zilongwang/ReadingBank huggingface dataset:
provide detail about how and when the evaluation of these additional risk minimisation activities will be undertaken and reported to the TGA. 2. The sponsor’s approach to simply updating the existing additional risk minimisation materials for intravenous Actemra with the information, precautions and instructions for using the new SC presentation is only acceptable if TGA approval for unsupervised home use of the SC formulation is obtained. The PSPAB will be guided by the PMAB evaluation of the supporting clinical data as to whether additional risk minimisation activities are required for the important identified risk: ‘Serious hypersensitivity reactions’, as it relates to the subcutaneous presentation. See Recommendation 1 See Recommendation 1 3. The sponsor should provide justification for the following identified differences between the EU and the proposed Australian routine risk minimisation activities, or alternatively include such information in the Australian PI to enhance safe use of the SC presentation: For the important potential risk: ‘Immunogenicity’, the ASA states: ‘The AU PI does not include the EU SPC data on the rate of formation of IgE antibodies following TCZ SC’. For the missing information: ‘Paediatric patients’, the ASA states: ‘The SPC includes a specific statement that the subcutaneous formulation has not been studied in children’. For the missing information: ‘Safety in For the missing information: ‘Paediatric patients’, the sponsor states: ‘The Australian PI section ‘Precautions’, Paediatric Use has been updated to include a statement on the absence of data with the subcutaneous formulation in subjects less than 18 old. The existing text on the clinical data with intravenous ACTEMRA has been updated to specify the ACTEMRA formulation used in those studies’. For the other issues the sponsor states: ‘A justification for the absence of this text in the Australian PI has been added to the updated version of the Australian Specific Annex to the EU-RMP’. This is acceptable. These issues remain outstanding for the Delegate’s consideration.
following convention: very common (≥10%); common (≥1% to <10%), uncommon (≥0.1% to <1%) or rare (≥0.01% to <0.1%). More Common Clinical Adverse Drug Reactions (≥1%) not reported in the controlled period. Blood and Lymphatic System Disorders Common: Leucopenia. General Disorders and Administration Site Conditions Common: Fatigue. Infections and Infestations Common: Pneumonia, sinusitis, pharyngitis. Investigations Common: Hepatic enzyme increased, blood cholesterol increased Metabolism and Nutrition Disorders Common: Hyperlipidemia, dyslipidemia. Musculoskeletal and Connective Tissue Disorders Common: Musculoskeletal pain. Psychiatric Disorders Common: Insomnia. Respiratory, Thoracic and Mediastinal Disorders Common: Dyspnoea Skin and Subcutaneous Tissue Disorders Common: Rash. Less Common Clinical Adverse Drug Reactions (<1%) Blood and Lymphatic System Disorders Uncommon: Neutropenia, lymphopenia.
Italy AIFA of moderate to severe active rheumatoid arthritis (RA) in patients who have responded inadequately to, or who are intolerant to one or more diseasemodifying antirheumatic drugs. Xeljanz can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see sections 4.4 and 4.5). both studies A3921069 and A3921044 are included in Section 5.1 of the SmPC. US 22 April 2013 Approved: 21 Feb 2014 Xeljanz (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Limitations of Use: Use of Xeljanz in combination with biologic DMARDs or with potent such as azathioprine and cyclosporine is not recommended. Clinical data for radiographic response: Results from both studies A3921069 and A3921044 are included in Section 14 of the approved USPI. Canada Planned for 2017 trial
daily is insufficiently acceptable. The sponsor proposed changes regarding durability of clinical response and updated safety data with TOF are acceptable for inclusion in the amended PI. The evaluator recommends the continued registration of TOF 5 mg twice daily treatment for the treatment of active RA is subject to regular periodic safety update reports and when available, the sponsor provides the TGA with the final clinical study report for the long term Study A3921024. VI. Pharmacovigilance findings Risk management plan Summary of RMP evaluation The sponsor submitted an Australian specific RMP (version 2.0; 28 January 2016; data lock point 15 June 2015) in support of this application and did not provide a revision with the Section 31 response. The proposed summary of safety concerns and their associated risk monitoring and mitigation strategies are summarised below. Table 9: Summary of safety concerns Summary of safety concerns Pharmacovigilance Risk Minimisation Routine Additional Routine Important identified risks Serious and other important infections *,^ Decrease in neutrophil counts and neutropenia - Decrease in lymphocyte counts and lymphopenia ^ Decrease in haemoglobin levels and anaemia - Lipid elevations and hyperlipidaemia - Nonmelanoma skin cancer *,^ Transaminase elevation and -
potential for drug induced liver injury Gastrointestinal perforation * Hypertension - - Creatine kinase increase - - Weight increase - - Important potential risks Malignancy (excl NMSC) including lymphoma *,^ Cardiovascular risk *,^ - Interstitial lung disease - - Progressive multifocal *,^ - - Rhabdomyolysis - - - Epstein-Barr events - QT prolongation - - - Reduction in renal function - Modified release only Gastrointestinal obstruction - - Missing Effects on pregnancy and the foetus # Use in breastfeeding - - Effect on vaccination efficacy and the use of live/attenuated vaccines -
