zilongwang/ReadingBank huggingface dataset:
It is recommended that the sponsor amends the RMP to list the use of follow up forms as routine risk minimisation activity. Should the Delegate request the RMP be amended as recommended by the evaluator, Biogen Idec will amend the RMP to list the use of follow up forms as routine risk minimisation activity. This response is considered unacceptable. The RMP is not the Delegate’s responsibility but that of the RMP evaluator and the director of the RMP section. Furthermore, in accordance with the relevant EU guideline, the use of specific questionnaires as a follow-up to a reported suspected adverse reaction is considered to be routine pharmacovigilance. Consequently the RMP should be amended accordingly. The RMP in its current version is unacceptable. The RMP is lacking discussion/provision of information about certain clinical aspects highly relevant to the use of the product in the targeted patient population. This includes the increased risk of antibody development for patients with high risk gene mutations (Gouw et al., Gosh et al.). It is recommended that the sponsor revised the RMP to include discussion on this point, and describes how it has been considered in the clinical development program and in the generation of the RMP. The eligibility criteria for the Phase III study were selected to ensure a representative study population of PTPs with severe haemophilia A. No inclusion or exclusion criteria in the Phase III study restricted the study population based upon gene mutations. In addition, genotype data were collected from study participants and was representative of the expected mutation frequencies in the general population of patients with haemophilia A. A revised RMP will include a discussion on the effect of the exclusion criteria across the clinical program and the implications for treatment of the target population. This response is considered insufficient. The sponsor states: A revised RMP will include a discussion on the effect of the exclusion criteria across the clinical program and the implications for treatment of the target population. However, the sponsor has not submitted the updated RMP, and it is unclear when the sponsor is going to submit the updated RMP. This recommendation remains. The consumer medicine information (CMI) and directions for use (DFU) are considered part of the risk Biogen Idec believes that the risk management described in the CMI and DFU is based upon information provided This response is considered unacceptable. In accordance with the
Efficacy in Control of Bleeding A total of 757 new bleeding events were observed during the study. Assessment of response to each injection was recorded by subjects at 8 to 12 hours post-treatment. A rating scale of excellent, good, moderate, and no response was used to assess response. Bleeding episodes are summarised in Table 6. Table 6: Summary of Efficacy in Control of Bleeding New bleeding episodes (n= 757) # of Injections to bleeding episodes 1 injection 661 (87.3%) 2 injections 79 (10.4%) 3 injections 13 (1.7%) ≥4 injections 4 (0.5%) (n=755) Median dose per injection (IU/kg) to treat a bleeding episode (IQR) 27.35 (22.73, 32.71) Median total dose (IU/kg) to treat a bleeding episode (IQR) 28.23 (23.26, 46.88) Response to first injection (n= 745) Excellent or good 78.1% Moderate 21.2% No response 0.7% Efficacy in Perioperative Management (Surgical Prophylaxis) Nine (9) surgical procedures were performed in nine subjects. Haemostasis was assessed post-operatively by the investigator using a 4-point scale of excellent, good, fair,
ADVERSE EFFECTS The most common adverse drug reactions observed in the multinational, open label, Phase 3 clinical study (incidence ≥1%) for ELOCTATE were arthralgia and malaise. No serious adverse drug reactions were reported in subjects who received ELOCTATE. In the multinational, open-label, Phase 3 clinical study with ELOCTATE, 164 subjects were evaluated, with 146 subjects treated for at least 26 weeks and 23 subjects treated for at least 39 weeks. Adverse drug reactions (ADRs) were reported in 9 of 164 (5.5%) subjects treated with routine prophylaxis or episodic (on-demand) therapy. Adverse drug reactions are considered adverse events assessed as related to treatment with ELOCTATE. Adverse drug reactions are summarised in 9. One (1) subject was withdrawn from due to an adverse drug reaction of rash. In the study, no inhibitors were detected and no events of anaphylaxis were reported. Table 9: Adverse Drug Reactions reported for ELOCTATE MedDRA2 System Organ Class MedDRA Preferred Term N=164* Number of Subjects n (%) Frequency Category3 Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) General disorders and administration site conditions Malaise Chest pain Feeling cold Feeling hot 2 (1.2) 1 (0.6) 1 (0.6) 1 (0.6) Common Uncommon Uncommon Uncommon Nervous system disorders Dizziness Dysgeusia Headache 1 (0.6) 1 (0.6) 1 (0.6) Uncommon Uncommon Uncommon Musculoskeletal disorders Arthralgia Joint swelling Myalgia 2 (1.2) 1 (0.6) 1 (0.6) Common Uncommon Uncommon Gastrointestinal disorders Abdominal pain, lower Abdominal pain, upper 1 (0.6) 1 (0.6) Uncommon Uncommon Vascular disorders Angiopathy1 Hypertension 1 (0.6) 1 (0.6) Uncommon Uncommon Cardiac disorders Bradycardia 1 (0.6) Uncommon Injury, poisoning, and procedural complications Procedural hypotension 1 (0.6) Uncommon
Bleeding treatment 1 dose per day (minor bleeding) 1-2 per day (moderate to severe bleeding) 1-2 per day 1 per day except for life threatening bleeding (13 per day) 1 per two days (minor and moderate bleeding) After 6-10 h then every 24 h (major bleeding) Surgical prophylaxis Loading dose then 1-2 per day 1-2 per day 1 per day (minor) 1-3 per day (major) 1 per one-two days (minor) After 6-10 h then every 24 h (major) Routine prophylaxis Twice weekly Two to three times per week Twice weekly Weekly (50 IU/kg) or every 10-14 days (100 IU/kg) The general approach is to modify dosage regimens (for example dosage intervals, based on individual factors. Romiplostim, aflibercept, etanercept and abatacept are examples of registered products that are fusion proteins combining the Fc fragment of IgG1 and another active molecule. Long plasma residency time is one purported advantage of such peptibodies (peptide plus antibody). Alprolix for “the control and prevention of haemorrhagic episodes in patients with haemophilia B (congenital factor IX deficiency or Christmas disease), including the control and prevention of bleeding in surgical settings.” was granted orphan drug status by the TGA on 20 September 2012. Eftrenonacog alfa is referred to as rFIXFc in this AusPAR. Regulatory status Alprolix received initial registration on the Australian Register of Therapeutic Goods (ARTG) on 1 May 2014. At the time this application was considered by the TGA, similar applications had been submitted to the USA (December 2012), Canada (March 2013), Japan (September 2013) and South Africa (December 2013), and were planned for New Zealand (2014) and the European Union (in 2015). Product Information The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1. For the most recent Product Information please refer to the TGA website at <>.
