zilongwang/ReadingBank huggingface dataset:
(PEG) precipitation (20% PEG 4000, pH 5.8), pasteurisation (10 hours at 60.5 ± 1.0 ºC) and 15 nm filtration to remove the smallest known viral particles (a process not utilized by all other currently available C1 esterase inhibitor products). Collectively, these processes result in reduction of at least 16.7 log10 for the enveloped viruses tested (HIV, Bovine Viral Diarrhea Virus (BVDV), Pseudorabies Virus (PRV)), at least 8.8 log10 for the non-enveloped viruses (HAV, Canine Parvovirus (CPV)), and >10 log10 reduction in prion-like material. Thus, while the infection-related risk with any plasma-derived product will never be zero, the manufacturing process for CINRYZE provides substantial protection against infections of C1 esterase inhibitor products to date and represents an important improvement in product safety. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived C1 esterase inhibitor product. It is strongly recommended that every time CINRYZE is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. Sodium Each vial of CINRYZE contains approximately 11.5 mg of sodium. To be taken into account by patients on a controlled sodium diet. Effects on fertility No studies on fertility or early embryonic and postnatal development were conducted because chronic dosing in animals would be expected to be associated with development of neutralising antibodies to the human protein. Effects in pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of CINRYZE in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. The use of CINRYZE may be considered during pregnancy, if necessary. Use in lactation It is unknown whether C1 esterase inhibitor is excreted in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from CINRYZE therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Paediatric use
Genetic, gender and age related differences in pharmacodynamic response Not applicable. Pharmacodynamic interactions Not applicable. Evaluator’s overall conclusions on pharmacodynamics No pharmacodynamic data derived from healthy volunteers or subjects with RCC have been submitted. The PD of cabozantinib was derived form in vitro and murine models and is described in the nonclinical evaluation. Given the mechanism of action and what is already know about TKIs this is acceptable. Dosage selection for the pivotal studies Pharmacokinetics and pharmacodynamics: dose finding studies None submitted. Phase II dose finding studies No formal dose finding studies have submitted. Study XL184-001 investigated the maximum tolerated dose of cabozantinib and was determined to be 140 mg once per day. Phase III pivotal studies investigating more than one dose regimen Study SL184-308 was the pivotal study for this application. The initial starting dose was 60 mg once per day. Dose adjustments were allowed for tolerability and are summarised in 7. Table 8: Cabozantinib dose reductions in Study XL184-308 Dose reductions occurred for 70% of subjects and equal proportions of patients were taking the 60 mg dose and 40 mg dose at the data cut-off. Evaluator’s conclusions on dose finding for the pivotal studies No formal dose finding has been undertaken. The 60 mg dose was carried forward into the pivotal At the data cut-off point an equal proportion of patients were receiving the 40 mg and 60 mg doses. This would indicate that the lowest effective dose may not have been established. The prescribing information contains sufficient information about dose adjustment based on tolerability. Clinical efficacy Studies providing evaluable efficacy data Studies to support the indication Treatment of RCC:
Number of Memorial Sloan-Kettering Cancer Centre RCC prognostic criteria: Karnofsky performance status score < 80% Haemoglobin < 13 g/dL (< 130 g/L) for males and < 11.5 g/dL (< 115 g/L) in females Corrected calcium > limit of normal Baseline characteristics of the OS population from the published article are described in the table below (Table 16). Table 16: Study XL184-308 Baseline characteristics of the OS population from the NEJM article Cabozantinib n=330 Everolimus n=328 Age, Md (range) 63 (32, 86) 62 (31, 84) Men 77% 73% ECOG 0 ECOG 1 68% 32% 66% 34% MSKCC prognostic risk cat Favourable Intermediate Poor 45% 42% 12% 46% 41% 13% Prior VEGFR TKI 1 2+ 71% 29% 70% 30% Previous systemic therapy Sunitinib Pazopanib Axitinib Sorafenib Beva Interleukin-2 Interferon alpha Nivo 64% 44% 16% 6% 2% 6% 6% 5% 62% 41% 17% 9% 3% 9% 7% 4% RT 33% 33% Nephrectomy 85% 85% Baseline data and deviations were generally balanced across arms. There was a higher rate of discontinuation in the everolimus arm; the imbalance was mainly due to
D3720C00001 Important potential risks Haemolytic anaemia Haptoglobulin and reticulocyte tests. In development Important missing information Immunocompromised population Pre-existing seizure disorder Pre-existing severe renal impairment Pre-existing significant hepatic disease Evaluation of safety data. Eligibility for enrolment includes subjects with the following conditions: Immunocompromised unless severely compromised Seizure disorders * CrCl ≥ 15 mL/min** Hepatic impairment unless as Child Pugh Stage C Study D3720C00002 Important potential risks Convulsions /Seizures Drug-induced injury impairment (including potential drug interactions with nephrotoxic agents) Haemolytic anaemia Targeted follow-up questionnaires for adverse events of acute renal failure, convulsions / seizures, drug induced liver failure and haemolytic anaemia. Haptoglobulin and reticulocyte (for Haemolytic anaemia). Fourth quarter 2012 Important missing information Asian population exposure Evaluation of safety data D3720C00005 Important missing information Asian population exposure Evaluation of pharmacokinetic data First Quarter 2012 Bacterial resistance surveillance programme Important potential risks Bacterial resistance development Important information Potential for off-label use Monitor changes in ceftaroline minimum inhibitory concentrations distributions among target pathogens (i.e. those pathogens identified in PI with clinical efficacy). Isolates will be collected from hospitals and medical centres across Europe, Latin America, Middle East-Africa and the Region. May also include In development Pacific
during the original registration application of Eylea. The apparent excess in the extractable volume compared to the actual volume needed for injection was considered in the final CMC Evaluation as acceptable based on the following justifications: The excess contained in the extractable volume in the glass vial (100 µL) and prefilled syringe (90 µL) is required to compensate for the “priming volume” (that is, the volume required to expel all the air from the syringe and properly prime the needle prior to administering the intravitreal injection), and the “average dead volume of the syringe and needle” in order to deliver the volume dose of 50 µL required for administration when the product is administered according to the recommended instructions provided in the labelling. The extractable volume in both the vial and prefilled syringe is determined using the current European Pharmacopiea (Ph. Eur) procedure and represents the minimum extractable volume necessary to enable the end user to remove the required volume of solution (50 µL) for a single dose. From the user testing that has been performed during pharmaceutical development, it is evident that based on the minimum fill volume contained in the glass vial and prefilled syringe, it would not be possible to reproducibly administer more than one single dose from each glass vial or prefilled syringe. medication error. This risk can be minimised by amending the package and/or amending the vial/PFS label, by clearly indicating, that the volume required for injection differs from the total volume provided. Alternatively, educational material informing treating physicians about the posology of the product may be distributed by the sponsor.