PK in healthy adults Single dose (45 + 15 split dose) 156-07-262 Single dose (Korean subjects) 156-KOA-0801 * Bioequivalence† - Single dose 156-11-295 * Food effect 156-11-295 * PK in renal impairment 156-09-282 * PK in ADPKD subjects General PK -Single dose 156-04-248 * -Multiple dose 156-04-001 * -Multiple dose 156-04-249 * -Multiple dose (90 + 30 split dose) 156-09-285 Renal impairment 156-06-260 156-09-284 Population PK and PK/PD analyses ADPKD subjects 156-11-296 * * Indicates the primary aim of the study. † Bioequivalence of different formulations. None of pharmacokinetic studies had deficiencies that excluded their results from consideration. There were two studies listed in the table of contents for the submission as studies not previously evaluated by the TGA. However, both of these have in fact been previously reviewed by the TGA and are therefore not reviewed in this report. These studies are listed in Table 3. Table 3: Pharmacokinetic studies not evaluated Study ID Subtopic(s) 156-96-205 Interactions with frusemide and hydrochlorothiazide 156-01-224 Population PK analysis in subjects with hyponatraemia or failure. Summary of pharmacokinetics The following is a summary of the new PK data contained in the submission. The information in the summary is derived from conventional pharmacokinetic studies unless otherwise stated. trial
European Union Submitted 22 November 2013 Approved 27 May 2015 Jinarc is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease United States of America Submitted 1 March 2013 Canada Submitted 27 March 2014 Approved 25 February 2015 JinarcTM (tolvaptan) is indicated to slow the progression of kidney enlargement in patients with autosomal dominant polycystic kidney disease (ADPKD). In ADPKD, kidney enlargement reflects renal cyst burden. Switzerland Submitted 3 October 2014 Approved 21 2016 Same as EU Japan Submitted 30 May 2013 Approved 24 March 2014 Suppression of progression of autosomal dominant polycystic kidney disease (ADPKD) in patients with increased kidney volume and a rapid rate of increase Republic of Korea Submitted 30 June 2015 Approved 1 December 2015 Same as EU Product Information The Product Information (PI) approved with the submission is described in this AusPAR can be found as Attachment 1. For the most recent PI, please refer to the TGA website at < >. II. Registration timeline Table 2: Registration timeline Description Date Submission dossier accepted and 1st round evaluation commenced 29 February 2016 1st evaluation completed 14 August 2016
Nonclinical There were no non-clinical (toxicology) objections to registration of either trametinib as monotherapy or trametinib in combination with dabrafenib. Clinical The clinical evaluator recommended rejection of the application. Overview of data Table 17: Studies relevant to this application Study ID Phase Study drug/s Population Endpoints / comments MEK111054 1 trametinib Solid tumours, lymphomas FTIH; dose escalation; anti-tumour activity. MEK113709 1 trametinib Solid tumours Food effect MEK113708 1 trametinib tumours Mass balance MEK115064 1 trametinib Solid tumours Absolute bioavailability MEK113583 2 trametinib BRAF mutant melanoma, 2nd line PK, efficacy, safety. MEK114267 “METRIC” 3 trametinib versus chemotherapy BRAF mutant advanced melanoma PK, efficacy, safety. Pivotal for monotherapy. BRF113220 Part A 1-2 trametinib, dabrafenibA BRAF mutant melanoma PK / interaction study BRF113220 Part B 1-2 trametinib, dabrafenibA BRAF mutant melanoma or colorectal cancer PK, dose escalation BRF113220 Part C 2 dabrafenibA + trametinib versus dabrafenibA BRAF V600E/K mutant advanced melanoma Pivotal for combination therapy. BRF113220 Part D 1-2 dabrafenibB; dabrafenibB + trametinib BRAF mutant melanoma PK A: gelatin capsule; B: HPMC capsule (commercial dabrafenib uses the HPMC capsule) Some aspects of BRF113220, unrelated to combination therapy, were evaluated in the CER for dabrafenib (PM-2012-02231-3-4).
Treatment of HER2-positive localised breast cancer following surgery, and in association with chemotherapy and, if applicable, radiotherapy. IV 4 mg/kg 2 mg/kg every 1 week 1 year SC - 600 mg every 3 weeks 1 year Locally Advanced Breast Cancer Treatment of HER2-positive locally advanced breast cancer in combination with neoadjuvant chemotherapy followed by adjuvant HERCEPTIN. IV 8 mg/kg 6 mg/kg 3 weeks 1 year SC - 600 mg every 3 weeks 1 year Metastatic Breast Cancer Treatment of patients with metastatic breast cancer who have tumours that overexpress HER2: As monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease; In combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or IV 4 mg/kg 2 mg/kg every 1 week Until disease progression SC - 600 mg 3 weeks Until disease progression trial trial
evaluation, the TGA has received a PSUR covering the period from 25 September 2013 to 24 March 2014 (inclusive). This report provides updates and new information related to the safety profile of trastuzumab. It is recommended to the Delegate that relevant sections of the draft PI be revised as follows: The duration for an effective contraception to be used after trastuzumab treatment should be increased from six months to seven months; The frequency for the following adverse reactions should be increased from common to very common based on Joint Analysis and/or ‘SC alignment’: white blood cell count decrease/leukopaenia – 15.4%, infection – 24.0%, ejection fraction decreased – 22.0%, nail disorder – 13.4%; A frequency should be assigned to following adverse reactions based on a new clinical data review: dermatitis – 5% common, and urticarial – 0.7% uncommon. and c., a recent Safety Related Request (SRR) was submitted by the sponsor which included these changes. This SRR was approved by TGA on 12 May 2014. recommended changes to the PI have been approved, no further action is required. It was also recommended to the Delegate that the relevant content of the CMI be updated accordingly to provide adequate information to patients.
