zilongwang/ReadingBank huggingface dataset:
52.5% male and 47.5% female Sex distribution: 54% males and 46% female Sex distribution: 59% male and 41% female. Sex distribution: 54% male and 46% female Dose 10 µg/kg 5 µg/kg 2.5 or 5 µg/kg 1 µg/kg Frequency of dosing Daily SC injections for seven days Single IV injection Daily SC injections for 7 days. Single SC injection Objectives Primary: Evaluate PK bioequivalence Secondary: Compare PD, safety, local tolerance. Primary: Evaluate PK bioequivalence Secondary: Compare PD and Safety Primary: Evaluate PD equivalence. Secondary: Safety, local tolerance, PK Primary: Evaluate PD equivalence. Secondary: Safety, local tolerance, PK. Main PK results Confirmatory analysis demonstrate that at 10µg/kg/day, EP2006 and Neupogen are bioequivalent within the predefined accepted criteria of 80-125% for the 90% confidence intervals of AUC and 75-133% confidence intervals of Cmax, both after the first dose and at steady state. Confirmatory analyses demonstrate that EP2006 is bioequivalent to Neupogen for both AUC and Cmax. The 90% confidence intervals were within the accepted range of 80-125% for AUC and for Cmax. Descriptive analyses demonstrate that the 90% confidence intervals for all single-dose and multiple-dose AUCs were included within the conventional 80-125% criterion, as was the 90% CI for Cmax after a single dose of 5 µg/kg. The CI for Cmax after a single dose of 2.5 µg/kg was within the boundaries of 75-133%. At 2.5 µg/kg and at 5 µg/kg (multiple dose) the CIs for Cmax were contained within the extended boundaries Descriptive analyses demonstrate that EP2006 is bioequivalent to Neupogen for both AUC and Cmax. The 90% confidence intervals were within the acceptance range of 80-125%. Evaluator’s overall conclusions on pharmacokinetics Pharmacokinetic equivalence was demonstrated between EP2006 and Neupogen by the Phase I studies. defined
These adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of adverse reactions: Very common: ≥1/10 Common: ≥1/100 to <1/10 Uncommon: ≥1/1000 to <1/100. Rare ≥1/10000 to <1/1000 Very rare <1/10000 System organ class Adverse reaction(s) Frequency Infections and infestations Pneumonia* respiratory tract infection Bronchitis, Influenza Candidiasis of mouth and throat Common Nervous system disorders Headache Very common Cardiac disorders Extrasystoles Uncommon Respiratory, thoracic & mediastinal disorders Nasopharyngitis Oropharyngeal pain Sinusitis, Pharyngitis Rhinitis, Cough, Dysphonia Very common Common Gastrointestinal disorders Abdominal pain Common Musculoskeletal and connective tissue disorders Arthralgia, Back pain Fractures** Common Common General disorders and administration site conditions Pyrexia Common Description of selected adverse reactions *Pneumonia
PRESENTATION AND STORAGE CONDITIONS Presentation DYMISTA 125/50 nasal spray is supplied as an amber glass bottle (type I) fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump with a white nasal adapter and clear plastic dust cap. The available pack sizes are: 4 mL bottle containing 28 sprays (starter pack) and 17 mL bottle containing 120 sprays. DYMISTA 125/50 contains the antimicrobial preservatives benzalkonium chloride and phenethyl alcohol. Storage Conditions DYMISTA 125/50 spray should be kept out of reach of children. Store below 25°C. Do not refrigerate. Do not freeze. Discard after 6 months of first opening the bottle. POISON SCHEDULE OF THE MEDICINE Schedule 4 – Prescription Only Medicine SPONSOR Meda Pharmaceuticals Pty Ltd Suite 1, Level 3, 110 Pacific Highway ST LEONARDS NSW 2065 Australia Telephone: 1800 048 987 Date of TGA Approval: 16 December 2013. Date of most recent amendment: Australian Registration Number AUST R 203131.
EMEA/CHMP/EWP/356954/2008: Guidelines on the Clinical Investigations of Medicinal Products for the Treatment of Pulmonary Arterial Hypertension; and CHMP/EWP/83561/2005: Guideline on Clinical Trials in Small Populations (effective December 2006). Regulatory status The international regulatory status at the time of this submission to TGA is listed in Table 1. Table 1: International regulatory status of Volibris at time of submission to TGA. Country / region Submission date Status Indications (approved or requested) EU 9 Dec 2014 CHMP: positive opinion received on 27 Oct 2015 EU: Commission Decision estimated by end of Dec 2015 Volibris is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III, including use in combination treatment (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease. US 5 Dec 2014 Approved: 2 Oct 2015 Letairis is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO 1): - To improve exercise ability and delay clinical worsening. - In combination with tadalafil to reduce the risks of disease progression and hospitalisation for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included trials predominantly in patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).