II. Quality findings Introduction Structure Elotuzumab consists of the complementarity determining regions (CDRs) of the antibody, MuLuc63, grafted onto human IgG1 heavy and kappa light chain framework regions. The predominant molecular isoform, heavy chain without C-terminal lysine and with the G0F/G0F glycoform, has an empirical formula of C6576H10142N1718O2092S42 with a calculated molecular mass of 148087 Daltons. Charge variant forms of the elotuzumab heavy chain exist with and without the C-terminal lysine residue. In heavy chain lacking a C-terminal lysine, glycine is the terminal residue. Physical and chemical properties Elotuzumab is a to very opalescent, colourless to slightly yellow liquid, pH 6.0, in an aqueous buffer. Based on the amino acid sequence defined by the nucleotide sequence, elotuzumab has an isoelectric point of 7.9 for the predominant charge variant, and a theoretical extinction coefficient of 1.61 mL mg-1 cm-1. Elotuzumab is produced from cell culture using an NS0 mouse myeloma-based cell line. The manufacturing process is initiated by thawing a vial of the working cell bank (WCB). The cell culture is expanded using a series of shake flasks, a cell bag bioreactor, and seed bioreactors to generate a sufficient amount of viable cells to inoculate the production bioreactor. Elotuzumab is purified using a series of chromatographic and filtration steps. The drug substance in filled bags is frozen and stored at ≤ -35°C. Stability Drug substance The sponsor proposed a shelf life of 36 months at -35°C for the drug substance. Stability data have been generated real time and stressed conditions. Stability data were generated under real time conditions to characterise the stability profile of the substance and to establish a shelf life. The real time data submitted support a shelf life of 36 months when stored at ≤ -35oC. Drug product Stability data have been generated under stressed and real time conditions to characterise the stability profile of the product. The product is not photostable. The proposed life is 36 months when stored at 5°C. Stability studies have been conducted in accordance with relevant ICH guidelines. trial
The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. For the most recent Product Information (PI), please to the TGA website <>. Copyright © Commonwealth of Australia 2018 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>. trial
Dose) relation to study drug) Female, 34 a None / None 3 Cycles (264 mg) cell carcinoma (Grade 2, serious, not related) 775 days (25 months) 928 days (~31 months) 3 Cycles (264 mg) cell carcinoma (Grade 3, serious, related) 1946 days (~63 months) 1172 days (~39 months) 3 Cycles (264 mg) Thyroid cancer 3, serious, related) 2021 days (70 months) 1247 (41 months) Female, 32 None / None 2 cycles (194 mg) Vulvar cancer 0 (Grade 3, serious, related) 637 days (21 months) 265 days (9 months) Female, 46 None / None 1 cycle (120 mg) cell carcinoma (Grade 3, serious, related) 155 days (5 months) 155 days (5 months) Female, 29 None / None 2 cycles (192 mg) Breast cancer (Grade 2, serious, related) 816 days (27 months) 434 days (14 months) Female, 44 None / family history of breast cancer 2 Cycles (192 mg) Breast cancer (Grade 3, serious, not related) 943 days (31 months) 527 days (17 months) Female, 28 None / None 2 Cycles (192 mg) Cervix carcinoma (grade 1, serious, not related) 695 days (23 months) 314 days (10 months) e
ddI didanosine DHHS Department of Health and Human Services DNA deoxyribonucleic acid dNTP 2' deoxynucleoside triphosphate DRV, D darunavir DTG dolutegravir DXA dual-energy x-ray absorptiometry EASC European AIDS Clinical Society EC50 concentration of a compound inhibiting virus replication by 50% EOP2 End of Phase 2 EVG, E elvitegravir (Vitekta) E/C/F/TAF elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (coformulated) EFV efavirenz eGFR estimated glomerular filtration rate eGFRCG estimated glomerular filtration rate calculated using the equation ESRD end-stage renal disease EU European Union EVG, E elvitegravir (Vitekta) FAS Full Analysis Set FDA Food and Drug Administration FDC combination FTC, F emtricitabine (Emtriva) FTC-DP emtricitabine diphosphate GCP Good Clinical Practice
Pharmacokinetics Studies providing pharmacokinetic data Table 4 below shows the studies relating to each PK topic. Table 4: Submitted pharmacokinetic studies. PK topic Subtopic Study ID PK in healthy adults General PKSingle dose Multi-dose 1245.1 1245.8 1245.5 None Bioequivalence † Single dose Multi-dose 1245.51 1275.3 1276.5 1276.9 Food effect 1245.3 1245.79 PK in special populations Target population § Single / multiple dosing Multi-dose PK-PD study 1245.2 1245.4 Hepatic impairment 1245.13 Renal impairment 1245.12 Neonates/infants/children/ adolescents None Elderly None Other special populations: PK-PD study in Chinese T2DM patients PK-PD study in Japanese T2DM patients 1245.44 1245.15 Genetic/ gender related PK Males versus females None Other genetic variable None PK interactions Metformin 1245.6 Glimepiride 1245.7 Pioglitazone 1245.17 Warfarin 1245.18
