Decentralised Procedure Public Assessment Report Albendazol Micro Labs 400 mg Kautabletten Albendazole - DE/H/5407/001/DC
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Decentralised Procedure
Public Assessment Report
Albendazol Micro Labs 400 mg Kautabletten
Albendazole
DE/H/5407/001/DC
Applicant: Micro Labs GmbH
Date: 02.04.2019
This module reflects the scientific discussion for the approval of Albendazol Micro Labs 400
mg Kautabletten. The procedure was finalised on 19.12.2018.TABLE OF CONTENTS I. INTRODUCTION ....................................................................................................................... 4 II. EXECUTIVE SUMMARY......................................................................................................... 4 II.1 Problem statement..................................................................................................................... 4 II.2 About the product ..................................................................................................................... 4 II.3 General comments on the submitted dossier .......................................................................... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles .. 6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ..................................................................... 6 III.1 Quality aspects ........................................................................................................................... 6 III.2 Non-clinical aspects ................................................................................................................... 6 III.3 Clinical aspects .......................................................................................................................... 6 IV. BENEFIT RISK ASSESSMENT ............................................................................................. 10 Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 2/10
ADMINISTRATIVE INFORMATION
Name of the medicinal product in the
Albendazol Micro Labs 400 mg Kautabletten
RMS
Name of the drug substance (INN
Albendazole
name):
Pharmaco-therapeutic group
P02CA03
(ATC Code):
Pharmaceutical form(s) and
400 mg, Chewable tablet
strength(s):
Reference Number(s) for the
DE/H/5407/001/DC
Decentralised Procedure
Reference Member State: DE
Concerned Member States: LU
Legal basis of application: Generic application Art 10.1
Micro Labs GmbH
Applicant (name and address) Lyoner Straße 14
D-60528 Frankfurt
Names and addresses of all proposed Micro Labs GmbH
manufacturer(s) responsible for Lyoner Straße 14
batch release in the EEA D-60528 Frankfurt
Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 3/10I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Albendazole Chewable Tablets 400 mg, in the treatment of cystic echinococcosis, alveolar echinococcosis, Trichinella infestation and treatment test for strongyl infestation, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This is a generic application (Art. 10(1) Directive 2001/83/EC) for Albendazole Chewable Tablets 400 mg. II.2 About the product Albendazole is a benzimidazole derivative with antiprotozoal and anthelmintic activity against intestinal and tissue parasites. Albendazole has larvicidal, ovicidal and vermicidal effects, which are presumably caused by an inhibition of the polymerisation of the tubulin of the cytoplasmic microtubule system of intestinal parasites. This leads to the interruption of the metabolism of the helminthes, including an energy loss, whereby an immobilization of the sensitive helminthes takes place. The applicant states the following in the submitted SmPC: Indication Albendazole is suitable for the treatment of the following helminthoses: Cystic echinococcosis (Echinococcus granulosus-infection, dog tapeworm infestation) - Inoperable progressive form - non-radically operable progressive form - preoperative support of surgical therapy Alveolar echinococcosis (Echinococcus multilocularis-infection, fox tapeworm infestation) - Inoperable progressive form - non-radically operable progressive form - preoperative support of surgical therapy Trichinella infestation (Trichinella spiralis infection, trichinosis) A treatment test for strongyl infestation (Strongyloidiasis, Strongyloides stercoralis) is indicated. Albendazole Micro Labs 400 mg chewable tablets are indicated in adults and adolescents with a body weight of ≥ 60 kg. Posology The medicinal product should not be used in patients weighting < 60 kg. Cystic or alveolar echinococcosis One treatment cycle comprises 400 mg albendazole (1 chewable tablet) twice a day for the duration of 28 days followed by a 14-day break. At least two but not more than three treatment cycles should be carried out. - preoperative: If surgical treatment is intended, this should be preceded with treatment with albendazole for 2 cycles as described above. If an operation is necessary before completion of two complete cycles, albendazole should be administered for as long as possible but not longer than for 28 days / cycle. - postoperative: If an operation is indispensable after less than 14 days of treatment, albendazole should be administered after the operation for at least 2 treatment cycles of 28 days each, with a 14-day interval between them. 2 complete treatment cycles should also be carried out if cysts still exist after preoperative treatment or after cyst rupture. Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 4/10