The search strategy described provides a comprehensive and broad search selecting relevant studies. However most of the available literature is case reports. The submission contained the following clinical information: 10 clinical studies have been conducted to evaluate the pharmacokinetic parameters of fomepizole in healthy volunteers and in patients with ethylene glycol and methanol poisoning to determine optimum dosing recommendation, interactions with ethanol, and the effects of renal dialysis on fomepizole plasma levels, since dialysis is commonly used as a component of the treatment for both EG and methanol poisonings. Three pivotal efficacy/safety studies conducted by the manufacturer: Studies S7 S8 (OMC-4MP-1) and S13 (OMC-4MP-2). Other efficacy/safety studies: these include many published studies and case reports. 272 literature references Paediatric data The submission did not include any paediatric clinical studies (conducted by the manufacturer). However, some case reports and case series of use of fomepizole in treatment of EG and methanol poisoning in infants and children were provided. Good clinical practice (GCP) The 3 main studies submitted by the manufacturer were conducted according to GCP ICH guidelines. Most of the other published studies were conducted with ethics approval from the investigating centre. Pharmacokinetics Studies providing pharmacokinetic data Table 2 below shows the studies submitted relating to each pharmacokinetic topic. Table 2: Submitted pharmacokinetic studies PK Subtopic Study ID PK in healthy adults General PK- Single dose S-2 S-3 Maraffa, 2008 Jacobsen, 1996 - Multi-dose McMartin , 2012 Bioequivalence† - Single dose S-2 - Multi-dose S-3 Food effect Not applicable. PK in special populations Target population - Single dose S1 S11
[0.91, 1.15] Mutation-Positive 14.2 (n=22) 16.6 (n=22) 0.83 [0.41, 1.67] Mutation-Negative 6.4 (n=119) 6.0 (n=134) 1.02 [0.78, 1.33] PFS median mths All Subjects 2.2 (n=659) 2.7 (n=657) 1.04 [0.93, 1.18] Mutation-Positive 7.0 (n=19) 4.1 (n=19) 0.16 [0.05, 0.49] Mutation-Negative 1.7 (n=106) 2.6 (n=123) 1.24 [0.94, 1.64] ORR2 % All Subjects 9.1 (n=659) 7.6 (n=657) 1.5 [-1.5, 4.5] Mutation-Positive 42.1 (n=19) 21.1 (n=19) 21.0 [-8.2, 46.0] Mutation-Negative 6.6 (n=106) 9.8 (n=123) -3.2 [-10.5, 4.4] 1 Cox proportional hazards model estimate of Iressa/docetaxel for PFS and OS and difference Iressa – docetaxel for ORR. 2 RECIST criteria. PFS: Progression-Free Survival, OS: Overall Survival, ORR: Overall Response Rate. Table 13: ISEL – Efficacy Results – Intent-to-Treat for OS, TTF and “Evaluable” for ORR Iressa po 250 mg daily Placebo Hazard Ratio1 or Difference [95% CI] OS median mths All Subjects 5.6 (n=1129) 5.1 (n=563) 0.89 [0.77, 1.02] Mutation-Positive NR (n=21) 4.3 (n=5) ND Mutation-Negative 3.7 5.9 1.16
analysis of variance AS ankylosing spondylitis BSA body surface area CCP cyclic citrullinated peptide CI confidence interval CRP C-reactive protein CSR Clinical Study Report Disease Activity Score including evaluation of 28 joints DAS28 (CRP) Disease Activity including evaluation of 28 joints and CRP DIP distal interphalangeal DMARD disease-modifying anti-rheumatic drug EE escape EU European ECLIA electrochemiluminescent immunoassay GI gastrointestinal GO gross osteolysis HAQ Health Assessment Questionnaire Hgb haemoglobin ITT intention to JSN joint space narrowing LFT liver function test LLOQ lower limit of quantification mAb monoclonal antibody MASES Maastricht AS Enthesitis Score MCS mental component summary
Multi-dose NDD Food effect NA PK in special populations Target population § Single dose Multi-dose NND C0524T14 PK/PD of 100 mg SC and 2 mg/kg IV golimumab in patients with RA Hepatic impairment NND Renal impairment NND NND Elderly NND Other NND Genetic/ PK Males versus females NND Other NND PK interactions NND Population PK analyses Healthy subjects NND Target population C0524T05 C0524T06 C0524T09 C0524T08 C0524T11 Trough PK for golimumab 50 mg and 100 mg in Phase 3 studies through week 104 Other NND NND: No new data were provided by the sponsor None of the pharmacokinetic studies had deficiencies that excluded their results from consideration. Summary of pharmacokinetics The information in the following summary is derived from conventional pharmacokinetic studies unless otherwise stated. NND gender- related
CRT Choice Reaction Time in the Cambridge Neuropsychological Test Automated Battery CSHQ Children’s Habits Questionnaire C-SSRS Columbia-Suicide Severity Rating Scale CTRS-R Connors’ Teacher Rating Scale – Revised: Short Form DAE Discontinuation due to Adverse Event DBP Diastolic Pressure DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th Edition – Text Revision DSST Digit Symbol Substitution Task ECG Electrocardiogram FAS Full Analysis Set FOCP Females of Childbearing Potential GGT Gamma-glutamyl transferase HAM-A Hamilton Anxiety Scale HAM-D Hamilton Depression Scale HCG Human Chorionic Gonadotropin HR rate HUI2/3 Health Utilities Index – Mark 2 and Mark 3 ICH International Conference on Harmonisation ITT Intention to Treat IVRS Interactive Voice Response System KBIT Kaufman Brief Intelligence Test K-SADS-PL Kiddie-Sads-Present and Lifetime – Diagnostic Interview LOCF Last observation carried forward LS Least squares MedDRA Medical Dictionary for Regulatory Activities MSS Medication Satisfaction Survey
Embryofetal [Esaki et al. (1980)] 1 3 0.9 2 6 1.8 and Hirayama (1979b)] GD15–PND20 0.5 1.5 0.4 1 3 0.9 2 6 1.8 Rat (RAC) Fertility [FDA report on Tenex] ♂ = 80 days (mated with untreated females); ♀ = 12 days + GD0–GD5 (mated with untreated males) 8 48 14 16 96 29 Rat (OFA) Embryofetal [FDA report on Tenex] GD6–GD15 1 6 1.8 3 18 5.4 10 60 18 Rat (RAC) [FDA report on Tenex] GD15–PND21 2 12 3.6 4 24 7.2 8 48 14 Rabbit (‘hare-type’ (presumably Belgian hare variety)) Embryofetal [FDA report on Tenex] GD6–GD18 0.5 7.5 2.2 1 15 4.5 5 75 22 Rabbit (NZW) Embryofetal [Esaki and Nakayama (1979)] GD6–GD18 0.5 7.5 2.2 1 15 4.5 2 30 9.0 Human ADHD patients (♂ + steady state [Clinical Study – [4 mg] 3.3^ –
AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Human Papillomavirus 9 valent Vaccine, Recombinant Proprietary Product Name: Gardasil 9 Sponsor: Merck Sharp and Dohme Australia Pty Ltd About the Therapeutic Goods Administration (TGA) The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is based on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website < >. the Extract from the Clinical Evaluation Report This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities.
