Zusammenfassung der Merkmale des Arzneimittels - Atomoxetin-neuraxpharm 25 mg Hartkapseln
II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical
IV BENEFIT RISK ASSESSMENT
8
| Name of the medicinal product in the RMS | Atomoxetin-neuraxpharm 10 / 18 / 25 / 40 / 60 / 80 / 100 mg Hartkapseln |
| Name of the drug substance (INN name): | Atomoxetine hydrochloride |
| Pharmaco-therapeutic group (ATC Code): | N06BA09 |
| Pharmaceutical form(s) and strength(s): | Capsule, hard; 10 / 18 / 25 / 40 / 60 / 80 / 100 mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/5269/001–007/DC |
| Reference Member State: | DE |
| Concerned Member States: | PL, UK |
| Applicant (name and address) | neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Straße 23 40764 Langenfeld Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Admin address: Pharmathen International S.A. 4, Dervenakion str. 15351 Pallini, Attiki Greece Manufacturer address: Pharmathen International S.A. Industrial Park Sapes, Block No 5 69300 Rodopi Prefecture Greece Pharmathen International S.A. 6, Dervenakion str. 15351 Pallini, Attiki Greece Pharmadox Healthcare Ltd KW20A Kordin Industrial Park PLA 3000 Paola Malta neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Straße 23 40764 Langenfeld Germany |
Based on the review of the data on quality, safety and efficacy, the application for “Atomoxetin-neuraxpharm 10 / 18 / 25 / 40 / 60 / 80 / 100 mg Hartkapseln” , indicated for
the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD.In adults, the presence of symptoms of ADHD that were pre-existing in childhood should be confirmed. Third-party corroboration is desirable and [Invented name] should not be initiated when the verification of childhood ADHD symptoms is uncertain. Diagnosis cannot be made solely on the presence of one or more symptoms of ADHD. Based on clinical judgment, patients should have ADHD of at least moderate severity as indicated by at least moderate functional impairment in 2 or more settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual's life.
Additional information for the safe use of this medicinal product: A comprehensive treatment programme typically includes psychological, educational and social measures and is aimed at stabilising patients with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired. Pharmacological treatment is not indicated in all patients with this syndrome and the decision to use the medicinal product must be based on a very thorough assessment of the severity of the patient's symptoms and impairment in relation to the patient's age and the persistence of symptoms.is approved.
II.1 Problem statement
N/A
II.2 About the product
Atomoxetine ((-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride) is a potent and highly selective inhibitor of the norepinephrine reuptake by interfering with the presynaptic norepinephrine transporter (NET). Atomoxetine has clearly lower affinity for noradrenergic receptors or other neurotransmitter transporters (e.g. for serotonin or dopamine) and their receptors. Of the two major oxidative metabolites of atomoxetine, 4-hydroxyatomoxetine equipotently interferes with the NET and also exerts some inhibitory activity at the serotonin transporter. Nevertheless, this inhibition is of minor clinical relevance, because 4-hydroxyatomoxetine is further metabolised and amounts only to 1 % of atomoxetine in plasma of extensive metabolisers and 0.1 % in plasma of poor metabolisers, respectively. The second major oxidative metabolite, N-desmethylatomoxetine, has clearly less pharmacodynamic activity than its parent substance.
Atomoxetine is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme.
II.3 General comments on the submitted dossier
This decentralised application according to Art. 10(1) of Dir. 2001/83/EC concerns a generic version of atomoxetine hydrochloride, under the trade names “Atomoxetin – neuraxpharm 10/ 18/ 25/ 40/ 60/ 80/ 100 mg Hartkapseln”. The originator product is “Strattera 10, 18, 25, 40, 60 mg hard capsules” by Eli Lilly and Company Ltd., registered since 27th May 2004 in the United Kingdom. These Marketing Atomoxetin-neuraxpharm 10 / 18 / 25 / 40 / 60 / 80 / 100 mg Hartkapseln, DE/H/5269/001–007/DC Public AR 4/8
Authorisations were subsequently extended to “Strattera 80 and 100 mg hard capsules” on 5th June 2008. Moreover, these strengths were complemented by “Strattera 4 mg/ml oral solution” on 3rd October 2014. Hence, data protection has already expired and generic applications are possible.
With Germany as the Reference Member State in this Decentralized Procedure, neuraxpharm Arzneimittel GmbH, Germany, is applying for the Marketing Authorisations for “Atomoxetin-neuraxpharm 10 / 18 / 25 / 40 / 60 / 80 / 100 mg Hartkapseln” in PL and UK.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
III.1 Quality aspects
Drug substance
The manufacturer of the active substance provided a valid Certificate of Suitability, which is also in line with the application form.
