Tammex

Loperamidas, 2mg, kietosios kapsulės

Vartojimas: vartoti per burną
Registratorius: DH-norm s.r.o., Čekija
Receptinis: Nereceptinis

Sudedamosios medžiagos: Loperamidas

Decentralised Procedure

RMS Day 210 Final Assessment report

OVERVIEW

Tammex 2 mg hard capsules

Loperamide hydrochloride

LT/H0107/001/DC

Applicant: DH-norm s.r.o.

TABLE OF CONTENTS

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ADMINISTRATIVE INFORMATION

Names of the assessors:

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IRECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Tammex 2 mg hard capsules for the symptomatic treatment of acute diarrhoea in adults and children over 12 years of age is considered approvable.

IIEXECUTIVE SUMMARY

II.1Problem statement

For generic application this section is not applicable.

II.2About the product

The active substance loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. Loperamide increases the tone of the anal sphincter, which helps reduce faecal incontinence and urgency. Loperamide is used for symptomatic treatment of acute diarrhoea in adults and children over 12 years of age. The recommended dose is two capsules initially, followed by 1 capsule after each loose stool, not earlier than 1 hour after the initial dose. The maximum daily dose should not exceed 6 capsules (12 mg).

II.3General comments on the submitted dossier

This decentralised application for Tammex 2 mg hard capsules is a generic application made according to Article 10(1) of Directive 2001/83/EC (as amended).

With Lithuania as the Reference Member State in this Decentralized Procedure., WALMARK, a.s. is applying for the Marketing Authorisations for Tammex 2 mg hard capsules in CMS: BG, CZ, EE, HU, LV, PL, RO, SK.

The active substance is not considered a new active substance.

The applicant has submitted documentation to prove that Tammex 2 mg hard capsules is essentially similar to reference medicinal product Imodium 2 mg hard capsules by McNeil Products Limited c/o Johnson &Johnson Limited, UK. Imodium has been authorised since 1975 in UK. Tammex 2 mg hard capsules have the same qualitative composition in terms of active substance, the same pharmaceutical form, and is claimed to be bioequivalent to Imodium (the applicant has submitted as report bioequivalence study).

The submitted documentation is of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory quality and clinical overviews have been submitted. They represent an adequate summary of the dossier.

The Applicant has provided an acceptable justification for not submitting a Risk Management Plan: Tammex 2 mg capsules, hard is generic medicinal product and for reference medicinal product Imodium no safety concerns requiring the submission of a Risk Management Plan have been identified.

Detailed description of the Pharmacovigilance system has been provided.

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

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inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

A commitment has been given that medicinal product Tammex will not be supplied until Walmark perform audit at API manufacturer Teva Pharmaceutical Fine Chemicals S.r.l., Italy, site.

The bioequivalence study was signed for compliance with GLP and GCP.

IIISCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance

The chemical-pharmaceutical documentation in relation to Tammex is in general of sufficient quality in view of the present European regulatory requirements.

Loperamide hydrochloride is an active substance which is described in Ph. Eur. The manufacturer of loperamide hydrochloride has submitted a valid Certificate of Suitability. The control tests and specifications for drug substance product are adequately drawn up. The proposed retest period of 5 years is justified for loperamide hydrochloride.

Drug Product

The finished product is conventional oral dosage forms capsules, containing 2 mg loperamide in the form of loperamide hydrochloride. The development of the product has been described, the choice of excipients is justified and their functions are explained.

The process has been validated and the results indicate that the manufacturing process consistently yields a drug product of appropriate quality.

The product specifications cover appropriate parameters for this dosage form. The acceptance criteria and limits are generally sufficiently justified.

The analytical methods applied for control of the drug product are described in sufficient detail. Validation of analytical methods has been presented. The batch analysis results show that the finished products meet the proposed specifications.

The capsules are packed in clear PVC/Al blister packs. 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 proposed shelf-life of 36 months with no special temperature storage conditions is considered acceptable.

III.2 Non clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of loperamide are well known. As loperamide is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. Since Tammex is a generic loperamide containing product the use of Tammex is not considered to increase the risk to the environment beyond or above that which may be caused by other loperamide containing products.