6: Additional pharmacovigilance activities (planned or ongoing) Additional activity Assigned safety concern Actions/outcome proposed planned of final data Pregnancy Registry (category 3). Planned study. No protocol available; concept sheet available. Exposure to vaccine during pregnancy. To monitor pregnancy outcomes in women exposed to 9vHPV vaccine during pregnancy. 9 months after final data available V503-021 Nordic Long-term Study (10-Year extension in subjects from V503-001) (category 3). Planned study (extension of – Registry study. Protocol available. Viral type replacement Long-term Effectiveness/ Immunogenicity Unanticipated safety signals To monitor the long term safety of 9vHPVvaccine. Q4, 2027 (first interim report: Q4, 2017) V503-002-20 Post Dose 3 Follow-Up Study (10-Year Post Dose 3 Extension) (category 3). Planned study (second extension of V503-002) – Clinical trial. Protocol available. Long-term Effectiveness/ Immunogenicity Unanticipated safety signals To evaluate immunogenicity and safety of V503 in subjects who were enrolled in Protocol V503-002 when they were between 9 and 15 of age. Post Authorization Safety Study (PASS) (category 3). Planned study. No protocol available; concept available. Unanticipated safety signals To assess the general safety of V503 in the course of routine clinical practice.
Pharmacovigilance plan Proposed pharmacovigilance activities The following table (Table 2) in the ASA outlines ongoing studies listed in the EU-RMP, which are relevant to Australian patients. Table 2: Ongoing studies listed in the EU-RMP, which are relevant to Australian patients.
risk, the Company has added precautionary language in the Warning and Precautions section of the prescribing information as described below. “Tumour lysis syndrome Tumour syndrome has been reported with IMBRUVICA therapy. Patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.” Tumour lysis syndrome is an important potential risk described in the EU Risk Management Plan and was also included in the Australian Specific Annex (ASA). The Company will continue to routinely monitor reports of tumour lysis syndrome in association with the use of ibrutinib. A full review of all reports of tumour lysis cases from worldwide clinical trials and post marketing sources is provided. To date, are no other new safety signals that have been identified from post-marketing surveillance. Evaluator comment: This PI entry is satisfactory matters The sponsor has amended the indication of Ibrutinib in Section 31 response, as proposed by the clinical evaluator in the Round 1 Evaluation, to: Chronic Lymphocytic Leukaemia/Small Lymphocytic Leukaemia (CLL/SLL) IMBRUVICA is indicated for the treatment of patients with CLL/SLL: Who have received at least one prior therapy Or for the frontline treatment of patients with CLL with 17p deletion The amended indication is in line with that approved in the USA, EU and Canada. The proposed amended indication is still supported by the clinical evaluator. Second benefit-risk assessment Second round assessment of benefits The benefits from ibrutinib remain the same as at the first round evaluation. Second round assessment of risks The risks of ibrutinib therapy now include an observed risk of tumour lysis syndrome. This AE is expected in the clinical context, and is appropriately warned for. The clinical management of patients anticipated to experience tumour lysis is a standard of care in oncology patients. This additional risk does not outweigh the benefits of ibrutinib. Second round assessment of benefit-risk balance The benefit-risk balance of ibrutinib, given the proposed usage in both CLL/SLL and MCL populations is favourable.