Additional exploratory endpoints included components of the macrovascular and microvascular composite endpoints, the composite endpoint of ‘heart failure requiring hospitalisation or CV death’, and all-cause mortality. Exploratory efficacy parameters included HbA1c, FPG (fasting plasma glucose), body weight, SBP (systolic blood pressure), and DBP (diastolic blood pressure). A clinical event committee was established for the central adjudication of potential cardiovascular end points. Comment: The number of efficacy endpoints is noted. Neuropathy was not assessed. There was no physiological assessment of heart function. Randomisation and blinding methods Randomisation as centrally via a computer generated random sequence and interactive voice and web response system. It was stratified for HbA1c, BMI, eGFR and geographical area. Analysis populations Table 1. Analysis populations in the EMPA-REG OUTCOME study Population Abbreviation Definition Screened set SCR All patients screened for the trial with informed consent give and who completed at least 1 screening procedure at Visit 1 Randomised set RS All patients from the screened set who were randomised to study medication Treated set TS All randomised patients who received at least 1 dose of study medication. This population was the basis of primary analysis On treatment set OS Patients who received treatment for at least 30 days (cumulative). Events were considered that occurred not later than 30 days after last intake of the study medication or until the end of the entire trial Full analysis set FAS All patients randomised, treated with at least 1 dose of medication and with a baseline HbA1c value Treated set follow up TS-FU All patients in the TS for whom a follow up visit was performed between 28 and 50 days after last intake of study medication Per Protocol set PPS All patients who were treated with at least 1 dose of study medication and did not have important protocol violations Sample size The trial continued until an adjudicated outcome event (a component of the 3-point MACE) had occurred in at least 691 patients. The criteria used to determine this sample size included:
Co-Administered Drug Dose of Drug (mg) Emtricitabine Dose (mg) N % Change of Emtricitabine Pharmacokinetic Parameters 2 (90% CI) Cmax AUC Cmin Tenofovir DF 300 once x 7 days 200 once x 7 days 17 20 ( 12 to 29) Indinavir 800 x 1 200 x 1 12 - Famciclovir 500 x 1 200 x 1 12 - d4T 40 x 1 200 x 1 6 - Zidovudine 300 BID x 7 days 200 once daily x 7 days 27 All interaction studies conducted in healthy volunteers = Increase; = Decrease; = no effect; “-“ = not applicable Table 3 Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Emtricitabine1 Co-Administered Drug Dose of Drug (mg) Emtricitabine Dose (mg) N % Change of Co-administered Drug Pharmacokinetic Parameters 2 (90% CI) Cmax AUC Cmin Tenofovir DF 300 once daily x 7 days 200 once daily x 7 days 17 Indinavir 800 x 1 200 x 1 12 - Famciclovir 500 x 1 200 x 1 12 - d4T 40 x 1 200 x 1 6 - Zidovudine 300 BID x 7 days 200 once daily x 7 days 27 17 (0 to 38) 13 ( 5 to 20) All interaction studies conducted in healthy volunteers = Increase; = Decrease; = no effect; “-“ = not applicable
Darunavir 800 + 100 ritonavir once daily 10 once 10 1.42 1.06 (0.84, 1.35)e NC 50 once daily 10 once daily 10 1.24 1.19 (0.96, 1.48) NC Efavirenz 600 once daily 40 once dailyc 11 0.78 0.86 (0.72, 1.02) NC Lopinavir 800/200 ritonavir once daily 10 once daily 10 2.19 1.47 (1.17, 1.85) NC Rilpivirine 25 once daily 25 once 17 1.01 1.01 (0.94, 1.09) NC Sertraline 50 once daily 10 once daily 19 1.00 0.96 NC NC = Not Calculated. a. All interaction studies conducted in healthy volunteers. b. All No Effect Boundaries are 70% -143% unless otherwise specified. c. Study conducted with DESCOVY (FTC/TAF). d. Mean ratio of tenofovir PK parameters (90% CI) was 3.16 (3.00, 3.33) for Cmax, 3.24 (3.02, 3.47) for AUC, and 3.21 (2.90, 3.54) for Cmin. e. Mean ratio of tenofovir PK parameters (90% CI) was 2.42 (1.98, 2.95) for Cmax, 2.43 (2.07, 2.84) for AUClast. f. Study conducted with Genvoya. There appears to be no apparent interaction between TAF and the commonly administered agents, such that the PK values of these agents remain unchanged in the presence of TAF. See table below: trial 4, 16) trial
200 mg itraconazole once daily on the PK of a single oral dose of 160 mg Pioglitazone; drug cocktail of S-warfarin, omeprazole and midazolam 9785-CL-0007 To determine the effect of multiple once daily administration of MDV3100 (160mg; four 40 mg capsules) on the PK of a single dose of pioglitazone (CYP2C8 substrate), (CYP2C9 substrate), omeprazole (CYP2C19 substrate) and midazolam (CYP3A4 substrate) in patients with CRPC. Population PK analyses Healthy subjects Study report 9785-PK-0002 To assess the extent of drug-drug interaction of gemfibrozil and itraconazole on single dose MDV3100 PK, using data from study Target population Study report 9785-PK-0001 To develop a population PK model of MDV3100, and population PK-PD models for its effect on antigen (PSA) concentration (a biomarker for prostate cancer progression) and spontaneously reported fatigue (the most frequently reported adverse event), using data from Study S-3100-1-01. Study report icon2147020 To investigate potential factors that may increases in plasma concentrations of MDV3100 metabolite M1 (also referred to as MDCP0001) in CRPC patients in Study CRPC2. Study report icon2147016 To document the relationship(s) of MDV3100 and its active metabolite M2 (also referred to as MDPC0002) steady‐state pre‐dose plasma concentrations (Cmin) with study efficacy and safety outcomes in Study CRPC2. Both healthy and target population Study report icon2147014 To a population PK model of MDV3100 after oral administration of MDV3100 liquid-filled capsules in healthy male subjects and in patients with CRPC, including cofactors that contribute to inter-individual warfarin S-