The non-clinical sections of the SmPC are acceptable and in accordance to the reference product in RMS.

III.3 Clinical aspects

Pharmacokinetics

Following oral administration, loperamide is well absorbed but undergoes substantial first pass extraction, and the systemic levels are therefore low. The half-life is in the range 9-14 hours and elimination occurs via oxidative N-demethylation. Unchanged loperamide and metabolites are

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mainly excreted in faeces. There is no restriction with respect to food in the labelling for the originator product.

To support the application, the Applicant has carried out a single dose bioequivalence study, in which Tammex 2x2 mg capsules are compared with Imodium 2x2 mg capsules following a single dose under fasting conditions, and submitted clinical study report (ARL/09/369).

The studies are performed in healthy volunteers. The results are shown below.

Pharmacokinetic parameters (geometric means and 90% CI)

*ln-transformed values

Pharmacodynamics

Loperamide binds to the opiate receptors in the gut wall, therefore the release of acetylcholine and prostaglandins is inhibited. Due to this effect, repulsive peristalsis is reduced and the movement of intestinal becomes slower. Furthermore, loperamide inhibits small intestinal secretion. The intestinal transit time is increased allowing for increased absorption of fluids and electrolytes.

Loperamide increases the tone of the anal sphincter, therefore sudden urge to defecate decreases. Since loperamide mainly accumulates in the gut wall and due to significant first-pass metabolism, only negligible amount reaches the systemic circulation and does not pass the blood-brain barrier.

No new pharmacodynamic data are submitted or required.

Clinical efficacy

The efficacy of loperamide has been demonstrated in a number of randomised clinical trials in adults and has been used since the 1970s for symptomatic treatment of diarrhoea. Effect has been demonstrated for several diarrhoeal disorders including acute non-specific diarrhoea and traveller’s diarrhoea. Loperamide has also been used for treatment of diarrhoea-predominant irritable bowel syndrome (IBS) and to treat diarrhoea in patients with inflammatory bowel disease (IBD).

Loperamide is regarded as effective treatment for patients with painless diarrhoea and is considered free of abuse potential.

No new efficacy data are submitted or required.

Clinical safety

Loperamide appears to be well tolerated and side-effects are generally gastrointestinal in nature. Common side-effects are dizziness, drowsiness, tiredness, or constipation. A very serious allergic reaction to this drug is rare. Headache and dizziness have also been reported as common side-effects.

Loperamide is contraindicated in patients hypersensitive to loperamide hydrochloride and should not be administered to patients with acute dysentery, acute ulcerative colitis, bacterial enterocolitis (caused by Shigella, Salmonella or Campylobacter) or pseudomembranous colitis. Furthermore, loperamide should not be used when inhibition of peristalsis is to be avoided, i.e. ileus and

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constipation, and should also be avoided in patients with abdominal distension and acute inflammatory bowel disease. The use is contraindicated in children less than 12 years of age.

No new safety data are submitted or required.

Pharmacovigilance system (DDPS)

The applicant has provided a Summary of the Applicant's Pharmacovigilance System, as well as a Pharmacovigilance statement of the MAH/EU QPPV. Due to internal reasons, the proposed MAH for all countries will be changed from present WALMARK, a.s. to company DH-norm s.r.o. All pharmacovigilance activities will be performed by WALMARK, a.s based on the contract with DH-norm, s.r.o. so the PV system given in module 1.8 is not changed.

Risk Management Plan

The present procedure is a generic application. According to well established safety profile of the reference product and proved bioequivalence between this generic product and the reference product, no Risk Management Plan is needed.

No risk minimization activities additional to recommendations included in the proposed Summary of Products Characteristics and Patient Information Leaflet are necessary.

Periodic Safety Update Report (PSUR)

Loperamide is found on the PSUR Synchronisation List published by the Heads of Medicines Agencies. The European Harmonised Birth Date has been set on 31-May-1973 with an allocated next data lock point of 31-May-2020. The applicant has not requested a different PSUR cycle upon approval.

IVBENEFIT RISK ASSESSMENT

The application contains an adequate review of published clinical data and the bioequivalence between Tammex 2x2 mg capsules and Imodium 2x2 mg capsules has been shown. The benefit-risk balance for the product is considered positive.