marketing requirement Treatment of adult patients with CLL who have received at least one prior therapy, or in first line in the presence of del17p or TP53 mutation in patients unsuitable for 30 Oct 2013 21 Oct 2014 N/A WM 12 Nov 2014 pending Canada Imbruvica (ibrutinib) is indicated for the treatment of patients with CLL, including those with del17p, who have received at least one prior therapy, of for the frontline treatment of patients with CLL with del17p. Clinical effectiveness of Imbruvica in the frontline setting is on the benefit observed in CLL paints with del17p who have received at least one prior therapy. Clinical data in the frontline setting are very limited. 16 April 2014 17 Nov 2014 N/A MCL who have received at least one prior therapy 23 Oct 2014 pending Switzerland Treatment of adult patients with MCL, characterised by translocation t (11,14) an/or expression of cyclin D1 in whom no partial response (PR) was achieved with prior therapy or progression after prior therapy 10 Jan 2014 10 Nov 2014 (accelerated approval) N/A, but Phase III Study is a requirement Treatment of adult patients with CLL who have received at least one prior therapy 30 Jun 2014 pending 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 PI, please refer to the TGA website at <>. II. Quality findings Drug substance (active ingredient) Ibrutinib has the following structure as shown in Figure 1. Figure 1: Chemical structure of ibrutinib. Ibrutinib is manufactured by chemical synthesis as a white to off-white solid. It contains one stereocentre and is synthesised as the R configuration. The electrophilic acryloyl group covalently interacts with a cysteine residue in the Btk active site (Cys-481). 1 trial
beagle dogs, 28 days 1, IV ♀ 25,5 NA 0.03 27 ♂ ♀ 20 20 NA NA 0.03 0.03 5, IV 1 ♂ ♀ 111.7 141.1 NA NA 0.1 0.2 27 ♂ ♀ 102.2 121.9 NA NA 0.1 0.2 15, IV 1 ♂ ♀ 352.3 351.7 NA NA 0.4 0.4 27 ♂ ♀ 335.6 335.9 NA NA 0.4 0.4 15, oral gavage 1 ♂ ♀ 172.7 167.6 NA NA 0.2 0.2 27 ♂ ♀ 163 165 NA NA 0.2 0.2 CPI-CL-001, human healthy volunteers, IV (60 min infusion) or PO n=12/group 200 mg, IV 400 mg, IV 800 mg, IV 1 1 1 NA NA NA 65.5 112.5 198.2 1048 900 792.8 NA NA NA 200 mg, PO 400 mg, PO 800 mg, PO 1 1 1 NA NA NA 69.9 110.9 218.8 838.8^ 665.4^ 656.4^ NA NA NA CPI-CL-011, human healthy volunteers, IV (5-7 min infusion), or PO n=12/group 800 mg, IV 1 NA 196 784 NA 800 mg, 1 NA 196 588^ NA CPI-CL-004, hospitalized adult febrile patients, IV (30 min infusion) 100 mg, IV 1 NA 22.3& 713.6 NA 200 mg, IV 1 NA 32.6& 521.6 NA 400 mg, IV 1 NA 70.6& 564.8 NA
mono amino oxidase inhibitors (MAOIs) and/or COMT inhibitors with possible fatal consequences. The effects of adrenaline may be reduced in patients treated with beta-blockers. Other immunotherapy products contraindicate use in patients with severe immune deficiency or autoimmune disease. It is recommended that a similar contraindication is applied or at least advice regarding use in these groups is added. The EU RMP (v3.0) includes use in patients with severe immune deficiency or autoimmune disease. Given this and given the evaluator’s comment, the proposed PI has been amended as follows: Acarizax is contraindicated: in patients with a known hypersensitivity to the any of the excipients in patients with forced expiratory volume in one second (FEV1) < 70% of predicted value (after adequate pharmacological treatment) at initiation of treatment in patients who have experienced a severe asthma exacerbation within the last 3 months in patients with active or poorly controlled autoimmune diseases, immune defects, immunodeficiency’s, immunosuppression or malignant neoplastic disease Concurrently, the following amendment is also proposed to the ‘precautions section of the AU PI for alignment with the current EU SPC (approved late 2015): Limited data is available on treatment with allergy immunotherapy in patients with autoimmune diseases in remission. Acarizax should therefore be prescribed with caution in these patients. This is acceptable from an RMP perspective. PI amendments are subject to final determination by the Delegate. The contraindications define some asthma parameters but should specifically contraindicate use in patients with ‘unstable and/or severe asthma’ as well as patients with defined FEV1 < 70% and in Asthma is a known risk factor for anaphylaxis, , and has previously been known to constitute a risk in AIT despite AIT having also been used to treat asthma. The safety profile of the population of subjects not well controlled by The sponsor’s response is acceptable from an RMP perspective however this recommendation
6: Study IBU/PROPHYL/2000 – curative group: Patient demographics Sex Male 13 (52.0%) Female 12 (48.0%) Born Inborn 19 (76.0%) Outborn 6 24.0% Birth weight (g) Mean (SD) 858.9 (155.5) Median 850.0 (Min; Max) 630.0; 1180.0 <750 9 (36.0%) 750 - 1000 10 (40.0%) 1000 - 1250 6 (24.0%) Gestational age (weeks) 6 Mean (SD) 25.7 (1.0) Median) 26.0 () Min; Max 24.0; 27.0 24- 25 3 (12.0%) 25- 26 8 (32.0%) 26- 27 (28.0%) 27- 28 7 (28.0%) Table 7: Study IBU/PROPHYL/2000 – curative group: Patient medical history APGAR at 1 minute (N=25) Mean (SD) 5.9 (2.7) Median 5.0 Min ; Max 1.0; 10.0 at 5 minutes (N=24) Mean (SD) 7.9 (2.4) Median 9.0 Min; Max 1.0; 10.0 Intubation in delivery room 23 (92.0%) surfactant intake within 24h after birth 20 (80.0%) Calculation of CRIB index before prophylaxis N = 24 Mean (SD) 6.7 (2.6) Median 7.0 Min; Max 2.0; 11.0 All newborn were mechanically ventilated birth but, on their third day of life, 4 were already under nasal CPAP.