Discontinue KADCYLA Do not administer KADCYLA. Repeat LVEF assessment within 3 weeks. If LVEF <40% is confirmed, discontinue KADCYLA. Do not administer KADCYLA. Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA. Continue treatment with KADCYLA. Repeat LVEF assessment within 3 LVEF = Left Ventricular Ejection Fraction Special populations Elderly: There are insufficient data to establish the safety and efficacy of KADCYLA in patients 75 years of age or older. No dose adjustment of KADCYLA is required in patients aged ≥ 65 years (see Precautions; Use in the Elderly). Children: The safety and efficacy of KADCYLA in paediatric patients have not been established. Renal impairment: No adjustment to the starting dose of KADCYLA is needed in patients with mild or moderate renal impairment (see Pharmacology; Pharmacokinetics in Special Populations). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data. Hepatic impairment: The safety and efficacy of KADCYLA have not been studied in patients with hepatic impairment. Instructions for use Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic drugs should be used. The reconstituted product does not contain preservative and is for single use in one patient only. Discard any residue. Using a sterile syringe, slowly inject 5 mL of Sterile Water for Injection (SWFI) into the 100 mg vial, or 8 mL of SWFI into the 160 mg vial. the vial gently until completely dissolved. SHAKE! Reconstituted solution should be inspected visually for particulate matter and discolouration prior to administration. The reconstituted solution should be free of visible particulates, clear to slightly opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if the reconstituted solution contains visible particulates, is cloudy or discoloured. Instructions for dilution Determine the volume of solution required based on a dose of 3.6 mg trastuzumab emtansine / kg body weight:
Table 1 Single-dose pharmacokinetics of NovoEight in 20* adult and adolescent subjects with severe haemophilia A (FVIII ≤ 1%) Dose: 50 IU/kg turoctocog alfa (single i.v. dose) *Full analysis set adjusted for dose and product strength and excluding outliers; N=20 Abbreviations: Inc. recovery = incremental recovery; AUC = area under the plasma concentration-time curve; CL= clearance; t½ = plasma elimination half-life; Vss = steady date volume of distribution; Cmax = peak plasma concentration; MRT = mean residence time Pharmacokinetic data from single-dose administrations of NovoEight in 14 paediatric subjects below 6 years of age and in 14 paediatric subjects from 6 to below 12 years of age are listed in tables 2 and 3. Table 2 Single-dose pharmacokinetics of NovoEight in children with haemophilia A (1 − < 6 years) Dose: 50 IU/kg turoctocog alfa (single i.v. dose); N = 14 Table 3 Single-dose pharmacokinetics of NovoEight in children with haemophilia A (6 − < 12 years) Dose: 50 IU/kg turoctocog alfa (single i.v. dose); N = 14
significantly reduced the pregnancy rate, from an expected 5.6% to an observed 1.9%, when taken within 72 hours after unprotected intercourse (p=0.001). There were no pregnancies observed in the women who were administered EllaOne more than 72 hours after unprotected intercourse (10% of women who received EllaOne). ii) Open-Label Study This study was a multi-centre open-label designed to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 48 to 120 hours after unprotected intercourse. Main inclusion criteria were women, 18 or greater years of age, with regular cycle length (24 to 35 days) presenting for emergency contraception between 48 hours and 120 hours of unprotected intercourse. In total, 1,533 healthy women with a mean age of 24 years received a dose of 30 mg ulipristal acetate (EllaOne). The primary efficacy measurement was the pregnancy rate, calculated as the number of pregnancies after administration of emergency contraception, divided by the number of subjects administered emergency contraception. Twenty-seven pregnancies occurred in 1,242 women aged 18 to 35 years evaluated for efficacy for a pregnancy rate of 2.1%. The number of pregnancies expected without emergency contraception was calculated based on the timing of intercourse with regard to each woman’s menstrual cycle. EllaOne significantly reduced the pregnancy rate, from an expected rate of 5.5% to an observed rate of 2.2%, when taken 48 to 120 hours after unprotected intercourse (p<0.001). iii) Phase II Comparative Study Study HRA2914-507 was a randomized double-blind study conducted in healthy cycling women at least 18 years old and who requested emergency contraception at one of the participating clinical sites in the US within 72 hours (3 days) of unprotected intercourse. It was designed as a non-inferiority to test the following hypothesis that 50 mg unmicronized ulipristal acetate had a pregnancy rate no worse than that of levonorgestrel with a non-inferiority margin of 2%. The efficacy evaluable (EE) population included 1,546 women (773 the ulipristal acetate group and 773 in the levonorgestrel group).
2 for UPA 90 days 10 mg daily 85.1% white; mean age 40.0 years; mean BMI 25.4; 96.0% of potential; mean (median) PBAC score at baseline = 319 (216). uterus < 16 weeks, at least one myoma ≥ 3 cm diameter, nil larger than 10 cm, eligible for or of 3 x 90 day placebo 13 5 mg (n= 96) or 10 mg (n= 98) 88.0% white; mean age 41.6 years; mean BMI 25.3; 92.1% of potential; mean (median) PBAC score at baseline = 452 (361). PBAC score > 100, uterus ≤ 16 weeks gestation at least one myoma ≥ 3 cm diameter, nil larger than 10 cm, fibroid related anaemia defined as Hb ≤ 10.2g/dL, eligible for surgery Double double dummy, active 13 5mg (n= 102) or 10 mg (n= 103) daily Mean age 40.4 years; mean BMI 25.5; 96.3% of potential; mean PBAC score > 100, uterus ≤ 16 weeks gestation 50 0 label