Trichinosis 2 times daily 400 mg albendazole (1 chewable tablet) for 6 days Normally only one treatment cycle is necessary. Confirmed diagnosis or suspicion of strongyl infestation (Strongyloidiasis) 400 mg albendazole (1 chewable tablet) once daily for 3 consecutive days Paediatric population Albendazole Micro Labs should not be used in children and adolescents weighing less than 60 kg, as the safety and efficacy have not been established in this patient group. Elderly people Experience with older patients (65 years and older) is limited. Reports show that no dosage adjustment is required. Dosage for renal impairment Because the excretion of Albendazole and its primary metabolite Albendazole sulfoxide is negligible from the kidney, it is unlikely that the clearance of these components will be altered in patients with renal insufficiency. Adjustment of dosage is not required. Nevertheless, patients with a history of renal insufficiency should be carefully monitored. Dosage for hepatic impairment In patients with hepatic dysfunction the warnings should be observed. Method of administration Albendazole Micro Labs 400 mg chewable tablets are for oral use. The tablets should be chewed. They should be taken with meals in the morning and in the evening. For a better absorption of active ingredients, a fat-containing diet is recommended for the period of treatment. This should be as solid as possible and contain over 40 g of fat per meal. Special warnings and precautions for use It should be pointed out, that Albendazole Micro Labs should not be used in children and adolescents with a body weight less than 60 kg. II.3 General comments on the submitted dossier This is a generic application for Albendazole Chewable Tablets 400 mg according to Article 10(1) of Directive 2001/83/EC. Since the pharmaceutical form differs from the reference product (chewable tablet vs. tablet), an application according to Art 10(1) is only accepted because it is proven by the applicant that oromucosal effects are strictly excluded. From a clinical and quality point of view, the applicant provided a sound scientific justification that no oromucosal effects are expected for Albendazole Micro Labs 400 mg chewable tablets in terms of solubility, stability, permeability and exposure time. The applicant Micro Labs GmbH applies through Decentralised Procedure with Germany acting as reference member state (RMS). The concerned member state is LU. The reference medicinal product chosen is Eskazole 400 mg Tabletten by GlaxoSmithKline GmbH & Co. KG registered since August 6th 1992. In support of this application, one open label, balanced, randomized, two-treatment, three-period, three-sequence, single dose, crossover, partial replicate oral bioequivalence study (754/16) in healthy, adult, human subjects under fed conditions was submitted. The bioequivalence study was performed with the chewable tablet resulting in respective recommendations for the posology of the Albendazole Chewable Tablets 400 mg only. The company did not seek scientific advice prior to submission. Albendazole is not considered a new substance. Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 5/10
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles
GMP:
GMP certificates and/or Manufacturing Authorisations have been provided for the manufacturers
involved in the production of the drug product.
A declaration by the Qualified Person (QP) of the manufacturer (batch release) stating that the active
substance manufacturer referred to in the application operates in compliance with GMP.
GCP/agreed ethical principles
The bioequivalence study was conducted in accordance with ICH “Guidance on Good Clinical
Practice” and has been approved by an Ethical Committee to ensure compliance with the Declaration
of Helsinki.
The applicant provided GCP inspection reports from EMA and MHRA as requested. Overall, no
critical findings were observed.
Recently, a routine inspection of clinical and bioanalytical facilities was conducted by the WHO.
Based on the inspection reports provided from WHO and FDA no concerns regarding the conduct of
studies at CRO were identified.
III. SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
A Certificate of Suitability of the monograph of the European Pharmacopoeia has been provided.
The Applicant’s / drug product manufacturer’s drug substance specification includes the specifications
of the Ph. Eur. Monograph for Albendazole and the additional specification required by the CEP.