Relative exposure A comparative assessment of systemic exposure of idarucizumab from clinical studies against the animal values is in Table 2. Human reference values are taken from several studies and included data from different patient groups, including elderly patients and patients with impaired renal function. Relative exposures attained in the animal studies (as AUC) were moderately low. Table 2. Systemic exposure of idarucizumab from clinical studies. Clinical exposure multiples Healthy volunteers Renal impairment 45 – 64 yrs1 > 64 No. DDB0136 (11R091) Rat (Wistar Han)NOAEL: 500 mg/kg/day, IV 500 IV Cmax: 181500 nM 7 6 6 7 AUC: 107500 nM 3 2 2 2 Study No. U12-3328 Monkey 150 IV Cmax: nM 2 2 2 2 AUC: nM 1 1 1 1 500 IV Cmax: 235000 nM 9 8 7 9 AUC: 223000 nM 6 5 4 3 Study No. U13-3376 Monkey no Cmax: 159750 nM 6 6 5 6 AUC: 173157 nM 5 4 3 3 Cmax: 163000 nM 7 6 5 6 AUC: 171000 nM 5 4 3 3 No. n00230533 Monkey no Cmax: 174500 nM 7 6 5 7 AUC: 202000 nM 5 5 4 3 ,
and in accordance with applicable regulatory requirements and Boehringer Ingelheim (BI) standard operating procedures (SOPs). Pharmacokinetics Studies providing pharmacokinetic data Table 3 below shows the studies relating to each pharmacokinetic topic and the location of each study summary. Table 3. Submitted pharmacokinetic studies. PK topic Subtopic Study ID * PK in healthy adults Safety, tolerability, and PKs 1321.1 PKs of IV doses of idarucizumab and to explore the effect of different doses of idarucizumab administered on the steady state PK/PD of dabigatran 1321.2 PKs and PDs of idarucizumab and to establish the idarucizumab dose(s) effective in reversing prolongation of blood coagulation time. PK in special populations Healthy Japanese subjects 1321.5 PKs of idarucizumab and to explore the effect of different of idarucizumab administered at or close to the steady state of dabigatran Population PK analyses Healthy subjects 01-02-05 Characterise the of idarucizumab and its binding interaction with dabigatran and to provide PK/PD simulations * Indicates the primary aim of the study. None of the pharmacokinetic studies had deficiencies that excluded their results from consideration. Evaluator’s conclusions on pharmacokinetics Idarucizumab is a humanised monoclonal antibody fragment, which is administered via IV injection or infusion. trial
Neutropenia Rash Neutropenia Rash Important potential risks Drug-drug interaction with CYP3A inducers Reproductive toxicity including teratogenicity - Drug-drug interaction with CYP3A substrates Photosensitivity Skin cancer Drug-drug interaction with CYP3A inducers Reproductive toxicity including teratogenicity Progressive multifocal leukoencephalopathy (PML) Intestinal perforation Drug-drug interaction with CYP3A substrates Missing information Safety in children Safety of breastfeeding Safety in patients with severe hepatic impairment Development of drug resistance Carcinogenicity Long-term safety Drug-drug interaction with oral contraceptive Safety in patients with severe renal impairment Safety in patients with chronic active hepatitis Safety of patients with concomitant immunisation Immunological effects and auto-immunity Safety in children Safety of breastfeeding Safety in patients with severe hepatic impairment Carcinogenicity Drug-drug interaction with oral contraceptive Safety in patients with severe renal impairment Safety in patients with chronic active hepatitis Safety of patients with concomitant immunisation For the important potential ‘Photosensitivity’ & ‘Skin cancer’; and the missing information: ‘Development of drug resistance’, ‘Long-term safety’ & ‘Immunological effects and auto-immunity’, the ASA states: “Not proposed for inclusion into ASA. Please refer to Table 7”. Table 7: ‘Summary Table of Risk Minimization Measures’ of the ASA provides the following justification for such omission, respectively, although it would appear no further links to the specified data or relevant correspondence between the sponsor and TGA have been provided to substantiate such justification: Information concerning photosensitivity was provided to TGA in the pre ACPM Response, and subsequently approved by TGA. Information concerning the risk of secondary malignancy was provided to TGA in the Response to the Section 31 Request (Clinical Evaluation), and subsequently approved by TGA. Clinical studies to date have not shown any increase in incidence of skin cancers. Not included in EU labelling, but provided as Missing Information in EU RMP following EMA evaluation. PAM to provide data on resistance mechanisms is planned for submission in EU in December 2015. Therefore, not included in ASA.