End of treatment course 2b Mean (median)% CFS in fibroid volume - 51.3 % (-63.4%) -43.7 % Percentage (number) of subjects with ≥25% reduction in fibroid volumea 80.0 (48/60) 79.8 (95/119) Percentage (number) of subjects with ≥50% reduction in fibroid volumea 66.7 (40/60) 64.7 (77/119) End of treatment course 3b Mean (median)% CFS in fibroid volume - 52.0% (-66.5%) -41.0% Percentage (number) of subjects with ≥25% reduction in fibroid volumea 81.8 (45/55) 78.3 (83/106) Percentage (number) of subjects with ≥50% reduction in fibroid volumea 65.5 (36/55) 62.3 (66/106) End of treatment course 4 Mean (median)% CFS in total fibroid volume -57.3% (-71.2%) -53.5% Percentage (number) of subjects with ≥25% reduction in fibroid volumea 84.0 (42/50) 82.3 (79/96) Percentage (number) of subjects with ≥50% reduction in fibroid volumea 66.0 (33/50) 69.8 (67/96) Follow up visit 3 months after end of treatment) Mean (median)% CFS in total fibroid volume -42.7 (-59.3) -33.7 (-58.8) Percentage (number) of subjects with ≥25% reduction in fibroid volumea 76.5 (39/51) 72.2 (70/97) Percentage (number) of subjects with ≥50% reduction in fibroid volumea 60.8 (31/51) 57.7 (56/97) a Denominator for percentage is number of subjects with non-missing myoma volume reduction at each visit b Assessment 2 weeks after menstruation following treatment course and placebo / NETA double blind period Other endpoints
Efficacy Studies providing efficacy data Table 5 shows studies which provided data for efficacy. Table 5. Studies which provided data for efficacy. All studies performed in COPD populations. Study Treatment arms (µg) (once daily unless otherwise specified No of N(n) 12 week and 24 week placebo controlled efficacy studies IIIa and safety R, DB, PG, PC 12 UMEC 125 UMEC 62.5 PLA 69 (56) 69 (62) 68 (50) yes IIIa Safety efficacy and PK R, DB, PG, PC 24 UMEC 125 VI 25 UMEC/VI 125/25 PLA 408 (312) 404 (298) 403 (325) 277 (183) IIIa Safety efficacy and PK R, DB, PG, PC 24 UMEC 62.5 VI 25 UMEC/VI 62.5/25 PLA 421 (324) 421 (318) 414 (332) 280 (204) 24 week active comparator efficacy IIIa Safety and efficacy R, DB, DD, PG, AC 24 UMEC 125 UMEC/VI 125/25 222 (165) yes 3361 3373 3374
Change from baseline N 196 200 197 97 99 97 Mean (SD) 1.4(7.094) 4.89 (9.333) 6.22 (8.747) 1.09 (5.892) 4.29 (8.594) 4.67 (8.758) Median 1.15 3.90 a 5.80 a 0.00 2.70c 3.50a Mental component summary Baseline N 203 203 204 104 102 104 Mean (SD) 43.51 (10.848) 42.77 (10.908) 43.48 (11.608) 42.11 (12.507) 43.27 (12.911) 42.81 (11.953) Median 43.90 42.00 41.65 41.80 43.70 41.40 Change from baseline N 196 200 197 97 99 97 Mean (SD) 1.53 (9.582) 3.35 (10.016) 4.79 (10.054) 0.63 (8.238) 3.01 (11.144) 3.52 (11.274) Median 0.25 2.65b 4.40a 0.00 0.70b 2.20b a p≤0.001 b p=NS c p<0.05 CROHN’S DISEASE The safety and efficacy of STELARA were evaluated in three randomised, double-blind, placebo-controlled clinical trials in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). The clinical development program consisted of two 8-week IV induction studies (UNITI-1 and UNITI-2) followed by a subcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy. Induction of Clinical Response and Remission UNITI-1 and UNITI-2 studies included 1409 (UNITI-1 n=769; UNITI-2 n=640) patients. In both studies, patients were permitted to concomitantly receive oral 5-ASA compounds, immunomodulators, corticosteroids, and/or antibiotics. Patients were randomised to receive a
Table 15: Very Common and Common Adverse Drug Reactions System Organ Class (SOC) NCI-CTC Grade 3-5 Reactions (≥ 2% difference between the study arms in at least one clinical trial) All Grade Reactions* (≥ 10% difference between the study arms in at least one clinical trial) Very common Common Very Common Infections and infestations Sepsis Abscess Infection Blood and the lymphatic systems disorders Febrile neutropenia Leucopenia Neutropenia Thrombocytopenia Anaemia Metabolism and nutrition disorders Dehydration Anorexia Nervous system disorders Peripheral sensory neuropathy Cerebrovascular accident Syncope Somnolence Headache Dysgeusia Headache Dysarthria **Peripheral sensory neuropathy Eye disorders Eye disorder Lacrimation increased Cardiac disorders Cardiac failure congestive Supraventricular tachycardia Vascular disorders Hypertension Thromboembolism (arterial) Deep vein thrombosis Haemorrhage Hypertension Respiratory, thoracic and mediastinal disorders Pulmonary embolism Dyspnoea Hypoxia Epistaxis Dyspnoea Epistaxis Rhinitis Gastrointestinal disorders Diarrhoea Nausea Vomiting Intestinal Perforation Ileus Intestinal obstruction Abdominal pain Gastrointestinal disorder Stomatitis Constipation Stomatitis Rectal haemorrhage Diarrhoea Endocrine disorders Ovarian failure Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome Exfoliative dermatitis Dry skin Skin discolouration Musculoskeletal, connective tissue and bone disorders Muscular weakness Myalgia Arthralgia Arthralgia Renal and urinary disorders Proteinuria Urinary Tract Infection Proteinuria General disorders and administration site conditions Asthenia Fatigue Pain Lethargy Mucosal inflammation General physical health deterioration Pyrexia Asthenia Pain Mucosal inflammation *Only Grade 2-5 adverse events were collected in study MO22224 **Difference of ≥ 10% was observed in study MO22224 Laboratory Abnormalities