Table 20: Percent 3-line gainers at Week 24, 52, 76/100, COPERNICUS, GALILEO, (full analysis set with LOCF). S=Sham and Af= Aflibercept COPERNICUS GALILEO 24 weeks 52 100 24 weeks 52 100 weeks n S Af S 73 Af 114 S 73 Af 114 S Af 103 S Af 103 S 68 Af 103 Gained 15 letters (%) 56 30 wt’d difference (95% CI) p-value 45% (33%, 57%) p<0.001 26% (12%, 40%) p<0.001 27% (13%, 40%) p<0.001 38% (24%, 52%) p<0.001 28% (13%, 43%) p<0.001 28% (13%, 43%) p<0.001 Table 21: Comparison of efficacy outcomes at 12 and 24 weeks GALILEO COPERNICUS POOLED Sham n=68 n=103 Sham n=73 Aflib. n=114 Sham n=141 n=217 Gained 15 letters (1) Week 12 8 (12%) 60 (58%) 7 (10%) 64 (56%) 15 (11%) 126 (58%) Week 24 15 (22%) 62 (60%) 9 (12%) 66 (58%) 24 (17%) 131 (60%) mean change in BVCA (2) Week 12 1.7 16.5 -4.2 16.7 -1.4 16.6 Week 24 3.3 18.0 -4.0 17.3 -0.5 17.7 mean change in central retinal thickness (2) Week 12 -75.1 -441.4 -88.5 -441.8 Week 24 -114.8 -457.2 -157.2 -453.1 Primary endpoint Secondary endpoints Comment: Most gains observed at 24 weeks were already gained by 12 weeks. Safety Aflibercept is already registered for neovascular (wet) age-related macular degeneration. No new safety concerns have emerged from the development program for the indication being considered in this application (macular oedema secondary to CRVO).
studies (CXA-101-01 and CXA-101-02) which investigated the PK of ceftolozane as a single entity. There did not appear to be any PK interaction between ceftolozane and tazobactam on the basis of the studies presented. Thus the PK of ceftolozane can be inferred from the combination PK studies presented and a more thorough investigated of the PK of ceftolozane may not be required. This would appear to be in agreement with the relevant guideline. One of the active substances is a new chemical substance. This case should be treated as a New Drug Application and the full characterisation of the pharmacokinetic profile (including interaction studies and studies in special populations and patients) is recommended to be made using the combination (and not only with just the new mono-component). Pharmacodynamics Studies providing pharmacodynamic data Table 2 shows the studies relating to each pharmacodynamic topic and the location of each study summary. 2: Submitted pharmacodynamic studies. PD Topic Subtopic Study ID Primary Pharmacology Effect on clinical and microbiological response CUBI-RAS-008 Secondary Pharmacology Effect on QTc Interval CXA-QT-10-02 Gender other genetic and Differences in PD Response Effect of gender Not conducted Effect of age Not conducted PD Interactions Not conducted Population PD and PK-PD analyses Healthy subjects CXA-101-PH-003 Target population CXA-101-PH-003 CUBI-RAS-003 ICPD ICPD 00319-2 * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable. None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Summary of pharmacodynamics The information in the following summary is derived from conventional pharmacodynamic studies in humans unless otherwise stated.
14 May 2013 * Please note change in Product Information ®Registered Trade Mark of ImClone LLC used under licence by Merck KGaA, Darmstadt, Germany. ™EGFR pharmDX is a Trade Mark of DakoCytomation Denmark A/S
List of abbreviations Abbreviation Meaning AE adverse event ANCOVA analysis of covariance ANOVA analysis of variance BP blood pressure BSA body surface area CC Cyclocort Cream® CPS clobetasol propionate CPSH clobetasol propionate shampoo DAE discontinuation due to AE DLQI Dermatology Life Quality Index HPA hypothalamic pituitary axis IGA Investigator Global Severity Assessment IOP intraocular pressure ITT intention to treat LLOQ lower limit of quantification LOCF last observation carried forward MED Minimal erythema dose min minute NSAID non-steroidal anti-inflammatory drug ODS overall disease severity
Copyright © Commonwealth of Australia 2013 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 <>.