investigators were provided with guidance as described in Table 14 to screen and exclude patients with asthma or mixed asthma. If there was any uncertainty with the diagnosis, investigators would call the country medical advisor or call the global medical monitor to assess the eligibility of the patient. 14: Investigator guidance for screening patients with asthma. Asthma COPD Medical history Asthma is often diagnosed in childhood (onset early in life) COPD is diagnosed later in life (>40 years of age) Past history of allergy, sinusitis, eczema, frequent respiratory infections and nasal polyps IgE levels/eosinophil counts could be high because of atopy Allergies and sinusitis are rare in COPD Many asthmatics are non-smokers or if smokers likely to be lower Family history of asthma usually present COPD is frequently associated with significant and long tobacco exposure Symptoms Characterized by episodic wheeze with chest tightness and dry cough Symptoms vary from day to day Symptoms at night/early morning Persistent or worsening dyspnea, often productive chronic cough Dyspnea during exercise Symptoms are slowly progressive Symptoms are more in the morning and during day Pulmonary Function Tests Asthmatic patients commonly have normal or slightly reduced FEV1/FVC ratio FEV1/FVC <70% predicted is required for the diagnosis of COPD Asthma usually reversible after bronchodilator challenge COPD not fully reversible or irreversible airflow obstruction To ensure the exclusion of patients with asthma or mixed asthma, investigators were required to check the patients’ medical records for any documented history of asthma. This was further validated by the sponsor’s clinical monitor by verifying source documents for patients. Investigators were also expected to discuss patients’ medical history with them to identify any undocumented diagnoses of asthma. Patients with asthma or a suspicion of mixed asthma were therefore excluded on clinical grounds as determined by the investigator. These included onset of symptoms, smoking history, increased IgE levels, increased eosinophils, and history of allergic rhinitis. Furthermore, in Studies A2303 and A2313, >60% of all patients had FEV1 reversibility >12% at baseline (62.9% [1342/2135] in Study A2303 and 65.6% [343/523] in Study A2313). These values are not substantially different from those that have been published for COPD patients.
Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease. Psoriasis: Flixabi is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen ultra-violet A (PUVA).’ 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. Quality findings Drug substance (active ingredient) Infliximab (SB2) is a chimeric human/mouse monoclonal antibody (mAb), which is typically a ‘Y’ shaped large glycoprotein consisting of four polypeptide chains (two identical heavy chains (HC) and two identical light chains (LC)), connected by disulphide bonds. Each chain presents constant and variable regions whereby in both chains, the variable region is murine whereas the constant region is of human origin (IgG1 and human kappa origins for the HC and LC, respectively). The molecular weight of SB2 is approximately 149 kilodalton (kDa) in glycosylated form. is 1 N-linked glycosylation site is located at asparagine 300 on each HC. There are no O-linked glycosylation sites. Drug substance manufacture The SB2 drug substance manufacturing process involves cell culture expansion, production in a bioreactor, harvest of the cell culture fluid (CCF), purification and dispensing, resulting in highly purified SB2 drug substance. All drug substance manufacturing are validated. Stability Stability data have been generated real time and accelerated conditions. Drug product The finished drug product is as 100 mg of a powder in a glass vial for intravenous (IV) injection. Drug product manufacture The drug product manufacturing process involves thawing of the formulated drug substance, mixing, bioburden reduction filtration, pooling, sterile filtration, filling lyophilisation and stoppering. A detailed description of the drug product manufacturing process has been provided. trial
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The following adverse reactions observed from Toujeo and Lantus from clinical investigations are listed below by system organ class and in order of decreasing incidence very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; not known: cannot be estimated from the available data. Within each frequency grouping, adverse reactions are presented in of decreasing seriousness. Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement. Table 7 reactions observed from Toujeo Clinical investigations MedDRA system organ classes Very common Common Uncommon Rare Very rare Immune system disorders Allergic reactions Metabolism and nutrition disorders Hypoglycaemia Nervous system disorders Dysgeusia Eyes disorders Visual impairment Retinopathy Skin and subcutaneous tissue disorders Lipoatrophy Musculoskeletal and connective tissue disorders Myalgia General disorders and administration site conditions Injection site reactions Oedema
Table 8 Cardiovascular and Cancer Events in ORIGIN LANTUS N=6264 STANDARD CARE N=6273 LANTUS vs STANDARD CARE n (Events per 100 PY) N (Events per 100 PY) Hazard Ratio (95% CI) Cardiovascular Co-primary endpoints CV death, non-fatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, non-fatal myocardial infarction, stroke, hospitalisation for heart failure or revascularisation procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of co-primary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or non-fatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or non-fatal) 331 319 1.03 (0.89, 1.21) Revascularisations 908 860 1.06 (0.96, 1.16) Hospitalisation for heart failure 310 343 0.90 (0.77, 1.05) Cancer Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15) Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.