The control tests and specifications for drug substance product are adequately drawn up.
Stability studies have been performed. No significant changes in any parameters were observed. The proposed retest period of 5 years is considered justified.
The development of the product has been described thoroughly, the choice of excipients is justified and their functions explained. And the choice of dissolution method/conditions have been fully justified.
The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. A risk assessment of elemental impurities has been presented indicating that the existing control strategies are sufficient. Batch analysis has been performed on 3 batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. Stability studies have been performed. No significant changes in any parameters were observed. The proposed shelf-life of 3 years by extrapolation for the drug product is considered acceptable.
III.2 Non clinical aspects
The pharmacodynamic, pharmacokinetic and toxicological properties of atomoxetine are well established and have been extensively summarised. This document also adequately refers to the compliance of the drug substance and drug product specifications with the current Ph Eur. monograph on atomoxetine. In addition, a CEP is available for manufacturing of the drug substance.
The toxicological characteristics of atomoxetine are also appropriately reflected in the proposed SmPC and PL regarding use of the product during pregnancy and lactation as well as concerning preclinical safety data. There are hence no objections against marketing authorisation from a preclinical perspective.
Since “Atomoxetin-neuraxpharm 10 / 18 / 25 / 40 / 60 / 80 / 100 mg Hartkapseln” is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
Pharmacokinetics / bioequivalence
To support the application, the applicant has submitted as report one bioequivalence study:
Study Title : ”A randomized, open label, balanced, two treatment, two sequence, two period, single dose, crossover, bioequivalence study of Atomoxetine 60mg hard capsules of Pharmathen S.A., Greece and Strattera 60mg hard capsules containing Atomoxetine 60mg of Eli Lilly in healthy, adult, human subjects under fasting conditions.”
A statement on the application of appropriate GCP standards in the submitted study has been provided. No inspections are regarded as needed for the time being.
Results :
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD (%CV), t max median, range) (n = 66)
| Treatment | AUC2 0-t ng/ml/h | AUC 0-∞ ng/ml/h | C max ng/ml | t max h |
| Test | 3969.724 ± 4588.6347 (115.59%) | 4145.679 ± 5060.2680 (122.06%) | 499.208 ± 164.5248 (32.96%) | 1.000 (0.50–8.00) |
| Reference | 3814.699 ± 4124.4661 (108.12%) | 4011.849 ± 4678.3240 (116.61%) | 473.034 ± 153.2191 (32.39%) | 1.000 (0.50–8.00) |
| *Ratio (90% CI) | 101.41% 98.57 – 104.34% | 101.33% 98.53 – 104.21% | 105.13% 98.95 – 111.69% | |
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | ||||
*ln-transformed values
2In some cases AUC (0–72)
Figure 1: Pharmacokinetic profiles of tested and reference products ‒ linear scale:
Based on the results reported by the investigators, formulation of atomoxetine 60 mg hard capsules is bioequivalent to the reference formulation (Strattera 60 mg hard capsules) with respect to the rate and extent of absorption under fasting conditions.
A biowaiver is requested for the 10 mg, 18 mg, 25 mg, 40 mg, 80 mg and 100 mg strength based on the results of the 60 mg bioequivalence study.
As all conditions mentioned in the Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6., are adequately fulfilled, a biowaiver can be granted for the 10, 18, 25, 40, 80 and 100 mg strengths based on the results of the 60 mg bioequivalence study.
Medicinal product subject to medical prescription.
Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet , May 2006). Both the first and the second test round met the success criteria of more than 90% of the subjects being able to locate the requested information, and of those, more than 90% being able to give the correct answer, to indicate that they understood the information presented. The general impression of the tested PL (content, language and layout) was mostly positive. In conclusion, the user test is considered acceptable.
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to atomoxetin.
The following summary of safety concnerns were submitted within the RMP:
| Summary of safety concerns | |
| Important identified risks | Suicidal ideation Hepatic injury Increased blood pressure an increased heart rate Peripheral vascular instability (Raynaud’s phenomenon) |
| Important potential risks | Cardiovascular and cerebrovascular outcomes – myocardial ischaemia, – tachyarrhythmia, – cerebrovascular accident QTc prolongation Aggression/hostility Seizures |
| Missing information | Use in pregnancy and lactation |
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
There are additional risk minimization measures. The educational materials are included in annex 10 and annex 11 of the RMP and have to be submitted in case of launch. The RMS informs that in case of launch in Germany the educational material should be in line with the originator and for generic products only one should be submitted in cooperation with the Germany medicines manufacturer’s Association.
With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.