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3.2.4. Discussion on chemical, pharmaceutical and biological aspects Drug Substance The active ingredient manufactured by Mylan Laboratories Limited, India, is documented via EDQM certificate of suitability CEP 2013-330, issued in 2/2015. No assessment on the drug substance has been conducted except stability data due to non-declaration of a re-test period on the CEP; some concerns on drug substance stability remain. Drug Product There are some “other concerns” identified for the drug products. Apart from the raised concerns the documentation of the drug products is adequate and the proposed shelf-life of 36 months without any special storage condition for Aripiprazole Mylan tablets and Aripiprazole Mylan orodispersible tablets is acceptable. 3.2.5. Conclusions on the chemical, pharmaceutical and biological aspects There are a few “other concerns” regarding the drug substance and the drug product. From the quality point of view Aripiprazole Mylan tablets and Aripiprazole Mylan orodispersible tablets could be recommended for approval provided the questions regarding the drug substance and drug product can be resolved and the requested information is provided. 3.3. Non clinical aspects 3.3.1. Pharmacology, Pharmacokinetics & Toxicology A non-clinical overview on pharmacology, pharmacokinetics and toxicology has been provided, which justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. The non-clinical aspects of the SmPC are in line with the SmPC of the reference product. The non-clinical overview report refers to 25 publications up to year 2014. The CHMP considers that the non-clinical overview is based on up-to-date and adequate scientific literature. It is agreed that no further non-clinical studies are required. 3.3.2. Ecotoxicity/environmental risk assessment The applicant states that an environmental risk assessment according to CHMP guideline CPMP/SWP/4447/00 (Note for Guidance on the Environmental Risk Assessment of Medical Products for Humane Use) has not been provided. This application is for a generic version of Abilify ® (aripiprazole) 5 mg, 10 mg, 15 mg and 30 mg tablets as well Abilify ® (aripiprazole) 10 mg and 15 mg orodispersible tablets, the products that were registered in the EU since 2004. Aripiprazole Mylan 5 mg, 10 mg, 15 mg and 30 mg tablets as well Aripiprazole Mylan 10 mg and 15 mg orodispersible tablets contain an identical amount of aripiprazole drug substance and has been formulated with a range of commonly used excipients to be pharmaceutically equivalent to Abilify ® 5 mg, 10 mg, 15 mg and 30 mg tablets, and Abilify ® 10 mg and 15 mg orodispersible tablets, respectively, and as such are not considered to pose any greater environmental risk than the reference products. Assessment report EMA/49072/2016 Page 12/37
Furthermore, given that Aripiprazole Mylan 5mg, 10mg, 15mg and 30mg tablets and Aripiprazole Mylan 10 mg and 15 mg orodispersible tablets are aimed at replacing rather than increasing prescriptions of Abilify ® 5 mg, 10 mg, 15 mg and 30 mg tablets and Abilify ® 10 mg and 15 mg orodispersible tablets, respectively, no increased environmental burden is expected from the marketing of these generic products. 3.3.3. Conclusion on non-clinical aspects There are no objections to approval of Aripiprazole Mylan 5 mg, 10 mg, 15 mg, 30 mg tablets and Aripiprazole Mylan 10 mg and 15 mg orodispersible tablets from a non-clinical point of view. 3.4. Clinical aspects Tabular overview of clinical studies Type of Study Study Identifier Objective(s) of the study Study Design and Type of control Test Product(s); Dosage Regimen; Route of Administration Number of Subjects Healthy subjects or Diagnosis of patients Duration of Treatment BE 14-VIN-657 To compare the rate and extent of absorption of Aripiprazole orodispersible tablets 10mg of Mylan Laboratories Limited and ABILIFY ® (aripiprazole) 10 mg orodispersible tablets of Otsuka Pharmaceutical Europe Ltd. In healthy, adult, human subjects under fasting condition. To evaluate the safety and tolerability of Aripiprazole orodispersible tablets 10 mg in healthy human subjects. An open label, balanced, randomized, single-dose, two-treatment, single-period, parallel bioequivalence study in healthy, adult, human subjects under fasting condition. Treatment controlled One tablet formulation, single dose, oral administration Enrolled: 60 (+3 extra) Completed: 60 Total subjects analysed for pharmacokinetics and statistical analysis: 60 Healthy a d u l t h u m a n Subjects Single dose BE BA141017 95-01 The objectives of this study were to compare and evaluate the oral bioavailability of Aripiprazole Tablets 10 mg with that of ‘ABILIFY’ (Aripiprazole) 10 mg Comprimes (Tablets) in healthy, adult, human subjects under fasting conditions and to monitor the safety of the subjects. An open label, randomized, single-period, twotreatment, parallel, balanced, single dose oral bioequivalence study in healthy, adult, human subjects under fasting conditions. Test Product-T: Aripiprazole Tablets 10 mg, Dosage Regimen: 10 mg Route of administration: Oral Reference Product-R ABILIFY ® (Aripiprazole Tablet) 10 mg, Dosage Regimen: 10 mg Route of administration: Oral No. of subjects dosed Group-I: 36 Group-II: 24 Completed-57 Subjects considered for pharmacokinetic and statistical analysis-57 (28 subjects in Test treatment and 29 subjects in Reference treatment) Healthy Subjects Single dose BE: Bioequivalence 3.4.1. Pharmacokinetics To support the application, the Applicant has submitted two bioequivalence studies. Assessment report EMA/49072/2016 Page 13/37
Page 1 and 2: 22 October 2015 EMA/49072/2016 Comm
Page 3 and 4: 1. Recommendation Based on the CHMP
Page 5 and 6: The proposed SmPC for Aripiprazole
Page 7 and 8: Manic episodes in Bipolar I Disorde
Page 9 and 10: Good Clinical Laboratory Practice (
Page 11: Manufacture of the product and proc
Page 15 and 16: ecommended. Under certain circumsta
Page 17 and 18: Group I Twelve subjects were enroll
Page 19 and 20: Table 1: Study No. BA14101795-01 -
Page 21 and 22: Descriptive statistics: Mean, stand
Page 23 and 24: AUC 0-72 and C max were within the
Page 25 and 26: amount of drug (aripiprazole) was r
Page 27 and 28: - After 60 seconds, subjects were i
Page 29 and 30: Population(s) studied Healthy volun
Page 31 and 32: ioanalytical method validation (EME
Page 33 and 34: The statistical analysis on the pha
Page 35 and 36: Discontinuation due to adverse even
Page 37: study design and the statistical an

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