decreased blood cortisol, decreased blood testosterone, decreased blood gonadotophin, decreased thyroxine, cytokine release syndrome and hair colour changes. Serious Adverse Reactions Reported in Other Clinical Trials The following serious adverse reactions were also reported in patients with advanced melanoma treated with YERVOY in clinical studies (regardless of dose or regimen). Adverse reactions presented elsewhere in the ADVERSE REACTIONS section are excluded. Infections and infestations Uncommon: septic shock Rare: respiratory tract infection Blood and lymphatic system disorders Uncommon: anaemia Rare: polycythemia Immune System Disorders Uncommon: infusion related reaction Rare: hypersensitivity, sarcoidosis Very Rare: anaphylactic reaction (shock) Endocrine disorders Rare: secondary adrenocortical insufficiency, hyperpituitarism, autoimmune thyroiditis Metabolism and nutrition disorders Common: dehydration Uncommon: hypophosphatemia, Rare: alkalosis, tumour lysis syndrome Psychiatric disorders Rare: confusional state, mental status change Nervous system disorders Uncommon: ataxia, dysarthria. Rare: GuillainBarré syndrome, meningism, autoimmune central neuropathy (encephalitis) Eye disorders Rare: episcleritis, scleritis, iritis, eye oedema, ocular myositis Ear and labyrinth disorders Rare: neurosensory hypoacusis Cardiac disorders Rare: myocarditis, cardiomyopathy, pericardial effusion (pericarditis) Vascular disorders Rare: angiopathy, peripheral ischemia, vasculitis, temporal arteritis, Raynaud’s phenomenon,
It is proposed that Onivyde be prescribed by physicians experienced in the use of therapies. Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official EU languages after the marketing authorisation has been granted by the European Commission. Overall international regulatory status The overall international regulatory status at time of the current submission to TGA is shown in Table 2. Table 2: International regulatory status. Country / region Submission date Approval date Status Indications (approved or requested) US 24 Apr 2015 22 Oct 2015 Approved Onivyde is a topoisomerase inhibitor indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. EU – centralised procedure 30 Apr 2015 CHMP positive opinion Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil (5-FU) and leucovorin (LV), in adult patients who have progressed following gemcitabine based therapy. Switzerland 5 Nov 2015 review Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil and leucovorin in patients who have been previously treated with gemcitabine. Canada 18 Dec 2015 Under review Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil and leucovorin in patients who have been previously treated with gemcitabine-based therapy. New Zealand 25 Mar 2016 Under review Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil and leucovorin in patients who have been previously treated with gemcitabine.
Subgroup of showed a negligible effect in favour of ivabradine (hazard ratio of 0.99). Secondary endpoints in RS population All-cause mortality in all the pre-specified subgroups except in the subgroup of “baseline HR <77bpm” except for the subgroup on baseline heart rate (p=0.0274) in favour of patients with baseline HR 77 bpm versus those with <77 bpm Cardiovascular death in all the pre-specified subgroups except in the subgroup of “baseline HR <77bpm” except for the subgroup on baseline heart rate (p=0.0379) in favour of patients with baseline HR 77 bpm versus those with <77 bpm Death from heart failure in all the pre-specified subgroups except in the subgroup of “baseline HR <77bpm” NA All-cause hospitalisation NA NA Cardiovascular hospitalisation NA NA Hospitalisation for worsening heart failure in all the pre-specified subgroups. except for the subgroup on ischaemic versus cause (p=0.0345) in favour of patients with CHF from an ischaemic cause versus those with CHF from a cause Secondary endpoints in RSBBdose population All-cause mortality Only the subgroups of “females”, “ischaemic cause”, “NYHA Class II”, “no hypertension” and “baseline HR 77 bpm” All the interaction tests had higher than 0.05 Cardiovascular death Only the subgroups of “females”, “ischaemic cause”, “NYHA Class II”, “no hypertension”, “baseline HR 77 bpm”, “age 65 years”, and “no DM” NA Hospitalisation for worsening heart failure in all the pre-specified subgroups except the subgroup of “age 65 years”. NA
Pulmonary exacerbations and bacterial sputum colonisation with long-term ivacaftor treatment. Routine pharmacovigilance; Study 105, two-year follow-up from Study 102, 103, 104; An observational to evaluate longterm, safety. Use in children between 6 and 11 years of age Routine pharmacovigilance; Study 105, two-year follow-up from Study 102, 103, 104, Study 110, Study 111, Study 112; Analysis of PK data from studies on the need to perform a dose-finding study in children 6 to 11 years of age; An observational study to evaluate longterm, safety. Reconciliation of issues outlined in the RMP report Table 7 summarises the recommendation of the RMP evaluation report and the sponsor’s responses to the issues raised. Table 7: Reconciliation issues outlined in the RMP Evaluation Report Recommendation in RMP evaluation report Sponsor’s response RMP evaluator’s comment 1. Safety considerations may be raised by the non-clinical and clinical evaluators through the consolidated section 31 request and/or the nonclinical and clinical evaluation reports respectively. 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. Vertex has the comments of the nonclinical and clinical evaluators into consideration and there are no resulting changes to the RMP. The sponsor’s response is satisfactory. 2. The sponsor should provide an update to the status of its overseas applications. Explanations need to be provided for any decision of rejection, deferral or withdrawal. An updated foreign regulatory status was submitted. No applications have been rejected, deferred or withdrawn internationally with respect The evaluator has noted the update of overseas regulatory status.
