (4.27%) 161 (3.43%) Investigations
Moderate 30 – 49 mL/min 10 mg once daily 15 mg once daily 15 mg daily for 3 weeks, followed by 20 mg once daily Severe 15 – 29 mL/min 10 mg once daily (Use with caution) Xarelto is contraindicated Severe < 15 mL/min Xarelto is contraindicated Patients above 65 years Based on clinical data, no dose adjustment is required for these patient populations (see Pharmacokinetic properties). Increasing age is associated with declining renal function. Body weight No dose adjustment is required for these patient populations (see Pharmacokinetic properties). Gender No dose adjustment is required for these patient populations (see Pharmacokinetic properties). Children and adolescents Xarelto is not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy. Ethnic differences No dose adjustment is required on ethnic differences (see Pharmacokinetic properties). Transition Xarelto from and to Vitamin K Antagonists (VKA) or Parenteral Anticoagulants Anticoagulant Transition From Xarelto Transition To Xarelto Vitamin K Antagonists (VKA) Transition from Xarelto to VKAs There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Limited clinical data is available to guide the process whereby patients are converted from Xarelto to VKAs. Transition from VKA to Xarelto: For patients treated for prevention of stroke and systemic embolism, VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 3.0. For patients treated for DVT and prevention of recurrent DVT and PE, VKA treatment should be stopped and
Net Clin. Outcome 361 (7.1) 366 (7.2) 727 (7.1) 391 (7.6) 0.320 0.95 (0.83, 1.10) 0.94 (0.83, 1.06) 0.337 ASA (N) 349 348 697 353 CV Dth/MI/St 27 (7.7) 24 (6.9) 51 (7.3) 36 0.234 0.64 (0.38, 1.07) 0.69 (0.45, 1.05) 0.084 Dth/MI/St 28 (8.0) 24 (6.9) 52 (7.5) 36 0.291 0.64 (0.38, 1.07) 0.70 (0.46, 1.07) 0.101
IWC International Workshop Criteria LDH Lactate dehydrogenase MAA Marketing Authorisation Application MedDRA Medical Dictionary for Regulatory Activities MINE Mesna, ifosfamide, etoposide MSKCC Memorial Sloan Kettering Cancer NCCN National Comprehensive Cancer Network NCI National Cancer Institute NE Not evaluable NHL Non-Hodgkin’s lymphoma NOS Not otherwise specified NR Not reported ORR Overall response rate OS Overall survival PD Progressive disease PFS Progression-free survival PMitCEBO Prednisone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, Oncovin (vincristine) PR Partial response PS Performance status PTCL Peripheral T-cell lymphoma R-DHAP Rituximab, dexamethasone, high-dose ara-C, and cisplatin RICE Rituximab-ifosfamide, carboplatin, etoposide SD Stable disease SD90 Stable disease for 90 days or longer SOC SPD System organ class Sum of product diameter
generally manageable and well within the province of oncologists areas of expertise. Accordingly the evaluator considers the benefit-risk balance favourable. List of questions None Recommendation regarding authorisation The evaluator considers that on balance and in view of the discussion indicated above there is evidence of definite efficacy for romidepsin in the treatment of advanced stage relapsed and refractory PTCL. Despite the fact that the studies involved were Phase II in nature without a direct comparator, the evaluator considers that the overall evidence of benefit versus the relative risks involved would support approval for marketing of this agent. It is also worth commenting that approval for romidepsin in the management of patients with advanced stage refractory and relapsed PTCL has been given by the US FDA. V. Pharmacovigilance findings Risk management plan The sponsor submitted a Risk Management Plan (EU-RMP Version 3.0 (dated 05/05/2012, DLP 31/10/2010), and Australian Specific Annex Version 1.0 (dated 08/06/2012)) which was reviewed by the TGA’s Office of Product Review (OPR). Safety specification Subject to the evaluation of the nonclinical aspects of the Safety Specification (SS) by the Toxicology area of the TGA Office of Scientific Evaluation and the clinical aspects of the SS by the Office of Medicines Authorisation, the summary of the Ongoing Safety Concerns as specified by the sponsor is as follows (Table 10): Table 10. Important identified and potential risks and missing information. OPR reviewer comment: Notwithstanding the evaluation of the non-clinical and clinical aspects of the SS, this is considered acceptable. Pharmacovigilance plan The sponsor proposes routine pharmacovigilance activities for important identified and potential and missing information (as stated above). Furthermore, additional activities are planned for some risks: clinical trials are planned to further study potential drug interactions and the risk in patients with impaired hepatic function, and a drug utilisation study in Europe is planned to study the risks in off-label use. Risk minimisation activities No additional risk minimisation activities are proposed for Istodax.