The sponsor should provide information on the post market experience of patients with central nervous system conditions that are taking enzalutamide. Pharmacovigilance plan The sponsor proposes routine pharmacovigilance activities for important identified and potential risks and missing information. Furthermore, additional activities are planned for some of the risks. These activities are summarised in Table 18. 18: Additional pharmacovigilance activities planned by the sponsor. Additional activity Assigned safety concern Actions/outcome proposed Estimated planned submission of final data Post authorisation safety study Category: 3 Ongoing Seizure The safety of enzalutamide in patients excluded from the pivotal study due to certain baseline factors considered predisposing for seizure. Study completion date: June 2018 Final report submission: March 2019 Clinical study Category: 3 Ongoing at time of RMP sign-off date. Patients with moderate or severe hepatic impairment (study concerned with severe hepatic impairment) Assess, in subjects with normal hepatic function and patients with severe hepatic impairment, the effect of severe hepatic impairment on the pharmacokinetics of enzalutamide and enzalutamide Study completion date: May 2014 Final report submission: November 2014 Clinical study Category: 3 Planned at time of RMP sign-off date; now ongoing Patients with moderate or severe hepatic impairment concerned with moderate hepatic impairment) Assess, in subjects with normal hepatic function and patients with moderate hepatic impairment, the effect of moderate hepatic impairment on the pharmacokinetics of enzalutamide and enzalutamide Draft protocol submission: February 2014 Final report submission: December 2015 Post- authorisation efficacy study Category: 3 Ongoing Data on the efficacy of enzalutamide in patients with metastatic Data on the efficacy of enzalutamide in patients with metastatic CRPC previously Report of interim Analysis: June 2015 Final report submission: December 2016
Specific conditions of registration applying to these goods The Xtandi EU-RMP, version 7.0 6 October 2014, Data Lock Point 16 September 2013 for Phase III Study MDV3100-03 and 1 July 2013 for the remaining studies in the Integrated Safety Population) and ASA version 1.2 (dated 17 October 2014), and any subsequent revisions, as agreed with the TGA will be implemented in Australia. Attachment 1. Product Information The PI approved for Xtandi at the time this AusPAR was published is at Attachment 1. For the most recent PI, please refer to the TGA website at <>. Attachment 2. Extract from the Clinical Evaluation Report
or following overdosage with ganglionic-blocking agents, antiadrenergic agents, veratrum alkaloids or other drugs used for lowering blood pressure in the treatment of arterial hypertension. The drug is sometimes injected to relieve acute bronchospasm, but it is less effective than epinephrine for this purpose. DBL Ephedrine Sulfate Injection has also been used in the treatment of bronchial asthma and reversible bronchospasm although more selective agents (beta adrenergic agonists) are now available. General dosage instructions Depending on the clinical circumstances, Ephedrine Sulfate Injection may be given subcutaneously, intramuscularly or intravenously. NA DBL Ephedrine Sulfate Injection is administered by the intramuscular, subcutaneous or intravenous Patients in shock may require intravenous administration to ensure absorption of the drug. When administered intravenously, the injection should be given slowly. Care should be taken to avoid extravasation, since this may result in tissue necrosis and sloughing. Ephedrine sulfate should be administered in the lowest effective dose. The parenteral adult dose should not exceed 150 mg in 24 hours. Adult dose for hypotension 25 to 50 mg (range 10 to 50 mg) injected subcutaneously or intramuscularly (equivalent to 0.2 to 1.0 mL of 5% solution) is usually adequate to prevent or minimize hypotension secondary to spinal anaesthesia. Repeat doses should be governed Up to 30 mg in increments of 3 to 7.5 mg. After the development of hypotension, by slow intravenous administration. The usual adult dose is 25 to 50 mg (range 10 to 50 mg) administered intramuscularly or subcutaneously. Additional doses should be based on patient response. The intravenous route may be used if an immediate response is required. The dosage for the intravenous route is
Table 5. Maximum systolic/diastolic blood pressure reduction from baseline - patients age <75 (based on complete DB phase database), study A6141079 Table 6.Maximum systolic/diastolic blood pressure reduction from baseline - patients age >=75 (based on complete DB phase database), study A6141079
* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Evaluation of non-target lesions *Complete Response (CR): Disappearance of all non-target lesions and normalization of marker level *Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits *Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions (1.) 1. Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion of the treating physician should prevail and the progression status should be confirmed later on by the review panel (or study chair). Evaluation of best overall response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Target lesions Non-Target Lesions New Lesions Overall Response CR CR No CR CR Incomplete response/SD No PR PR Non-PD No PR SD Non-PD No SD PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having “symptomatic deterioration”. effort should be made to document the objective progression even after discontinuation of treatment. In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. Confirmation The main goal of confirmation of objective response is to avoid overestimating the response rate observed. In cases where confirmation of response is not feasible, it should be made clear when reporting the outcome of such studies that the responses are not confirmed.