Infections and infestations Fungal skin infection Infection Upper respiratory infection Injury, poisoning and procedural complications Procedural pain Fracture of penis Skin laceration Open Scrotal haematoma Joint injury Penis injury Investigations Blood glucose increased Blood pressure systolic increased Body temperature increased Eosinophil count increased Metabolism and nutrition disorders Fluid retention Musculoskeletal and connective tissue disorders Back pain Pubic pain pain Ligament disorder Ligament pain Musculoskeletal discomfort Nervous system disorders Headache Dizziness Dysgeusia Paraesthesia Burning sensation Hyperaesthesia Hypoaesthesia Psychiatric disorders Abnormal dreams Depression Sexual inhibition Renal and urinary disorders Dysuria Pollakiuria Reproductive system and breast disorders Penile haematomaa Penile swellingb Penile painc Penile ecchymosisd Penile blister Pruritus genital Painful erection Erectile dysfunction Dyspareunia Penile erythema Penile adhesion Penis disorder Peyronie’s disease Sexual dysfunction Testicular pain Scrotal erythema Genital discomfort Genital haemorrhage Pelvic pain Penile size reduced Penile vein thrombosis Scrotal oedema Scrotal pain Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Blood blister Skin discolouration Skin hyperpigmentation Erythema Pigmentation disorder Skin nodule Blister Granuloma skin Night sweats Penile ulceration Rash erythematous
I. Introduction to product submission Submission details Type of submission: Biosimilar medicine Decision: Approved Date of decision: 18 October 2017 Date of entry onto ARTG 9 November 2017 Active ingredient: Adalimumab Product name: Amgevita Sponsor’s name and address: Amgen Australia Pty Ltd 115 Cotham Road Kew, VIC, 3101 Dose forms: Pre-filled syringe and Pre-filled syringe with pen injector Strengths: 20 mg/ 0.4 mL and 40 mg/ 0.8 mL Container: Pre-filled syringe Pack sizes: Amgevita 20 mg solution for injection in single-use pre-filled syringe: Carton containing 1 pre-filled syringe Carton containing 2 pre-filled syringes Amgevita 40 mg solution for injection in single-use pre-filled syringe or pre-filled SureClick pen (for patient use): Carton containing 1 pre-filled syringe or pre-filled pen Carton containing 2 pre-filled syringes or pre-filled pens Carton containing 4 pre-filled syringes or pre-filled pens Carton containing 6 pre-filled syringes or pre-filled pens. Approved therapeutic use: Rheumatoid Arthritis Amgevita is indicated for reducing and symptoms, as well as inhibiting the progression of structural damage in adult patients with moderate to severely active rheumatoid arthritis. This includes the treatment of patients with recently diagnosed moderate to severely active disease who have not received methotrexate. Amgevita can be used alone or in combination with methotrexate. Juvenile Idiopathic Arthritis Polyarticular Juvenile Idiopathic Arthritis
Bioequivalence (250 mg) 1011 BE (fasted) - CIC versus IRT BE (fasted) - CIC versus PIC 36/35 36/35 BE shown – 250 mg doses BE shown – 250 mg doses Food Effect (250 mg) 1011 Food Effect - CIC fast/fed Food decreases BA by ~ 14%. Mass balance (250 mg) 1009 14C crizotinib 6/6 PKs and ADME investigated. PK Drug-Drug Interaction 1015 Ketoconazole / Crizotinib 15 Systemic exposure increased. Table 1 continued: Submitted clinical studies with clinical pharmacology data; n = subjects entered/evaluated. Topic Primary Aim n Comment Patients with advanced cancer – single and multiple dose studies Single and multiple dose; Various QD and BID Asian versus non-Asian; PK interaction; Food effect 1001 Phase I, open-label, single-arm efficacy and safety in patients with advanced cancer. n=208 (total) Comprehensive PK data in patients with advanced cancer; dose-escalation (n=37), and RP2D cohorts (n=171; 250 mg BID) including ALK+ NSCLC (n=119). Trough concentrations only 1005 Phase II, open-label, single-arm, efficacy and safety in patients with ALK+ advanced NSCLC. n=136 Limited data only. Population-PK Study Structural PK population variability in CL and Vd; effects of H2 N=250; 3184 crizotinib Covariates weight, sex, race, and ECOG status as predictors of CL/F, weight as a predictor of V 2/F, Q/F, and group
Table 1. Demographic and Disease Characteristics in Randomised Phase 3 Study 1007 (Full Analysis Population) Characteristics Crizotinib N=173 Chemotherapy N=174 Sex, n (%) Male Female 75 (43) 98 (57) 78 (45) 96 (55) Age n (%) Median (range) <65 >65 years 51 (22-81) 146 (84) 27 (16) 49 (24-85) 151 (87) 23 (13) Race, n (%) White Other 90 (52) 2 (1) 79 (46) 2 (1) 91 (52) 3 (2) 78 (45) 2 (1) Smoking Status, n (%) Never smoked Ex-smoker Current smoker Not reported 108 (62) 59 (34) 5 (3) 1 (<1) 111 (64) 54 (31) 9 (5) 0 Disease Stage, n (%) Locally advanced Metastatic Not reported 7 (4) 165 (95) 1 (<1) 16 (9) 158 (91) 0 Histological Classification, n (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Adenosquamous carcinoma Other Not reported 163 (94) 0 1 (<1) 4 (2) 4 (2) 1 (<1) 160 (92) 3 (2) 1 (<1) 3 (2) 7 (4) 0 Brain Metastases, n (%) Present Absent 60 (35) 113 (65) 60 (34) 114 (66) Prior EGFR TKI Therapy, n (%) Yes No 20 (12) 153 (88) 21 (12) 153 (88) ECOG PS, n (%) 0 1 2 Not reported 72 (42) 84 (49) 16 (9) 1 (<1) 65 (37) 95 (55) 14 (8) 0