Characteristics (N) 025 Phase I/II, Single center; Open label; 15 U/kg to 60 U/kgb velaglucerase alfa ghu EOW, IV infusion 9 months Patients with Type 1 Gaucher disease who had received no treatment within 12 months prior to study entry; patients exhibited anemia, thrombocytopaenia, deficient GCB activity as measured in leukocytes. Patients with splenectomy were excluded. 12 41.7 (18.8 - 69.8) Male and Female 025EXT Phase I/II, Multicenter; 60 U/kg velaglucerase alfa ghu EOW, IV infusion 60 monthsc Open label extension study of patients completing week 41 in TKT025 10 38.8 (18 - 63) Male and Female 032 III, Multicenter, Randomised, Double-blind, Parallel group, Controlled; 45 U/kg or 60 U/kg velaglucerase alfa ghu EOW, IV infusion 12 months Patients with Type 1 Gaucher disease who had received no treatment within 30 months prior to study entry; patients had deficient GCB activity as measured in leukocytes or by genotype analysis; patients exhibited decreased haemoglobin and platelet counts and increased spleen and liver volume. Patients with splenectomy were excluded. 25 26.0 (4.0 - 62) Male and Female 039 Phase III, Multicenter, Randomised, Double-blind, Active comparator, Controlled; 60 U/kg velaglucerase alfa ghu EOW, IV infusion for 60 minutes 60 U/kg imiglucerase EOW, IV infusion for 1-2 hours 9 months Patients with Type 1 Gaucher disease who had received no treatment within 12 months to study entry; patients had deficient GCB activity as measured in leukocytes or by genotype analysis; patients exhibited decreased haemoglobin and platelet counts and increased spleen and liver volume. 35 29.7 (3.0 - 73) Male and Female 034 Phase II/III, Multicenter, Open Patients previously treated for a minimum 40 35.6 (9.0 - 71) Male and
I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Approved Date of decision: 15 December 2016 Date of onto ARTG 5 January 2017 Active ingredient(s): Venetoclax Product name(s): Venclexta Sponsor’s name and address: AbbVie Pty Ltd 241 O’Riordan St, Mascott NSW 2020 Dose form(s): Film-coated tablets Strength(s): 10 mg, 50 mg and 100 mg Container(s): Plastic bottles and blister trays (with plug-assist) Pack size(s): Starter pack for up-titration –week 1 (14 times 10 mg tablets), week 2 (7 times 50 mg tablets), week 3 (7 times 100 mg tablets), and week 4 (14 times 100 mg tablets) The 100mg tablet strength is supplied as a blister pack (112 tablets) and in HDPE bottles (120 tablets) Approved therapeutic use: Venclexta is indicated for the treatment of: patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) with 17p deletion, or patients with relapsed or refractory CLL for whom there are no other suitable treatment options. Note to indications. The indications are approved based on overall response rates. Duration of response and improvements in overall survival. of administration: Oral (PO) Dosage: The starting dose of Venclexta is 20 mg once daily for 7 days. The Venclexta dose must be administered according to a weekly dose titration schedule to the recommended daily dose of 400 mg over a period of 5 weeks as shown in Table 6. [see Attachment 1 PI]. The 5-week dose titration schedule is designed to gradually reduce tumour burden (debulking) and decrease the risk of TLS.
Table 28. Study 355 Incidence of Common Treatment Emergent Adverse Events by Body System and Preferred Term by Treatment Group (≥ 10% Overall) : Safety Population Table 29. Study 108 Overall Summary of Adverse Events 30. Study 108 Number of Subjects with Adverse Events by Preferred Term 1 Investigator verbatim term: lip papule Treatment-related adverse events (adverse drug reactions) Pivotal studies Study 310 had no summary of Treatment AEs, only a table (Table 14.3.1.3 Adverse Events by System Organ Class and Preferred Term and Relationship to Study Treatment (Safety Population)) which was a 129 page listing of all AEs. studies Table 31. Study 304 Treatment-Related, Treatment-Emergent Adverse Events Reported in at Least 5% of Subjects in Any Treatment Group (Safety Population) Table 32. 108 Number of Subjects with Treatment-Related Adverse Events by Preferred Term Treatment-related SAEs Table 33. Study 310 Serious Adverse Events Related to Study Treatment: Safety Population CBZ = carbamazepine; ZNS = zonisamide were no treatment related SAEs in studies 304 and 355 and only 1 in study 314. Deaths and serious adverse events Pivotal studies One death in Study 3 - unexplained cause. Other studies One in Study 304 - due to RTA. 8 subjects reported 12 SAEs in 314, only 1 SAE (Hyponatraemia) was Treatment-related.
Table 5 Treatment Emergent Adverse Events occurring in >/= 1% of Zonisamide treated patients and greater than placebo Body System and COSTART Preferred Term Number (%) of Subjects All Doses Placebo (N=498) (N=350) Any adverse event 388 (77.9) 237 (67.7) Body as a whole Abdominal pain 36 (7.2) 12 (3.4) Allergic Reaction 5 (1.0) 2 (0.6) Flu syndrome 20 (4.0) 10 (2.9) Pain 18 (3.6) 11 (3.1) Viral Infection 7 (1.4) 4 (1.1) Cardiovascular Vasodilatation 7 (1.4) 2 (0.6) Digestive Anorexia 54 (10.8) 15 (4.3) Constipation 14 (2.8) 4 (1.1) Diarrhoea 29 (5.8) 13 (3.7) Dry mouth 5 (1.0) 2 (0.6) Dyspepsia 13 (2.6) 3 (0.9) Nausea 48 (9.6) 28 (8.0) Hematologic and Lymphatic Ecchymosis 11 (2.2) 3 (0.9) Leukopenia 7 (1.4) 0 (0.0) Metabolic and Nutritional Weight loss 20 (4.0) 6 (1.7) Musculoskeletal Arthralgia 5 (1.0) 3 (0.9) Myasthenia 5 (1.0) 1 (0.3) Nervous system Abnormal gait 13 (2.6) 5 (1.4) Agitation/irritability 37 (7.4) 17 (4.9) Altered cognitive function 78 (15.7) 23 (6.6) Anxiety 19 (3.8) 11 (3.1) Ataxia 28 (5.6) 8 (2.3) CNS depression 141 (28.3) 65 (18.6) Confusion 28 (5.6) 9 (2.6) Depression 31 (6.2) 10 (2.9)