Oral candidiasis Upper respiratory tract infection Nasopharyngitis Rhinitis Oral herpes Herpes zoster Blood and lymphatic disorders Neutropenia Leukopenia Anaemia Febrile neutropenia Thrombocytopenia Lymphopenia Metabolism and nutrition disorders Decreased appetite Hypokalaemia Hypomagnesaemia Dehydration Hyperglycaemia Hypophosphataemia Psychiatric disorders Insomnia Depression Nervous system disorders Peripheral neuropathy Headache Dysgeusia Dizziness Hypoaesthesia Lethargy Neurotoxicity Eye disorders Lacrimation increased Conjunctivitis Ear and Labyrinth Disorders Vertigo Tinnitus Cardiac disorders Tachycardia Vascular disorders Hot flush Deep vein thrombosis Pulmonary embolism Respiratory, thoracic and mediastinal disorders Dyspnoea Cough Oropharyngeal pain Epistaxis Rhinorrhoea Interstitial lung disease Gastrointestinal disorders Nausea Constipation Diarrhoea Vomiting Abdominal pain Stomatitis Dry mouth Dyspepsia Gastrooesophageal reflux disease Mouth ulceration Abdominal distension Hepatobiliary disorders Alanine aminotransferase increased Aspartate aminotransferase increased Hyperbilirubinaemia Skin and subcutaneous tissue disorders Alopecia Rash Pruritus Nail disorder Night sweats Palmar plantar erythrodysaesthesia Dry skin Erythema Hyperhidrosis Angioedema Musculoskeletal and connective tissue Arthralgia and Myalgia Pain in extremity Muscle spasms
benefit. More recent studies have used dacarbazine as the comparator arm in trials of novel therapies. Response rates obtained with dacarbazine in these studies have been less impressive. Dacarbazine continues to be listed in the NCCN and ESMO guidelines as an option for 2nd or later line chemotherapy. In addition, the current Australian guideline recommends the following: For patients who have been exposed to both doxorubicin and ifosfamide, dacarbazine is considered the next most active approved agent. It is also noteworthy that other regulatory authorities with similar standards to the TGA, such as the FDA and EMA, have accepted dacarbazine monotherapy as an acceptable comparator given their approvals for trabectedin and eribulin. As above, dacarbazine is registered in Australia for the treatment of STS. Overall it is considered that the sponsor’s choice of dacarbazine monotherapy as the comparator agent in the pivotal study is acceptable. Table 3: Published studies of dacarbazine monotherapy in STS Study Design Indication N Dacarbazine regimen ORR Median PFS Median OS Gottlieb 1976 Phase II STS 53 Various 17% - - Buesa 1991 Phase II STS – various 2nd line 44 1200 mg/m2 Day 1 of a cycle 18% (95% CI: - - 1996 Case series STS – various 2nd line 14 1200 mg/m2 Day 1 of a cycle 0% - 5 mths Zucali 2008 Case series STS – various 2nd line 40 800 mg/m2 on day 1; or 400 mg/m2 on days 1 and 2; or 300 mg/m2 on days 1, 2 and 3. 21-day cycle for all 7.5% 2 mths 13 mths 2011 II RCT Vs. + STS – various 2nd line 52 1200 mg/m2 Day 1 of a cycle 4% (95% CI: 2 mths 8.2 mths Phase III RCT 173 1000 mg/m2 6.9% 1.5 12.9
the patients had a baseline ECOG performance status (PS) of 1 and 17% had a baseline ECOG PS of 2. Most patients presented with metastatic disease at study entry as the initial manifestation of pancreatic cancer (77% in the TARCEVA arm, 76% in the placebo arm). Survival was evaluated in the intent-to-treat population based on follow-up survival data including 551 deaths. Results are presented for the 100 mg dose cohort (504 deaths) in Figure 4. The adjusted HR for death in the TARCEVA group relative to the placebo group was 0.82 (95% CI: 0.69 0.98;p = 0.028). The percentage of patients alive at 12 months was 23.8% in the TARCEVA group compared to 19.4% in the placebo group. The median overall survival was 6.4 months in the TARCEVA group compared with 6 months in the placebo group. Figure 4: Kaplan-Meier curve for overall survival of patients in TARCEVA 100mg dose cohort by treatment group in Study PA.3 6: Study PA.3 Efficacy Results TARCEVA 100 mg plus gemcitabine (n = 261) Placebo plus gemcitabine (n = 260) p-value Median survival 6.4 months 6 months Hazard ratio, mortality (TARCEVA:placebo) (95% CI) 0.82 (0.69 – 0.98) 0.028 % patients at 12 months 23.8 19.4 The median PFS was 3.81 months (16.5 weeks) in the TARCEVA group (95% CI; 3.58 4.93) compared with 3.55 months (15.2 weeks) in the placebo group (95% CI; 3.29 3.75; p = 0.006). The median duration of response was 5.5 months, ranging from 0.85 months 12.8+ months. The objective response rate (complete response and partial response) was 8.6% in the TARCEVA group and 7.9% in the placebo group. The proportion of patients who experienced complete response, partial response or stable disease was 59% and 49.4% respectively, for the TARCEVA and placebo groups (p = 0.036). INDICATIONS Non-small cell lung cancer:
General disorders and administration site conditions Fatigue 52 14 4 45 16 4 Metabolism and nutrition disorders Anorexia 52 8 1 38 5 <1 Respiratory, thoracic and mediastinal disorders Dyspnoea Cough 41 33 17 4 11 0 35 29 15 2 11 0 Infections and infestations* Infection 24 4 0 15 2 0 Eye disorders Conjunctivitis Keratoconjunctivitis sicca 12 12 <1 0 0 0 2 3 <1 0 0 0 * severe infections, with or without neutropenia, have included pneumonia, sepsis and cellulitis. In another double-blind, randomised, placebo-controlled Phase III study (BO18192) conducted in 889 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy, no new safety signals were identified.