Absolute (sd) 1010 Absolute bioavailability 14 /14 Abs BA ~ 43%; PIC:IV 250:50 mg. (250 mg) 1008 BE (fasted) – PIC vs IRT 24/24 BE shown – 250 mg doses. (250 mg) 1011 BE (fasted) - CIC vs IRT BE (fasted) - CIC vs PIC 36/35 36/35 BE shown – 250 mg doses BE shown – 250 mg doses Food Effect (250 mg) 1011 Food Effect - CIC fast/fed Food decreases BA by ~ 14%. Mass balance (250 mg) 1009 14C radiolabelled crizotinib 6/6 PKs and ADME investigated. PK Interaction 1015 Ketoconazole / Crizotinib 15 Systemic exposure increased. Patients with advanced cancer – single and multiple dose studies Single and multiple dose; Various qd and bd Asian vs non-Asian; PK interaction; Food effect 1001 Phase I, single-arm efficacy and safety in patients with advanced cancer. Comprehensive PK data in patients with advanced cancer; dose-escalation (n=37), and RP2D cohorts (n=171; 250 mg bd) including ALK+ NSCLC (n=119). Trough Only1 1005 Phase II, efficacy and safety in patients with ALK+ advanced NSCLC. Limited data only. arm,
Table 22. Datasets for Studies 1001, 1005, 1007, 1014 Study 1001 ALK-positive NSCLC subset of study only 1005 Study 1007 Study 1014 CSR 60 day update 120 day update CSR 60 day update 120 day update 60 day update 120 day update CER 1 1 2 1 1 2 1 2 2 Number in safety population 119a 136b 149 136a 261b 439 (mature safety population 261) 71 116 19 Key efficacy populations RE n=116 RE n=143 RE n=76 RE n=133 RE n=259 See note ‘d’ First visit 7.1.2010 Cut-off 1.6.2011 1.2.2011 Comment safety data on SAEs and deaths only safety and efficacy data safety data on SAEs and deaths only Updated safetyc and efficacyd data Information on SAEs and deaths only on SAEs Information on SAEs
Table 45. Peri natal death rates* and peri natal deaths and severe congenital anomaly (SCA) rates combined according to gravida’s nausea and vomiting (N/V) status and the drugs prescribed for N/V within the first 84 days of pregnancy. *Fetal deaths at 20 weeks and neonatal deaths. 46. Summary of all submitted studies relevant to pregnancy. Table continued across two pages. Reference Details and relevant findings. Comments Collins, 1964 Review. Based on animal data, not recommended in early pregnancy. No evidence of fetal damage - quoting Mellin et al.,1963 - McBride, 1963 Reported an incidence of congenital abnormalities of 0.1% in 6,000 deliveries of women who had taken cyclizine, from a total of 21,562 deliveries over 5years 1957-1962 congenital heart disease, 5 cleft palate and/or hare-lip, 5 anencephaly, 1 myeloencephalocele, 2 hydrocephalus, 1 bilateral cataract, 1 Part of nonclinical submission McBride, 1969 Reported an incidence of cleft palate of 0.4% in 1,125 deliveries of women who had taken cyclizine in the first 3 months from a total of 25,333 deliveries over 6 years 1956-61 Incidence among mothers with nausea and vomiting who did not take cyclizine was 3.64% of 1,100 deliveries ( no significant difference) Incidence mothers who did not take cyclizine was 0.08% of 24,208 deliveries. (significantly different from those with N/V suggesting N/V was the cause) Not in nonclinical submission Mellin et al., 1963. Of 266 babies with malformations, no mothers had cyclizine. Letter Part of nonclinical submission Milkovich L and van den Berg, 1976 Human incidence. While the results contain no signal for cyclizine the study contained only 111 patients who had taken cyclizine, and the standard error for the Severe congenital anomaly rate at 5 years was comparatively high. Precautions Not in nonclinical submission Sadusk et al., 1965 Is in list of references for the sponsor’s Clinical Summary, but paper is only in nonclinical dossier. The report of the findings of a Food and Drug Administration (FDA) committee that on the basis of lack of evidence - Part of nonclinical submission
the information provided in response to these include 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. overload. A statement ‘Infusion rate and volume need to be adapted according to clinical conditions, most notably in the elderly or in the paediatric population.’ has been included in the revised PI documents” and the important potential risk: ‘Hypervolaemia and haemodilution in high risk patients’ has now been included as a safety concern. [information redacted]If Albunate is supplied in Australia, assurance is provided that safety surveillance will be performed in accordance with CSL Behring's on-going routine pharmacovigilance practices”. response is acceptable. Notwithstanding the evaluation of the clinical aspects of the safety specification: ‘Potential for off-label use’ of the states that the potential for off-label use is a class-effect for all HA products and it cannot be excluded that HA products are used outside the approved indications. Consequently it is suggested that the sponsor consider including use’ as an important potential risk. It is noted that routine pharmacovigilance and routine risk minimisation activities are already proposed for this ongoing safety concern and only the ASA need be revised accordingly. The sponsor states: “The definition of important identified risk and important potential risk (Good Pharmacovigilance practices (GVP) I) is ‘what constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health’. Currently, there is no available data and/or evidence showing that off-label use of HAS causes serious individual risk or public health concerns. Therefore, use’ has not been listed in the ASA Summary table of Safety Concerns as an important potential risk. Spontaneous and other reports of off-label use will be reviewed in accordance with CSL Behring's ongoing routine pharmacovigilance practices.” This is acceptable.