Difficulty concentrating 32 (6.4) 7 (2.0) Difficulty with memory 25 (5.0) 5 (1.4) Dizziness 77 (15.5) 29 (8.3) Emotional lability/moodiness 20 (4.0) 10 (2.9) Fatigue 33 (6.6) 22 (6.3) Hypesthesia 8 (1.6) 4 (1.1) Incoordination 6 (1.2) 3 (0.9) Insomnia 27 (5.4) 11 (3.1) Mental slowing 15 (3.0) 7 (2.0) Nervousness 9 (1.8) 3 (0.9) Nystagmus 18 (3.6) 7 (2.0) Paresthesia 16 (3.2) 6 (1.7) Psychomotor slowing 8 (1.6) 3 (0.9) Psychosis/Psychotic Disorder 5 (1.0) 3 (0.9) Schizophrenic/Schizophreniform behaviour 7 (1.4) 2 (0.6) Somnolence 80 (16.1) 29 (8.3) Speech & Language abnormalities 29 (5.8) 6 (1.7) Tiredness 43 (8.6) 24 (6.9) Tremor 16 (3.2) 7 (2.0) Renal and Urinary disorders Nephrolithiasis* >1% Respiratory Cough increased 8 (1.6) 4 (1.1) Pharyngitis 21 (4.2) 10 (2.9) Rhinitis 8 (1.6) 4 (1.1) Sinusitis 7 (1.4) 4 (1.1) Skin and Appendages Acne 5 (1.0) 2 (0.6) Rash 14 (2.8) 8 (2.3) Sweating 5 (1.0) 1 (0.3) Special senses
Zonisamide was authorised in Japan on 31 March 1989 and in Europe on 10 March 2005. It is approved in 42 countries worldwide including the United States (US) and EU member states. The monotherapy indication is approved in Japan. A similar application to extend the indications was approved in the EU in June 2012 and is under evaluation in Switzerland (see Table 1). No such submission has been made in the USA, Canada or NZ. 1. International regulatory status for Zonegran extension of indication to include monotherapy. Country Marketing Status Proposed Indication Marketing approval date Approved Indication* EU (centralised procedure) Approved Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy. 27 June 2012 Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy. Switzerland Submitted Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy. Pending Pending USA Authorised for adjunctive use only *EU, Switzerland and the US have an existing adjunctive use indication. Product Information The approved Product Information (PI) current at the time this AusPAR was prepared can be as Attachment 1. II. Quality findings There was no requirement for a quality evaluation in a submission of this type. III. Nonclinical findings There was no requirement for a nonclinical evaluation in a submission of this type. IV. Clinical findings Introduction A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found at Attachment 2 of this AusPAR. trial
A 5.1 Project: PREDL- Manhole chamber lining Specification file : design specifications First page --------------------------------------------------------------- Specifications according tot he standard specification regulations for the construction (Bauwesen StLB) PREDL-Manhole rehabilitation through the cone DESIGN SPECIFIACTIONS FOR THE REHABILITATION OF FOUL AND STORM WATER MANHOLES Task : Place : State : Constructor : The specifications were processed accordingly to the fundamentals of the German Constructions Procedures VOB part B and C. For the contract design, the German Official Contracting for the Accomplishment of Construction Performance have to be taken as a basis, VOB Part B. Subsequently are valid the agreements 1 to 8. Only the specification description without any modification is valid for the contractor. The tenderer is obliged to make a view oft he building site before he hands over his tender.
Note: Please save your paper as the surname of the first listed author and your reference number, eg Smith_076 The Fourth Australiasian Ground Control in Mining Conference 2018 Paper Number: (refer to Abstract Notification email) Title of paper (use ‘Title’ style) Author One1, Author Two2 and Author Three3 (initials and surnames only) 1. Position title, Organisation Name, City State Postcode. Email: 2. Position title, Organisation Name, City State Postcode. Email: 3. Position title, Organisation Name, City State Postcode. Email: …etc Note: If appropriate, authors may list their AusIMM membership status (eg: MAusIMM, GAusIMM, FAusIMM(CP), etc). Affiliations for other organisations will not be included. ABSTRACT (USE 1’ 300 word abstract here…(Use ‘Body Text’ style) Note: Do not use extra returns between paragraphs, or double spaces between sentences. (USE 1’ STYLE) Text here… (Use ‘Body Text’ style) Figures should be placed within the body of the paper soon after being mentioned. Note: only high quality, high resolution images are acceptable. Original graphics files (tifs, jpgs, etc) are preferred. Crop images to best reflect subject matter. Insert image using ‘Image style’ FIG 1 – Caption … Tables should be placed within the body of the paper soon after being mentioned. TABLE 1 Caption … Column 1 (Use ‘Table text header row’ style) Column 2 Column 3 X (Use ‘Table text’ style’) 10 50 Y 20 55 Z 30 62
X 40 50 Y 60 50 Z 20 35 x 15 10 1 (USE 1’ STYLE) Text here… (Use ‘Body Text’ style) Other styles available to use: Bullets level 1 Bullets level 2 Numbers 1 Quotes Heading level 2 (Use ‘Heading 2’ style) Text here… (Use ‘Body Text’ style) Heading level 3 (Use ‘Heading 3’ style) Text here… (Use ‘Body Text’ style) CONCLUSIONS (USE 1’ STYLE) Text here… (Use ‘Body Text’ style) ACKNOWLEDGEMENTS (USE 1’ Text here… (Use ‘Body Text’ style) Note: please acknowledge collaborators here or anyone who has helped with the paper. It may also be appropriate to acknowledge company approval to publish. REFERENCES (USE 1’ STYLE) List references here (Use ‘Reference List’ style) Note: List references alphabetically by author surname. Do not use a numbered list. Refer to the AusIMM Guide to Authors for further instructions and information about the correct formatting of references.