Table26. Exposure to Soolantra in clinical studies according to dose and duration. Study type/ Indication Proposed dose Other dose ≥ 3 mo. ≥ 6 mo. ≥ 12 mo. Any dur’n ≥ 3 mo. ≥ 6 mo. ≥ 12 mo. Any dur’n Clinical pharmacology 17 0 Indication 1 Vehicle-controlled1 1042 Active-controlled 839 784 717 14394 97 Uncontrolled 4843 Subtotal Indication 1 839 784 717 2027 97 TOTAL 839 784 717 2044 97 1 Excluding studies controlled by both vehicle and active. 2 Study RD.03.SRE.40106, median exposure 84 days. 3 Study RD.03.SRE.40051, median exposure 82 days. 4 Includes 478 subjects in Study RD.03.SRE.40173, with median exposure 113 days. The sponsor states: ‘A total of 2431 of the 3999 subjects in the clinical development program were exposed to Ivermectin 1% Cream: 268 healthy subjects and 2163 subjects with PPR. The figure of 2163 subjects with PPR includes 116 subjects exposed to Ivermectin 1% Cream BID, which was explored in Phase II before the QD regimen was confirmed for the Phase III program. Consequently, a total of 2047 subjects with PPR were exposed to the to-be-marketed formulation and regimen: Ivermectin 1% QD.’ Adverse events Note: In this section, a semicolon is used to separate observations relating to different patients. All adverse events (irrespective of relationship to treatment) Pivotal studies Study RD.06.SRE.18170 AE’s Study RD.06.SRE.18170 (see Table 27). Table 27. All AE’s Study RD.06.SRE.18170. Table 27 (continued). All AE’s Study RD.06.SRE.18170. Study RD.06.SRE.18171 AE’s Study RD.06.SRE.18171 (see Table 28).
Table 1. Overseas regulatory status. Country/Region Date submitted or intend to submit Approval date Proposed indication United States of America 20 December 2013 19 December 2014 Soolantra cream is indicated for the topical treatment of inflammatory lesions of rosacea. Europe procedure) 22 March 2015 Soolantra is indicated for the topical treatment of inflammatory lesions of rosacea (papulo-pustular) in adult patients. Austria, Estonia, Germany, Malta and Spain 8 April 2014 AT: 02 June 2015 ET: 08 June 2015 DE: 29 April 15 Malta: 02 April 2015 ES : 02 June 2015 Belgium, Bulgaria, Czech Republic, Denmark, Finland, France, Hungary, Ireland, Latvia, Luxembourg, Lithuania, Poland, Portugal, Romania, Slovakia and United Kingdom 9 April 2014 BE: 03 April 2015 BG : 10 June 2015 CZ : 13 May 2015 DK : 22 April 2015 FI: 26 June 2015 FR: 21 July 2015 HU: 14 April 2015 IE: 24 April 2015 LV: 13 July 2015 LU: 01 July 2015 LT: 13 may 2015 PL: 23 July 2015 PT: 08 April 2015 RO: 26 May 2015 SK: 11 june 2015 UK: 17 2015 Cyprus, Greece, Iceland, Italy, The Netherlands, Norway and Sweden 10 April 2014 Cyprus: pending Greece: pending IS: 29 April 2015 IT: 13 July 2015 NL: 04 may 2015 NO: 23 April 2015 SE: 22 April 2015
explored in Phase II before the QD regimen was confirmed for the Phase III program. Consequently, a total of 2,047 subjects with PPR were exposed to the to-be-marketed formulation and regimen: ivermectin 1% QD.’ Only studies in which at least 1 subject was treated with the formulation proposed for registration contribute data to the two tables below Tables 8 and 9. 8. Exposure to Soolantra and comparators in clinical studies. Study type/ Indication Controlled studies studies Total Sool Sool Vehicle Other iver cream Other active cream Sool Clinical pharmacology 17 17 Indication 1 Pivotal 909 461 0 418 0 909 Other 731 206 146 532 484 1215 Subtotal Indication 1 1640 667 146 950 484 2124 TOTAL 1640 667 146 950 501 2141 Table 9. Exposure to Soolantra in clinical studies according to dose and duration. Study type/ Indication Proposed dose Other dose ≥ 3 mo. ≥ 6 mo. ≥ 12 mo. Any dur’n ≥ 3 mo. ≥ 6 mo. ≥ 12 mo. Any dur’n Clinical pharmacology 17 0 Indication 1 1042 Active-controlled 839 784 717 14394 97 Uncontrolled 4843 Subtotal Indication 1 839 784 717 2027 97 839 784 717 2044 97
The second analysis sought to determine if the container code entries in the eCRF that did not an IVRS assignment were possibly simple transcription errors. Error logs associated with drug shipment to sites were examined. on this comparison it became apparent that 76% of the incorrect container numbers (defined as those containers that did not match the IVRS assignment) captured in the eCRF were transcription errors (because the container did not exist at the site). The overall conclusion from these analyses was that the true proportion of errors in medication dispensations was therefore likely even lower than the 0.38% that was derived, based on eCRF entries.
The product should be used once reconstituted and must be discarded if it is not used within one hour of reconstitution. use, any remaining vaccine and container must be disposed of safely, preferably by heat inactivation or incineration, according to locally agreed procedures. OVERDOSE No case of overdose has been reported. PRESENTATION AND STORAGE CONDITIONS One dose of freeze-dried vaccine and one dose of diluent in separate vials (type I glass), each equipped with a stopper (halo-butyl) and a flip off cap (aluminium/polypropylene), with one syringe (polypropylene) and two needles (stainless steel). Pack size of 1 powder vial and 1 diluent vial, 1 syringe and 2 needles. Store in a refrigerator (2C – 8C). Do not freeze. Keep the vials in the outer carton in order to protect from light. NAME AND ADDRESS OF THE SPONSOR sanofi-aventis pty ltd Talavera Corporate Centre – Building D Park NSW 2113 Tel: 1800 829 468 POISON SCHEDULE OF THE MEDICINE S4 Prescription Only Medicine DATE OF INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (ARTG) 23 August 2010