Tm tubular maximum for reabsorption TZD thiazolidinedione ULN upper limit of normal ULOQ upper limit of quantification UGT uridine diphosphate glucuronosyltransferase II. Quality findings Drug substance (active ingredient) Dapagliflozin is a synthetic aryl glycoside. It has multiple chiral centres but the drug is a single enantiomer. Epimerisation is unlikely. Figure 1. Chemical structure of dapagliflozin dapagliflozin (propylene glycol, monohydrate solvate) The structure is not closely related to that of other antidiabetic drugs; it perhaps bears some similarity to miglitol (Figure 2). Figure 2. Chemical structure of miglitol. The drug substance used in tablet manufacture is the 1,2-propanediol, monohydrate solvate of dapagliflozin (1,2-propanediol is also known as propylene glycol). The drug substance is crystalline. Dapagliflozin aqueous solubility is relatively high and independent of pH. Drug product The proposed 5 mg and 10 mg (as dapagliflozin) tablets are, immediate release, film coated tablets with conventional formulations. Both strengths are yellow; they are distinguished by size, shape (5 mg round; 10 mg diamond) and tablet markings (‘5’ and ‘1427’; vs ‘10’ and ‘1428’). Neither is scored. Some clinical trials also used 2.5 mg tablets. The Phase III clinical formulation differed from the proposed formulation but no impact on bioavailability is expected. The tablets are packed in aluminium/aluminium blisters in 7 or 28 tablet packs. Supportive dissolution and disintegration data are available from the proposed manufacturing sites. The proposal was considered acceptable. Levels of impurities in dapagliflozin tablet batches are low although the proposed limits are lax. Limited on-going related substance testing will be done via an annual program testing stability of a batch. The approach was considered acceptable. Tablet stability data otherwise support the proposed shelf life of 24 months when stored below 30C.
DN04043 3 months 5 46 105 0.17 0.2 50 357 816 1.29 1.6 200 1135 2591 4.1 5 DN05030 [pivotal] 6 months 5 40 91 0.143 0.2 25 200 457 0.72 0.9 150 1024 2337 3.7 5 DN01103 6 months 15 99 226 0.36 0.4 75 409 935 1.47 1.8 150 844 1927 3.04 4 DN06073 [carc.] 2 years 0.5 3.6 8 0.013 0.02 2 14 32 0.050 0.06 10 74 169 0.266 0.33 Dog (Beagle) DN03050 1 month 5 62 142 3.3 4 25 351 800 19 23 250 2265 5172 120 150 3 months 5 70 159 3.7 5 30 560 1277 30 37 180 2258 5154 120 149 DN05031 [pivotal] 12 months 5 52 118 2.7 3.4 20 230 525 12.2 15 120 1265 2888 67 83 Human Single dose 10 mg 0.438 – 0.803 – Effect on food and water consumption and body weight changes Treatment with dapagliflozin increased water consumption and urine output at all doses tested in rats and dogs. These parameters were not assessed in the mouse toxicity studies
4. Is the indication appropriate or should it specify the severity of acne? The ACPM advised that as the pivotal studies excluded subjects with severe acne the indication should be qualified. 5. Where would this product be placed in the treatment algorithm for acne? The clinical trials recruited subjects aged ≥ 12 y with moderate acne (GAAS score of 3). While conservative, non-pharmaceutical measures may improve such acne significantly, resolution is uncommon without maintenance topical and/or oral therapy. Resolution of acne within 12 weeks of topical dapsone as monotherapy is realistic for mild acne, but sustained resolution with no ongoing treatment is unlikely. Topical dapsone likely will be a used as an addition to existing treatment options for acne, in monotherapy, combination therapy and/or maintenance treatment. The ACPM expressed some concern over the lack of data on bacterial resistance. The ACPM advised to facilitate responsible management of antibiotic medicines as a general standard that all antibiotic use should be carefully monitored for the appearance of resistance. The ACPM advised that implementation by the sponsor of the recommendations outlined above to the satisfaction of TGA, in addition to the evidence of efficacy and safety provided would support the safe and effective use of this product. Outcome Based on a review of quality, safety and efficacy, TGA approved the registration of Aczone dapsone 7.5% w/w topical gel bottle indicated for: The topical treatment of acne vulgaris in patients 12 years of age and older Specific conditions of registration applying to these goods The Aczone (dapsone) Australian RMP, version 1.0, dated 29 October 2015 (data lock point 31 May 2015), and any subsequent revisions, as agreed with TGA will be implemented in Australia Attachment 1. Product Information The PI approved for Aczone 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
Evaluator’s overall conclusions on clinical safety The safety data seen in the pivotal study in men with osteoporosis was similar to that seen previously in studies in postmenopausal women with osteoporosis. The long term studies in postmenopausal women with osteoporosis did not identify any additional risks with the exception of the cases of osteonecrosis of the jaw. While the patients who developed these events also had local risk factors the incidence is significant and should be better reflected in the Product Information. The post-marketing review of adverse events states that there is sufficient evidence to add drug sensitivity as a post marketing adverse drug reactions to the national product labelling. This is not reflected in the proposed Product Information included in the submission. First round benefit-risk assessment First round assessment of benefits The benefits of Prolia in the proposed usage are: Increase in BMD at all skeletal measured: lumbar spine, proximal femur (total hip, femoral neck, trochanter), and distal radius compared with placebo at 12 months. The magnitudes of the mean BMD increases observed in males with osteoporosis were similar to those observed in studies in postmenopausal women. Increases in BMD were associated with a decrease in new vertebral, non vertebral, and hip fractures in studies in previously evaluated studies (20030216 and 20040138). It is reasonable to extrapolate the same in men with osteoporosis. Safety in men with osteoporosis was similar to that seen in postmenopausal First round assessment of risks The risks of Prolia in the proposed usage are: AEs which are similar to those previously documented for denosumab. Osteonecrosis of the jaw is likely in a small number of subjects with long term use of denosumab. First round assessment of benefit-risk balance The benefit-risk balance of Prolia, given the proposed usage, is favourable. First round recommendation regarding authorisation Based on the clinical data submitted, it is recommended that the application be approved. Clinical questions No clinical questions.