Explosion-protected Ex d LED tubular light fitting made of plastic and very lightweight, size 4. For use in Ex-Zones 1, 2, 21 and 22. Using state-of-the art LED technology and high luminous efficacy a long service life of up to 100,000 hours is achieved. Version : Size 4 Length : 1.382 mm Enclosure material : Polycarbonate Weight : 2 kg Lamp wattage : 49 W Diffusor : without Diffusor Luminous flux : 5.263 lm Luminaire efficiency : 109 lm/W operational voltage AC : 240 V Application range (Zone) : 1 , 2 , 21 , 22 Gas explosion protection : II 2 G Ex d op is IIC T4 Gb Dust explosion protection : II 2 D Ex tb IIIC 100 °C Db Min. ambient temperature : -50 °C Max. ambient temperature : +60 °C Type of protection (IP) : IP66 / IP68 (10 M / 1 H) For further information, see : Web code 6036A Manufacturer's name : STAHL Schaltgeräte GmbH Type : 6036/1248-050-0120-01
Section: Hauteur du local: : mm Resistance au feu: R 60 Charge de dimensionnement Nd = kN Charge d’incendie Nfid = kN Choc Qd = kN Hauteur Qd: mm Détail de base: Détail de tête: pce 992 R Fabrication et livraison de colonnes mixtes acier-béton préfabriquées. Type ORSO®-V. Protection incendie vérifiée avec certificat AEAI valide. Surface: Tube en acier chromé 130 Forme de la colonne: Modèle: Section: Hauteur du local: mm Resistance au feu: R 60 Protection incendie vérifiée avec certificat AEAI valide Charge de dimensionnement Nd = kN Charge d’incendie Nfid = kN Choc Qd = kN Hauteur Qd: mm Aiguisé rond avec grain 320 Détail de base: Détail de tête: ORSO® -B 500 Constructions à ossature 510 Colonnes en béton _______________________________________ 511 R Fabrication et livraison de colonnes en béton armé préfabriquées Type ORSO®-B avec plaque de tête et plaque de base 101 Forme de la colonne: Section: mm Hauteur de la pièce: mm Résistance au feu: R 60 Charge de la colonne Nd = kN Détail de base: Détail de tête: pce
Explosion-protected LED linear luminaire plastic-made. The state-of-the art LED technology with high luminous efficacy and a long service life up to 100,000 hours. The luminaire includes a luminous flux up to 6,000 lumen. With a central lock for easy-open and -closing feature. Including a trough wiring with 5 cores for two-ended electrical connection. Enclosure material : Polyester resin glass fibre-reinforced Lamp material : Polycarbonate Lamp wattage : 28 W Rated operational voltage AC : 240 V Rated operational voltage DC : 250 V Application range (Zone) : 1 , 2 , 21 , 22 Gas explosion protection : II 2 G Ex d e op is IIB T4 Dust explosion protection : II 2 D Ex tb IIIC 100 °C Min. ambient temperature : -30 °C Max. ambient temperature : +55 °C Type of protection (IP) : IP66 / IP67 Through wiring : with 5 conductors Connection : 1 x M25 Ø 7 – 17 mm Plug : 2 x M25 x 1,5 Width : 184 mm Height : 125 mm Length : 700 mm For further information, see : www.r-stahl.com Web code 6002A Manufacturer's name : STAHL Schaltgeräte GmbH Type : 6002/1142-5301-151
The event will include: a free sausage sizzle traditional drumming, a cultural exhibition, workshops lots of free children’s activities and more. For more details: Call: Edwige 0418 367 417 or email: Visit for regular updates If you need help filling in the please call us. Note that all requests to perform and/or have a stall/display will be subject to the committee’s approval and will need to meet all risk/safety requirements and legal obligations. We aim to have a draft program issued for feedback in Dec 2016. Final event details and program to be confirmed 2 weeks prior to the event or earlier (may be subject to change depending on circumstances beyond our control). The organisers will liaise with key contact regarding the outcome of your expression of interest, any requirements, changes etc. EXPRESSION OF INTEREST (EOI)
on these pollutants to assist students in explaining the effect they have on waterways. Further investigation can be conducted to find out how these pollutants get into the waterway by participating in Gutter Guardians. Click to view the Gutter Guardians resource. Finally, students can discuss, plan, justify, undertake and evaluate actions they can take to improve local biodiversity in and around the waterway and/or school. Essential questions What are catchments? What effects water quality? How can water quality be tested? What actions can we take to support healthy ecosystems and improve biodiversity? Goals Students will understand Students will know Students will be able to The concept of a catchment The concept of an ecosystem What affects water quality What actions can be taken to support healthy waterways Identify some macroinvertebrates Take action to improve biodiversity Links to the South Australian Teaching for Effective Learning Framework – Domain 4 Personalise and connect learning 4.1 build on learners’ understandings 4.2 connect learning to students’ lives and aspirations 4.3 and assess learning in authentic contexts 4.4 communicate learning in multiple modes Links to the Australian Curriculum - (teachers to determine specific links for year levels) Learning Areas Science English Mathematics Geography Cross-curriculum priorities Sustainability OI 2. All life forms, including human life, are connected through ecosystems on which they depend for their wellbeing and survival. OI 7. Actions for a more sustainable future reflect values of care, respect and responsibility, and require us to explore and understand environments. OI 9. Sustainable futures result from actions designed to preserve and/or restore the quality and uniqueness of environments. General capabilities Engagement activities - To capture students’ interest and find out what they think they know about macroinvertebrates and their habitats. Activity 1: Learning about macroinvertebrates Duration: 1- 1.5 Materials: A4 coloured, laminated pictures of macroinvertebrates (can be downloaded by clicking ) Students have a dictionary race to find out the meanings of biodiversity, catchment, ecosystem, habitat, and macroinvertebrates. Discuss the meanings and ask them to identify how concepts are all connected. Draw a mind map to represent their ideas. Distribute one A4 picture of macroinvertebrates to each student. Students discuss the pictures in groups. Find out what they know about macroinvertebrates, where they might live, how they are connected to each other and any other related information. Discuss similarities and differences.