Product Information The approved Product Information (PI) current at the time this AusPAR was prepared can be as Attachment 1. For the most recent Product Information please refer to the TGA website at <>. II. Quality findings 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 A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 2. Introduction ETN is a recombinant, humanized tumour necrosis factor (TNF) receptor fusion protein, which has high affinity binding to TNF and blocks its interaction with cell surface TNF receptors. Clinical rationale JIA encompasses a diverse group of arthritic conditions of unknown aetiology that begin before the sixteenth birthday, and persist for at least 6 weeks. It is one of the most physically disabling conditions of childhood, with prevalence in Australia of 0.3% according to the Australian Institute of Health and Welfare 2012 report. JIA is a heterogeneous disorder, and the subtypes have varying clinical and laboratory features that may reflect distinct immunopathogenic processes. The pathogenesis of each subtype is multifactorial and likely to be triggered by environmental stimuli in genetically susceptible individuals. JIA is a WHO endorsed, internationally accepted umbrella term that has replaced all previously used nomenclatures such as juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA). Further information is contained within the Clinical Evaluation Report (CER) at Attachment 2. Guidance The TGA has recommended review and consideration of one specific regulatory guideline pertaining to the requested extension of indication. The TGA has adopted the EU guideline CPMP/EWP/422/04 “Guideline on Clinical Investigation of Medicinal Products for the Treatment of Juvenile Idiopathic Arthritis” (effective 26 June 2009). The sponsor has recommended consideration of 2 related guidelines in reviewing this submission: Committee for Medicinal Products for Human Use (CHMP) guidelines on Clinical Trials in Small Populations (July 2006) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines on Choice of Control Group in Clinical Trials (January 2001).
identified or explained. Furthermore to be consistent references to the ‘global RMP’ in Section 3.8.1 of the ASA should be amended to refer to the Consequently the sponsor should revise the ASA accordingly and provide an updated version to the TGA for review. 2. Safety considerations may be raised by the clinical evaluator and/or the Clinical Evaluation Report. It is important to ensure that the information provided in response to these includes a consideration of the relevance for the RMP, and any specific information needed to address this issue in the RMP. For any safety considerations so raised, the sponsor should provide information that is relevant and necessary to address the issue in the RMP. The sponsor acknowledged this recommendation. The clinical evaluator has suggested wording for the indication which differs from that stated in the updated ASA. Consequently the sponsor should revise the ASA accordingly if required, preferably before this application is approved. 3. Even though uveitis and scleritis are no longer classified as important potential risks, the sponsor should amend the ASA to state that routine pharmacovigilance and routine risk minimisation are nevertheless applied to these safety concerns. The sponsor acknowledged this recommendation and has added the following sentence to Section 2.1 of the ASA: ‘Routine pharmacovigilance is conducted for all adverse reactions in addition to the risks identified in the RMP.’ This proposal is only acceptable if the sponsor provides an assurance that future Periodic Safety Update Reports (PSURs) will specifically report on the safety concerns: uveitis and scleritis. 4. The studies referenced in the pharmacovigilance plan will generate safety data that will simply support the safety profile of the medicine, while others will generate data that will provoke applications to amend the Australian registration details. It is acknowledged that the sponsor’s correspondence dated August 2013 states that all paediatric study reports and updates that are submitted to the EU will also be submitted to Australia with the same timelines. Nevertheless to The sponsor acknowledged this recommendation and revised the ASA accordingly. Attachment I –Additional pharmacovigilance activities and estimated Australian submission dates of the updated ASA does not appear to be consistent with or as comprehensive as Table 85: ‘Ongoing and Planned Additional PhV Studies/Activities in the Pharmacovigilance Plan’ of the updated EU-RMP. Consequently the sponsor should correct this oversight and revise the ASA preferably before this application is approved.