Prolia® is supplied as a sterile, preservative-free, clear, colourless to slightly yellow solution for injection at pH 5.2. The solution should not be used if cloudy or discoloured. The solution may contain trace amounts of translucent to white proteinaceous particles. Each 1 mL single-use pre-filled syringe or vial contains 60 mg of denosumab in 1 mL (60 mg/mL). Product is for single-use in one patient only. Dispose of any medicinal product remaining in the pre-filled syringe or vial. It is recommended to store pre-filled syringes and vials in a refrigerator at 2° to 8°C in the original carton. Do not freeze. Protect from direct light. Do not excessively shake the pre-filled syringe or vial. Do not expose to temperatures above 25°C. If removed from the refrigerator, Prolia® should be kept at room temperature (up to 25°C) in the original container and must be used within 30 days. Pre-filled syringe with automatic needle guard; Pre-filled syringe*: Pack size of one, presented in blistered (pre-filled syringe with or without an automatic needle guard) or unblistered packaging (pre-filled syringe only). The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions. * Not available in Australia. Vial*: Pack size of one. A 27 gauge needle is recommended for the administration of Prolia®. Do not re-enter the vial. * Not available in Australia. NAME AND ADDRESS OF THE SPONSOR Amgen Australia Pty Ltd ABN 31 051 057 428 Level 7, NSW 2113 Medical Information: 1800 646 998 POISON SCHEDULE OF THE MEDICINE S4 Prescription Medicine DATE OF APPROVAL
For the most recent Product Information (PI), please to the TGA website < > Copyright © Commonwealth of Australia 2017 This work is copyright. You may reproduce the 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
tmax Time to maximum plasma concentration VAS Visual analogue scale V1 Apparent volume of the central or plasma compartment in a two compartment model V2 Apparent volume of the peripheral compartment in a model Vss Apparent volume of distribution at steady state Vz Apparent volume of distribution during terminal phase WPAI Work Productivity and Activity Impairment questionnaire
Phases Phase 1 28 days Phase 2 6 extension (double blind) Patients on active treatment continued on same treatment Patients on placebo were re-randomised to one of the 4 active treatment groups CS31 was an open label extension of Part 2 of CS29. Patients on 10 µg were re-randomised Measurement of primary endpoint (nocturnal voids) Nocturnal voids were recorded in a diary on 3 consecutive 24 hour periods at baseline and during the first four weeks of the study (Days 8, 15, 22, 28). The pre-specified time point was 28 days. Results Table 4: Results Study CS29; Nocturnal voids Nocturnal voids Placebo (n = 156) 10 µg (n = 155) 25 µg (n = 152) 50 µg (n = 148) 100 µg (n = 146) Baseline (mean) 3.3 3.2 3.4 3.4 3.2 Day 28 (mean) Diff (mean) p value versus placebo 2.4 -0.9 2.4 -0.8 0.93 2.4 -1.0 0.31 2.2 -1.2 0.02 1.8 -1.4 < 0.0001 Responders 28 day % p value versus placebo 47% 47% 0.94 50% 0.55 53% 0.27 71% < 0.0001 A post-hoc, unplanned, subgroup analysis (of CS29, to 28 days) by sex suggested that women achieved a similar response to men at lower doses. This may be related to size/weight. Women Table 5: Post-hoc, subgroup analysis (of CS29, to 28 days) of women Nocturnal voids Placebo (n = 66) 10 µg (n = 73) 25 µg (n = 65) 50 µg (n = 71) 100 µg (n = 66) Day 28 (mean) Diff (mean) p value versus placebo 2.5 -0.9 2.2 -1.2 0.07 2.1 -1.2 0.02 1.9 -1.2 0.01 1.5 -1.5 < 0.0001
NAME OF THE MEDICINE NOCDURNA® sublingual wafers Desmopressin Synonyms of desmopressin: DDAVP 1-Desamino-8-D-Arginine vasopressin. Desamino-cys-1-D-Arginine-8-vasopressin. CAS Nos.: Desmopressin base 16679-58-6 Desmopressin acetate 62288-83-9 Molecular formula and molecular mass: C48H74N14O17S2 (acetate trihydrate) MW = 1183.2 C46H64N14O12S2 (free base) MW = 1069.2 Physical and chemical characteristics: A white, fluffy powder, soluble in water, in alcohol and in glacial acetic acid. DESCRIPTION NOCDURNA, a sublingual wafer, contains the active substance, desmopressin (present as the hydrated acetate), a synthetic structural analogue of the natural pituitary hormone, arginine vasopressin. The difference lies in the desamination of cysteine and substitution of L-arginine by D-arginine. NOCDURNA also contains gelatin, mannitol and citric acid. PHARMACOLOGY Pharmacodynamics Pharmacotherapeutic group: Vasopressin and analogues. ATC code: H01B A02 Mechanism of action NOCDURNA contains desmopressin, a synthetic analogue of naturally occurring anti-diuretic hormone arginine vasopressin (AVP). Desmopressin mimics vasopressin’s anti-diuretic effect, binding to the V2 receptors in the renal collecting tubules of the kidneys, causing reabsorption of water into the body. This reabsorption in turn decreases night-time urine production. Due to the proposed low gender-specific doses (25 micrograms for females and 50 micrograms for males), and the limited duration of action of NOCDURNA, the antidiuretic activity is limited to the night time sleep period. Pharmacodynamic effects In study CS29, the weight-corrected NOCDURNA dose that induced 50% maximum achievable drug effect on nocturnal urine volume differed significantly between females and