Additionally, particle size distribution is specified. The re-test period of 5 years is certified by the
CEP. The applicant proposes a re-test period of 5 years that is in compliance with the re-test period
certified in the CEP.
Drug Product
The drug product is a generic version of the European reference medicinal product, Brand Eskazole®
400 mg Tabletten albendazol tablets and is a white to off-white coloured, oblong shaped, biconvex
tablets debossed with "AL" and "400" on either side of breakline on one side and other side plain.
The development of the product has been described, the choice of excipients is justified and their
functions explained.
The product specifications cover appropriate parameters for this dosage form. Validations of the
analytical methods have been presented. Batch analysis has been performed. The batch analysis results
show that the finished products meet the specifications proposed.
The conditions used in the stability studies are according to the ICH stability guideline. The control
tests and specifications for drug product are adequately drawn up. The shelf-life is 2 years without any
recommendation for storage.
III.2 Non-clinical aspects
There are no objections to approval of Albendazol Micro Labs 400 mg Tabletten from a non-clinical
point of view.
Environmental Risk Assessment (ERA)
Since Albendazole 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
This application is based on the originator Eskazole 400 mg Tabletten by GlaxoSmithKline GmbH &
Co. KG registered since August 6th 1992. The applicant did not conduct any clinical studies except the
bioequivalence study 754/16.
Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 6/10Pharmacokinetics To support the application, the applicant has submitted as report one open label, balanced, randomized, two-treatment, three-period, three-sequence, single dose, crossover, partial replicate oral bioequivalence study (754/16) in healthy, adult, human subjects under fed conditions. The objective of this study (754/16) was to assess the bioequivalence of Albendazole Chewable Tablets 400 mg (test) compared with that of Eskazole® 400 mg Tabletten Albendazol of GlaxoSmithKline GmbH & Co. KG, München, in healthy, adult, human subjects under fed conditions and to monitor adverse events and ensure the safety and tolerability of subjects. The study was conducted as an open label, balanced, randomized, two-treatment, three-period, three- sequence, single dose, crossover, partial replicate oral bioequivalence study in healthy, adult, human subjects under fed conditions with a screening period of 28 days prior to enrolment. In each study period, the subjects received either test (T) or reference (R) products as per the randomization schedule. A washout period of 7 days was maintained between each consecutive dosing period. With regard to bioequivalence study 754/16, the design of the study, the widening of the acceptance range as well as the high fat fed conditions are considered acceptable according to the current guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **. The handling of the test and reference product before administration was sufficiently described. The drug intake procedure of Albendazol Micro Labs 400 mg in this study allows only conclusions on bioequivalence for the chewed tablet. Pharmacokinetic evaluation/statistical methods Primary pharmacokinetic parameters such as Cmax and AUCt and secondary parameters AUCinf, Tmax, Kel, t1/2, residual area, AUCt/AUCinf for albendazole and albendazole sulfoxide were determined for test and reference products for each subject. The reference-scaled procedure was applied for Cmax of the Albendazole as the reference within subject variability of the Cmax was more than 30%. Hence a widened BE acceptance range (77.39 – 129.21%) was employed. The test product was considered as bioequivalent to the reference product, if the 90% Confidence Intervals for geometric least square mean ratios of Ln-transformed parameters AUCt for Albendazole fell within the acceptance range of 80.00-125.00%. Individual and mean concentrations, individual and mean pharmacokinetic parameters, geometric means, ratios of means and ANOVA for Cmax and AUCt are submitted for Albendazole sulfoxide as a supportive evidence. Analytical methods The plasma samples of subjects were analysed using LC-MS/MS over a validated concentration range of 0.50991 ng/mL to 250.36 ng/mL for Albendazole and 5.0924 ng/mL to 2500.3 ng/mL for Albendazole Sulfoxide. Albendazole-D3 and Albendazole Sulfoxide –D7 were used as internal standards. Out of a total of 2867 plasma samples analysed, altogether 127 samples were re-analysed due to analytical reasons like “above upper limit of quantification” or “beyond modified calibration curve” (122). Additionally, five (5) samples were repeated due to non-analytical reasons like “positive predose” (1) and “Investigational Purpose” (4). The analytical method was adequately validated, including pre-study and within-study validations. Incurred samples reanalysis was performed and confirmed reliability of the initial results. Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 7/10