Recommendation Eight AIPJ should produce and regularly update a brief matrix outlining possible integration and synergies with other Australian aid investments (both those funded by AusAID and other Australian Government agencies). This matrix should inform the design and implementation of AIPJ activities. Response: AusAID agrees with this recommendation. Actions: AusAID will work with the ISP to establish these relationships, consider options for working together and implement those joint activities. Recommendation Nine AIPJ should draft a brief Donor Coordination Framework, explaining how its activities will avoid duplication and maximise complementarity with other donor-funded law and justice programs in Indonesia – particularly those funded or managed by the World Bank (Justice for the Poor), USAID (Changes for Justice, Educating and Equipping Tomorrow’s Justice Reformers), UNDP (Strengthening Access to Justice in Indonesia), the TAF-managed Prison Reform Program and the Open Society (Open Society Justice Initiative). Response: AusAID agrees with this recommendation. Actions: AusAID will task the ISP to produce a brief donor coordination framework and to update it with each work plan submission to AusAID and Bappenas (the latter being the institution responsible for donor coordination in this sector).
†Frequencies are categorised as follows: very common 10%; common from 1% to <10%; uncommon from 0.1% to <1%; rare from 0.01% to <0.1%) Adverse Events Reported in Comparative Therapeutic Studies 305 and 307/602 at a rate of  1% Possibly Related to Therapy or Causality Unknown Protocol 305 Voriconazole vs Fluconazole (oral therapy) Protocol 307/602 Voriconazole vs Conventional Amphotericin B (IV/oral therapy) Vori N = 200 N (%) Fluc N =191 N (%) Vori N =196 N (%) Ampho B† N = 185 N (%)
—— 2010, Meat processing, . AusVet Animal Health Services 2006, A review of the structure and dynamics of the Australian beef cattle industry, report to the Commonwealth Government Department of Agriculture, Fisheries and Forestry, . Beef Central 2015, ‘JBS concludes $1.45 billion Primo deal’, Beef Central, 30 March. Bindon, B and Jones, N 2001, ‘Cattle supply, production systems and markets for Australian beef’, Australian Journal of Experimental Agriculture, vol. 41, no. 7, pp. 861–77, . Bureau of Infrastructure, Transport and Regional Economics (BITRE) 2009, Australian transport statistics yearbook 2009, Canberra, . —— 2007, Estimating traffic and congestion cost trends for Australian cities, working paper 71, Canberra, . Bureau of Meteorology (BoM) 2012, Australian climate averages—climate classifications, Bureau of Meteorology, . Chadee, D & Mori, H 1996, ‘Developments in the Japanese beef market following import liberalisation’, Review of Marketing and Agricultural Economics, vol. 64, no. 1, 19–30. City of Wagga 2013, Revenue and pricing policy 2013/2014, City of Wagga Wagga, . COAG Road Reform Plan (CRRP) 2011, feasibility study report to COAG, Melbourne, . Commonwealth Government Department of Agriculture 2015, Land use and management information for Australia, . ——2014, Total meat exports by state of production: fiscal YTD to June 2014, . Commonwealth Government Department of Foreign Affairs and Trade (DFAT) 2015, Partnership Agreement Fact Sheet, —— Korea–Australia Free Trade Agreement: quick guide—key agricultural product outcomes, . —— 2014b, Outcomes at a glance, . —— 2014c, Japan–Australia Economic Partnership Agreement, . Commonwealth of Australia 2015, Our North, Our Future: White Paper on Developing Northern Australia, Canberra, . Deards, B 2015, ‘Beef and veal’, Agricultural commodities: March quarter 2015, pp. 102–111, Australian Bureau of Agricultural and Resource Economics and Sciences, Canberra. Durr, P, Graham, K & Eady, S 2010, GIS mapping of cattle market service using the National Livestock Identification System (NLIS)—final report, . Engineers Australia 2010a, Infrastructure report card 2010: Australia, November, . —— 2010b, Infrastructure report card 2010: Queensland, November, . —— Infrastructure Report Card 2010: New South Wales, July, .
Table Distribution of southern beef cattle producing farms, by farm business debt and equity ratio, at 30 June 2013ap percentage of farms Farm business debt unit Herd size Southern Australia Medium Large Very Large <$100 000 % 73 (6) 68 (7) 44 (17) 31 (21) 62 (5) $100 000 and <$250 000 % 10 (32) 13 (33) 21 (32) 7 (55) 13 (18) $250 000 and <$500 000 % 7 (31) 9 (35) 14 (30) 8 (45) 9 (18) $500 000 and <$1m % 5 (50) 5 (37) 9 (35) 15 (31) 6 (21) $1m and <$2m % 4 (56) 3 (30) 9 (25) 20 (28) 6 (17) ≥$2m % 1 (151) 2 (47) 4 (32) 20 (20) 4 (21) Total % 100 – 100 – 100 – 100 – 100 – Average farm debt at 30 June $ 182 000 (31) 238 000 (24) 399 000 (26) 1 372 000 (16) 335 000 (12) Farm business equity ratio b ≥90 per cent % 80 (5) 82 (4) 68 (8) 57 (12) 76 (3) 80 and <90 per cent % 11 (24) 10 (30) 23 (23) 21 (24) 14 (13) 70 and <80 per cent % 5 (67) 5 (41) 3 (48) 9 (40) 5 (30) 60 and <70 per cent % 4 (50) 2 (71) 4 (33) 7 (64) 3 (27) <60 per cent % 1 (24) 1 (83) 2 (53) 6 (36) 2 (29) Total % 100 – 100 – 100 – 100 – 100 – Average farm business equity ratio at 30 June % 93 (2) 92 (2) 91 (2) 87 (2) 91 (1) Population of farms no. 6 626 – 6 899 – 3 990 – 1 616 – 19 130 – a Excludes debt for large corporate farms. b Equity ratio defined as total owned capital at 30 June less debt as a percentage of total owned business capital p Preliminary estimate. Note: Figures in parentheses are standard errors expressed as a percentage of the estimate. Source: Australian Agricultural and Grazing Industries Survey