25 Pos. control 99# 21 67 50 2 positive 24 0 6.25 12.5 25 Pos. control 0 2 5§ 11^ 26 ^ NA 0 69 77 38 DMF 1 positive 3 0 29.7 42.4 60.5 Pos. control NA 0.5 4.5 22.4 56.0 34.0 NA 1 41 56 ND 2 negative 22 0 7.5 Pos. control NA 0 2.5 44.0 NA 58 ND MMF 1 positive 3 0 312 446 Pos. control NA 0.5 6.0 8.5 37.3 NA 39 56 ND 3 positive 22 0 28.8 41.0 Pos. control NA 0 3.0 4.0 46.0 NA 32 54 ND * excluding gaps; § only 69 metaphases scorable; ^ not analysed statistically (only 4 metaphases scorable); # 99% of metaphases were pulverised; NA = not applicable; ND = no data; values in bold are significant
Good clinical practice The sponsor provided a statement that all studies were conducted in accordance with the principles of Good Clinical Practice. Pharmacokinetics Studies providing pharmacokinetic data Table 10 below, shows the studies relating to each pharmacokinetic topic and the location of each study summary. Table 10. Submitted pharmacokinetic studies. PK topic Subtopic Study ID * PK in healthy adults General PK - Single dose IKP/ID33 * 109HV101 109HV102 * - Multi-dose FG-PK-03/04 * Bioequivalence† n/a Food effect FG-PK-02/02 * C-1903 * PK in special populations Target population § - Single dose 109MS101 * - Multi-dose n/a Hepatic impairment n/a Renal impairment n/a n/a Elderly n/a PK Males versus females n/a PK interactions Aspirin (ASA) 109HV106 * Avonex (Interferon β-1a) 109HV103 * Copaxone (glatiramer acetate) 109HV104 * Healthy subjects n/a
V. Pharmacovigilance findings Risk management plan The sponsor submitted a Risk Management Plan which was reviewed by the TGA’s Office of Product Review (OPR). The following table (Table 27) summarises the OPR’s evaluation of the RMP, the sponsor’s responses to issues raised by the OPR and the second round OPR evaluation of the sponsor’s responses.
List of the most common abbreviations Abbreviation Meaning λx Terminal phase elimination rate constant 3TC Lamivudine ABC Abacavir AE Adverse event ALT Alanine aminotransferase AIDS Acquired immunodeficiency syndrome ALP Alkaline aminotransferase ART Antiretroviral therapy AST Aspartate aminotransferase AUC (0 - ∞) Area under the concentration-time curve from time zero to infinity AUC (0 – 24) Area under the concentration-time curve from time zero to 24 hours AUC (0 – τ) Area under the concentration-time curve over the dosing interval %AUCex Percentage of AUC(0 - ∞) obtained by extrapolation BD Twice daily BID Twice daily BCRP Breast cancer resistance protein BilT bilirubin BMI Body mass index BP Blood pressure C24 Concentration at 24 hours CDC Centres for Disease Control CER Clinical evaluation report CI Confidence interval CK Creatine kinase CL/F Apparent clearance oral administration trial
Clinical questions and Second round evaluation of clinical data submitted in response to questions Question 1 The FDC is a 22 mm x 11 mm, film coated tablet. The depth and circumference have not been stated in the clinical component of the dossier. The Sponsor is requested to supply the depth and circumference measurements. ViiV Healthcare response For Triumeq Tablets, the typical thickness is 7.6 mm and the approximate maximum circumference is 54.6 mm. For Kivexa Tablets, the typical thickness is 8.3 mm (as stated in our response to Question #2) and the approximate maximum circumference is 51 mm. In addition, Atripla, another fixed-dose combination HIV product marketed in Australia has similar dimensions: Atripla (EFV/TDF/FTC FDC): 20 mm x 10.4 mm. Evaluator comment Response accepted. Triumeq is a relatively large tablet which may cause some patients difficulty. Question 2 What are the dimensions of Kivexa tablets and Tivicay tablets? ViiV Healthcare response The dimensions of Kivexa and Tivicay tablets are provided below: Kivexa: 20.3 mm by 8.9 mm; typical thickness is 8.3 mm Tivicay: 9 mm round tablet; typical thickness is 4.7 mm. Evaluator comment Response accepted. Question 3 Does the Triumeq tablet swell in the presence of water? ViiV Healthcare response Triumeq Tablets do not swell in water. An experiment was performed where tablets from three batches were placed in water at room temperature and the dimensions were compared after 1, 3 and 10 minutes. No increases in dimensions (length, width and thickness) were observed. The tablets disintegrate by erosion in water, which would not be expected to cause difficulties in swallowing the tablets. Evaluator comment Response accepted. The information is reassuring. Question 4 The only submitted study in which the FDC was administered was ING114580, in which 54 healthy adults were administered 1 tablets and 12 were administered 2 tablets.