Results Table 1. Pharmacokinetic parameters in Study No.: 754/16 (non-transformed values; arithmetic mean ± SD, tmax median, range) Table 2. Additional pharmacokinetic data for Albendazole and Albendazole sulfoxide in Study No.: 754/16 Table 3. Bioequivalence evaluation of Albendazole and Albendazole sulfoxide in Study No.: 754/16 Since the AUC was truncated at 72 hours, the extrapolated AUC has not been calculated, which is acceptable. No subjects had a pre-dose level of or in excess of 5% of the Cmax value. Tmax was not observed at the first sample time point after dosing in any subjects. The ANOVA detected a statistical significant sequence effect for the ln-transformed Cmax of albendazole and a treatment effect for the ln-transformed Cmax of albendazole sulfoxide which have been reasonably justified by the applicant. However, for bioequivalence purposes results for the parent compound albendazole are considered only. Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 8/10
The 90 % confidence intervals of the differences of least squares means for the ln-transformed
pharmacokinetic parameters Cmax and AUC0-72h of albendazole sulfoxide and AUC0-72h of albendazole
are within the bioequivalence acceptance limits of 80.00 – 125.00%. For the ln-transformed
pharmacokinetic parameter Cmax of albendazole, a widened acceptance range of 77.23-129.48% is
applicable.
Conclusion
Based on the pharmacokinetic parameters, the test product (T) Albendazole Chewable Tablets 400 mg
is considered bioequivalent with the reference product (R) Eskazole 400 mg Tabletten Albendazol of
GlaxoSmithKline GmbH & Co. KG, in healthy, adult, human subjects under fed conditions for the
chewed tablet only. Thus, a marketing authorization can be granted.
Safety
Four subjects developed a total of eight adverse events. Out of these, six adverse events were moderate
in nature and possibly related to study drug. Two adverse events were mild in nature and unlikely
related to the study drug. The other adverse events reported are already labelled in the product
information. No deaths or serious adverse events were reported. No safety signal was identified.
Pharmacodynamics
No such studies are required for this application.
Clinical efficacy
See assessment of bioequivalence study.
Clinical safety
See assessment of bioequivalence study under “Pharmacokinetics”.
Legal Status
In Germany, like the originator, Albendazol Micro Labs is a prescription only medicinal product.
User Testing
A readability test has been performed. The results of the Readability testing of the Package Leaflet for
Albendazole Tablets indicate the leaflet is well structured and organized, easy to understand and
written in a comprehensive manner. The leaflet is user-friendly.
Summary Pharmacovigilance system
The applicant has submitted a signed Summary of the applicant's and/or 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.
Risk Management Plan
The applicant has submitted a RMP with the following safety concerns:
Summary of safety concerns
Important identified risk Hepatic impairment
Myelosuppression leading to pancytopenia, aplastic
anaemia, agranulocytosis, and leukopenia
Important potential risks Neurological disorders
Missing information None
Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 9/10The submitted Risk Management Plan is approvable.
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.
Periodic Safety Update Report (PSUR)
Use the below statement in case a substance is listed in the published EURD list.
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.
• In case the active substance will be removed in the future from the EURD list because the
MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose
DLP and frequency for further PSUR submissions together with a justification.
IV. BENEFIT RISK ASSESSMENT
Bioequivalence has been shown between Albendazol Micro Labs 400 mg KauTabletten and Eskazole
400 mg Tabletten Albendazol of GlaxoSmithKline GmbH & Co. KG, in healthy, adult, human
subjects under fed conditions for the chewed tablet only.
Based on the review of the data on quality, safety and efficacy, the application for Albendazol Micro
Labs is approved. For intermediate amendments see current product information.
Albendazol Micro Labs 400 mg Kautabletten, DE/H/5407/001/DC Public AR 10/10You can also read