TEAEs suspected to be related to study drug during TP1, by preferred term (1% or greater total incidence of either system organ class (SOC) or preferred term (PT), study GP15-302 Preferred term ERELZI N=264 n (%) Enbrel N=267 n (%) Number of patients with at least one TEAE 35 (13.3) 37 (13.9) Nasopharyngitis 2 (0.8) 4 (1.5) Upper respiratory tract infection 3 (1.1) 3 (1.1) Weight increased 3 (1.1) 3 (1.1) n (%)=number of subjects (percentage) with adverse events; N=number of subjects studied; PT=preferred term; SOC=system organ class; TEAE=treatment-emergent adverse event; TP1=Treatment Period 1 The overall incidence of SAEs was low and comparable, with no SAE occurring in more than one patient. Similar safety profiles and comparisons were observed in TP2 and Extension Period. The table below provides a list of the TEAEs with a suspected causal relationship to study treatment from baseline to week 52, in those patients who continuously received either ERELZI or the reference medicine. TEAEs suspected to be related to study drug (baseline to week 52), by preferred term (1% or greater total incidence) Preferred term ERELZI N=164 n (%) Enbrel N=171 n (%) Number of patients with at least one TEAE 34 (20.7) 33 (19.3) Nasopharyngitis 4 (2.4) 2 (1.2) Viral upper respiratory tract infection 2(1.2) 4 (2.3) Upper respiratory tract infection 2 (1.2) 3 (1.8) Pharyngitis bacterial 2 (1.2) 0 Rhinitis 0 2 (1.2) Upper respiratory tract infection bacterial 2 (1.2) 0 Weight increased 2 (1.2) 3 (1.8) Gamm-glutamyltransferase increased 2 (1.2) 0 Psoriasis 0 3 (1.8)
not recommended. Certican has not been evaluated with full dose tacrolimus in controlled clinical trials. OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats. Reported experience with overdose in humans is very limited. is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year old child where no adverse events were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. General supportive measures should be initiated in all cases of overdose. The Poisons Information Centre (telephone 13 11 26) is available for advice. PRESENTATION AND STORAGE CONDITIONS Certican tablets to yellowish, marbled, round, flat with bevelled edge) 0.25mg (engraved with “C” on one side and “” on the 60’s; 0.50 mg (engraved with “CH” on one side and “” on the other): 60’s; 0.75 mg (engraved with “CL” on one side and “” on the other): 60’s; 1.0 mg (engraved with “CU” on one side and “” on the other): 50’s, 60’s, 100’s, 120’s. Certican dispersible tablets (white to yellowish, marbled, round, flat with bevelled edge) 0.10mg (engraved with “I” on one side and “” on the other): 0.25mg (engraved with “JO” on one side and “” on the other): 50’s, 60’s, 100’s, 120’s Not all presentations are marketed in Australia. Store below 30°C in the original packaging. Protect from light and moisture. NAME AND ADDRESS OF THE SPONSOR Novartis Pharmaceuticals Australia Pty Limited ( No: 18 004 244 160) 54 Waterloo Road NORTH RYDE NSW 2113 ® = Registered Trademark POISON SCHEDULE OF THE MEDICINE Prescription Only Medicine (Schedule 4) DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG) 17 March 2005
SYR-322/CPH-002 Metabolism SYR-322-014 Mass balance -Multi-dose Study SYR-322-101 Bioequivalence† - Single dose Study SYR-322-027 Commercial formulation Food effect Study SYR-322-026 25 mg dose Study SYR-322/CPH-006 SYR-322-CPH-007 Study SYR-322-005 PK in special populations Target population§ Single dose None -Multi-dose Study SYR-322-002 Target population PK Hepatic impairment Study SYR-322-023 Hepatic impairment Renal impairment Study SYR-322-006 Renal impairment children/ adolescents None Elderly Study SYR-322-022 General PK Study SYR-322/CPH-003 General PK Genetic/ gender-related PK Males versus females SYR-322-022 General PK PK interactions MET, cimetidine Study SYR-322-005 Interaction caffeine, tolbutamide, dextromethorphan, midazolam, fexofenadine Study SYR-322-015 Interaction
Table Summary of efficacy results for exenatide in combination with basal insulin compared to placebo (ITT subjects) Least Squares Mean or Percentage of subjects Variable Exenatide (N=137) Placebo (N=122) Between Treatment Difference (95% CI) Primary Objective Haemoglobin (A1c%) Baseline Week 30 Change 8.3 6.7 -1.7 8.5 7.4 -1.0 -0.20 -0.71 (-0.95 to -0.47) p<0.001 Secondary Objectives Proportion reaching glycaemic target Haemoglobin A1c <7.0% Haemoglobin A1c ≤6.5% 56% 42% 29% 13% -- -- Body weight (kg) Baseline Week 30 Change 95.4 93.6 -1.78 93.8 96.3 +0.96 1.6 -2.74 (-3.74 to -1.74) Change in insulin dose at Week 30 U/day U/kg 13 0.15 20 0.20 -6.5 (-12.24 to -0.79) -0.05 (-0.10 to 0.00) Fasting serum glucose (mmol/L) Baseline Week 30 Change 7.4 6.1 -1.28 7.4 6.5 -0.87 -0.01 -0.41 (-0.99 to 0.18) Change in glucose excursion (mmol/L) Morning 2-hour Midday 2-hour Evening 2-hour -2.0 -0.5 -1.6 -0.2 -0.3 0.1 -1.8 (-2.5 to -1.2) -0.3 (-0.8 to 0.3) -1.7 (-2.3 to -1.1) Abbreviations: CI=confidence interval. When exenatide was added to existing basal insulin therapy (insulin glargine), the dose of basal insulin was decreased by 20% in patients with an HbA1c ≤8.0%, per
24 123 10.3 48 317 26.4 Estimated values for carcinogenicity study based on values from (B6C3F1) ♂ 3 3.4 0.3 7.5 11 0.9 18.75 28 2.3 ♀ 3 13.2 1.2 7.5 38 3.2 18.75 97 8.1 Rat 26 weeks Study: S0##C3R100^ (Slc:SD) 3 14.6 1.2 12 69.6 5.8 48 272 23 3 months Study: S0##S2R10A^ study (F344/DuCrj) – day 91 3 17 1.4 12 73.8 6.2 24 198 17 3 months Study: S0##S2R10B^ (F344/DuCrj) – day 91 48 357 30 75 623 52 150 1184 99 Dog 3 months Study: S0##S2D100^ (HRP Beagle) – day 90 5 2.6 0.2 20 27 2.3 80 471 39 12 months S0##C4D100^ (CSK Beagle) – day 365 5 4.6 0.4 15 35.3 2.9 45 484 40 Human (healthy subjects) steady state [120 mg] 12 – # = animal: human plasma AUC0–24 h; ^Mean male and female AUC values; bolded and shaded = NOAEL.