pilsicainide plasma concentration via inhibition of OCT2 transporter; has not been studied. Dofetilide or pilsicainide with dolutegravir is contraindicated due to potential toxicity caused by high dofetilide or pilsicainide concentration. Oxcarbazepine Phenytoin Phenobarbital Carbamazepine St. John’s wort Dolutegravir Co-administration with these metabolic inducers may decrease dolutegravir plasma concentration and has not been studied. with these metabolic inducers should be avoided. Antacids containing polyvalent cations (e.g., Mg, Al) Dolutegravir AUC 74% Cmax 72% C24 74% Co-administration of antacids containing polyvalent cations decreased dolutegravir plasma concentration. Dolutegravir is recommended to be administered 2 hours before or 6 hours after taking antacid products containing polyvalent cations. Calcium supplements Dolutegravir AUC 39% Cmax 37% C24 39% TRIUMEQ is recommended to be administered 2 hours before or 6 hours after taking products containing calcium, or alternatively, administer with food. Iron supplements Dolutegravir AUC 54% Cmax 57% C24 56% TRIUMEQ is recommended to be administered 2 hours before or 6 hours after taking products containing iron, or alternatively, administer with food. Metformin Metformin Co-administration of dolutegravir has the potential to increase metformin plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Lower metformin doses may be considered for patients treated with dolutegravir and metformin. Rifampicin Dolutegravir AUC 54% Cmax 43% C 72% Rifampicin decreased dolutegravir plasma concentration. Since the dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin, the co-administration of rifampicin with TRIUMEQ is not recommended. Oral contraceptives (Ethinyl estradiol (EE) and Effect of dolutegravir: EE AUC 3% Dolutegravir did not change ethinyl estradiol and norelgestromin plasma concentrations to a clinically relevant extent. No dose adjustment of oral
The vaccine may contain traces of glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B. The manufacture of this product includes exposure to bovine materials. No evidence exists that any case of vCJD (considered to be the human form of bovine spongiform encephalopathy) has resulted from the administration of any vaccine product. Hexaxim is a whitish, cloudy suspension. PHARMACOLOGY Mechanism of action Hexaxim induces the production of antibodies against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b. CLINICAL TRIALS The primary vaccination schedules that have been used are: 6, 10, 14 weeks with and without hepatitis B vaccination at birth; 2, 3, 4 months without hepatitis B vaccination at birth; 2, 4, 6 months with and without hepatitis B vaccination at birth. Results obtained in the clinical studies for each of the components are summarised in the tables below: Table 2: Percentage of individuals with antibody titres seroprotection/seroconversion rates* one month after primary vaccination with Hexaxim Antibody titres seroprotection/seroconversion rates 6-10-14 Weeks N†=123 to 220 2-3-4 Months N†=145 2-4-6 Months N†=934 to 1270 % % % Anti-diphtheria ( 0.01 IU/ml) 97.6 99.3 97.1 Anti-tetanus ( 0.01 IU/ml) 100.0 100.0 100.0 Anti-PT ( 4 fold rise) 93.6 93.6 96 Anti-FHA ( 4 fold rise) 93.1 81.9 97.0 Anti-HBs ( 10 mIU/ml) With hepatitis B vaccination at birth 99.0 / 99.7 Without hepatitis B vaccination at birth 95.7 94.0 98.8 type 1 ( 8 (1/dilution)) 100.0 97.7 99.9
Systemic hypersensitivity reactions and immune mediated injection site adverse events but incidence low round assessment of benefit-risk balance The benefit-risk balance of dulaglutide, given the proposed usage, is favourable. First round recommendation regarding authorisation Based on the clinical data included, it is recommended the application is approved. Clinical questions Pharmacokinetics No questions submitted. Pharmacodynamics No questions submitted. Efficacy No questions submitted. Safety No questions submitted. References Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus CPMP/EWP/1080/00 30 May 2002, adopted by TGA 23 October 2002 Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 FDA 2008. Hauschke D, Steinijans VW, Diletti E. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol. 1990; 28(2):72-78.
Pharmacokinetics Studies providing pharmacokinetic data The submitted pharmacokinetic (PK) studies are summarised in Table 3. There were no studies excluded from consideration. 3: Submitted pharmacokinetic studies PK topic Subtopic Study ID * PK in healthy adults General PK; Single dose Study R668-AS-0907 * Study R668-HV-1108 * TDU12265 * Bioequivalence; Single dose Study PKM12350 * Study PKM14161 * Study PKM14271 * PK in special populations Target population; dose Study R668-AD-0914 * Study R668-AD-1026 * Population PK analyses Target population Study * Indicates the primary PK aim of the study. Evaluator’s conclusions on pharmacokinetics The basic pharmacokinetics of dupilumab has been adequately described by the sponsor in the draft PI and have been adequately characterised. However, the sponsor has made the assumption that the elimination of dupilumab will be identical to that for other monoclonal antibody drugs. The sponsor has not confirmed this in mass balance studies. The sponsor has studied the effect of ADA on the PK. The effect of ADA on elimination was clinically significant and resulted in an increase of 17.8% in elimination rate constant. Greater disease severity, as measured by Eczema Area and Severity (EASI) score, also contributed to an increase in clearance. Interactions between dupilumab and other immunomodulatory drugs have not been studied. Hence, combinations of these drugs should be contraindicated. Dupilumab has the potential to be used extensively in the paediatric population. The PK in this population will need to be carefully characterised. Effects on vaccines will need further investigation. There were few older patients in the PK studies. The effects of aging on the PK of dupilumab have not been adequately characterised.