Phase II Evaluate the effects of fenofibric acid (SLV348) on changes of DME Fenofibric acid, 135 mg, once oral 110 T2DM with Diabetic DME 12 months Full Phase III Evaluate the benefit of versus placebo both with in limiting the of DR placebo Fenofibrate 160 mg tablet, once daily, oral 1593 T2DM 4 Pharmacokinetics Studies providing pharmacokinetic data No new information available. Evaluator’s overall conclusions pharmacokinetics No new information available. Pharmacodynamics Studies providing pharmacodynamic data No new information available. Evaluator’s overall conclusions of pharmacodynamics No new information available. Dose selection for the pivotal trials ACCORD-Eye Study: 160mg tablet on
Uncommon Asthenia, Chills, Face Oedema, Fatigue, Gait Disturbance, Malaise, Non-cardiac Pain, Oedema Peripheral, Pain, Pyrexia, Thirst Immune System Disorders Uncommon Hypersensitivity Infections and Infestations Uncommon Nasopharyngitis, Pharyngitis , Pneumonia, Rhinitis Injury, Poisoning and Procedural Complications Uncommon Fall, Intentional Drug Misuse, Medication Investigations Uncommon Platelet Count Decreased, Weight Decreased Metabolism and Nutrition Disorders Uncommon Decreased Appetite, Dehydration, Hyperglycaemia, Increased Appetite Musculoskeletal and Connective Tissue Disorders Uncommon Arthralgia, Muscle Twitching Nervous System Disorders Uncommon Ageusia, Anosmia, Convulsion, Depressed Level of Consciousness, Lethargy, Loss of Consciousness, Memory Impairment, Parosmia, Sedation, Speech Disorder, Tremor Psychiatric Disorders Uncommon Anxiety, Attention Deficit/hyperactivity Disorder, Confusional State, Delirium, Depression, Disorientation, Drug Abuse, Euphoric Mood, Hallucination, Visual, Nervousness Renal and Urinary Disorders Uncommon Anuria, Dysuria, Proteinuria, Urinary Hesitation Reproductive System and Breast Disorders Uncommon Vaginal Haemorrhage Respiratory, Thoracic and Mediastinal Disorders Uncommon Dyspnoea, Intranasal Hypoaesthesia, Nasal Congestion, Nasal Dryness, Nasal Mucosal Disorder, Pharyngolaryngeal Pain, Postnasal Drip, Rhinorrhoea, Sneezing, Throat Irritation, Upper Airway Obstruction, Upper Respiratory Tract Congestion Skin and Subcutaneous Tissue Disorders Uncommon Hyperhidrosis, Night Sweats, Pruritus Generalised, Urticaria Vascular Disorders Uncommon Cardiovascular Insufficiency, Hot Flush, Hypotension, Lymphoedema
System Organ Class Adverse Reaction by Frequency Very common ≥ 1/10 Common ≥ 1/100 to <1/10 Uncommon ≥ 1/1000 to <1/100 Not (cannot be estimated from available data) Immune system disorders Hypersensitivity Metabolism and nutrition disorders Anorexia Decreased appetite Psychiatric disorders Depression Paranoia Confusional state Disorientation Mental status changes Anxiety Euphoric mood Dysphoria Emotional lability Disturbance in attention Nervous system disorders Dizziness Headache Somnolence Amnesia Parosmia Dysgeusia Tremor Lethargy Hypoasthesia Insomnia Sleep disorder Eye disorders Vision blurred Cardiac disorders Tachycardia Bradycardia Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Dyspnoea Oropharyngeal pain Throat tightness Gastrointestinal disorders Nausea Stomatitis Vomiting Constipation Dry mouth Mouth ulceration Gingival ulceration Lip ulceration Impaired gastric emptying Abdominal pain Dyspepsia Stomach discomfort Tongue disorder Aphthous stomatitis Swollen tongue*
Missing 21 (6) Average dose (µg)a 206 (58) ≤800 µg >800-≤1600 µg 54 (15) >1600-≤2400 µg 27 (8) >2400-≤3200 µg 47 (13) >3200 µg 21 (6) Missing 3 (<1) a The average dose per BTP episode and the average daily dose were calculated for the titration and post titration periods combined. BTP=breakthrough pain. Table 21: Average Study Drug Dose per Breakthrough Pain Episode by Weeks or Months of Exposure in Patients with Cancer and Breakthrough Pain. Studies 099-14, 3039, Length of exposure Number (%) of patients by average dose per BTP episode (mcg) <200 (N=49) (N=91) (N=100) (N=79) ≥800 (N=18) (N=21) Total (N=358) ≥1 day 49 (100) 91 (100) 100 (100) 79 (100) 18 (100) 21 (100) 358 (100) ≥1 week 27 (55) 69 (76) 75 (75) 79 (100) 17 (94) 4 (19) 271 (76) ≥2 weeks 19 (39) 54 (59) 63 (63) 74 (94) 16 (89) 2 (10) 228 (64) ≥1 month 17 (35) 35 (38) 53 (53) 67 (85) 16 (89) 1 (5) 189 (53) ≥3 months 7 (14) 24 (26) 38 (38) 53 (67) 12 (67) 0 134 (37) ≥6 months 3 (6) 15 (16) 18 (18) 33 (42) 11 (61) 0 80 (22) 15.
5. Relative exposure to fidaxomicin at the end of repeat-dose toxicity studies Species Study duration Dose (mg/kg/day) Actual or Nominal AUClast (µg.h/mL) Exposure ratio# AUC Dog beagle 14 days PO Capsule 58 N 0.09 1 144 N 0.3 4 461 N 2 24 14 days PO Capsule 771 N 4.7 58 1067 N 16 196 14 days PO gavage 30 N 2.4 – 7.6 29-93 60 N 1.7 – 8.5 21-104 120 N 6 73 3 PO Gavage 108 N 0.7 9 364 N 5.4 66 1038 N 11.2 137 Monkey Cynomolgus 4 weeks PO capsule 34 A 0.25 3 102 A 0.75 9 Human healthy volunteers Single dose PO [400 mg] 0.0817 # = animal:human plasma AUC0–24 h ; ND-not detected in plasma, LLOQ=0.5 µg/mL 6. Relative exposure to the fidaxomicin metabolite OP-1118 in repeat-dose toxicity studies Species Study duration (number) Nominal Dose (mg/kg/day) AUC0–last (µg.h/mL) AUC exposure ratio# AUC Dog (beagle) 14 days PO Capsule 460 0.045 0.3 14 days PO capsule 771 0.4 2 1067 1.8 10 30 0.3-0.8 2-5 60 0.06-0.6 0.3-3 WIL-