VLIST OF QUESTIONS as proposed by RMS

V.1Quality aspects

Potential serious risks to public health

Drug Substance

None

Drug Product

None

Points for clarification

Drug Substance

None

Drug Product

None

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V.2Non clinical aspects

Potential serious risks to public health

None

Points for clarification

None

V.3Clinical aspects

Potential serious risks to public health

None

Points for clarification

None

Pharmacovigilance system

None

Risk Management Plan

None

VIRECOMMENDEDCONDITIONSFORMARKETING

AUTHORISATION AND PRODUCT INFORMATION

VI.1 Conditions for the marketing authorization

Legal Status

OTC product.

Follow-up measures

None

Specific obligations

None

VI.2 Summary of Product Characteristics (SmPC)

The SPC has been amended in accordance with the RMS and CMS comments and is now acceptable.

VI.3 Package Leaflet (PL) and User Testing

VI.3.1Package Leaflet

The PL has been amended in accordance with the RMS and CMS comments and is now acceptable.

VI.3.2Assessment of User Testing

Assessment of the User Testing is attached in the ‘QRD Guidance and Checklist for the Review of

User Testing Results.

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VI.4Labelling

The labelling has been amended in accordance with the RMS and CMS comments and is now acceptable.

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VIIAPPENDIX

QRD GUIDANCE AND CHECKLIST

FOR THE REVIEW OF USER TESTING RESULTS

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QRD GUIDANCE AND CHECKLIST FOR THE REVIEW

OF USER TESTING RESULTS

[Disclaimer: This guidance has been set up to provide practical information on how to evaluate user testing reports which are based on the readability testing method as described in Annex 1 of the EC Readability Guideline. This does not exclude the submission and evaluation of user testing reports based on other methods than the one outlined above, for which specific assessment guidance may be issued once experience has been gained

Useful links: More detailed practical guidance can be found in the following documents:

• EC Readability Guideline http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/2009_01_12_readability_guideline_final.pdf
• “Operational procedure on Handling of “Consultation with target patient groups” on Package

Leaflets (PL) for Centrally Authorised Products for Human Use http://www.emea.europa.eu/htms/human/qrd/qrdplt/27737805en.pdf “Consultation with Target Patient Groups-meeting the requirements of Article 59(3) without the need for a full test-Recommendations for Bridging” http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Consulation _PatientsGroups/CMDh_100_2007_Rev1_clean_April09.pdf

• “Position paper on user testing of package leaflets” http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Consulation _PatientsGroups/CMDh_234_2011.pdf
• [MRP/DCP relevant document – link to be inserted]

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(In case of bridging report, multiple bridging is, in principle, not acceptable. However, a maximum of 3 bridging procedures could be accepted for one product: e.g. first bridging to address the scientific content, a second one to address the device and a last one to address the layout of the PL).

- Grounds for bridging based on a sound justification:

extensions for the same route of administration

reference to test on same class of medicinal product

reference to test with same safety issues other ______________________

(In case no full user testing or bridging report has been provided, a justification should be submitted.)

(The following are examples of what are not considered valid justifications for not performing User Testing:

• • Administration in a hospital setting only,

• • Administration by a healthcare professional only,

• Compliance with the QRD templates,

• Long established use of the product.

Reasons [assessor’s views on acceptability or not of the justification/bridging report – assessment of justification/bridging]

On 17 January 2012, a CHMP opinion was adopted for an Article 30 referral of Directive 2001/83/EC (as amended) harmonising the Summary of Product Characteristics, Labelling and package Leaflet of Protium (Pantoprazole) medicinal products.

Due to the changes required to the package leaflet (both style as well as content), the justification provided through the bridging report can no longer be accepted.

1TECHNICAL ASSESSMENT

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• Recruitment

Comments/further details________________________________________________________________

Guidance regarding Recruitment

The following points should be taken into consideration when assessing recruitment methods:

• Is the recruitment method well defined? Is it clear that serious thought was given to the composition of the test group? (e.g. in terms of variables such as sex, age, education, experience with the medicinal product, existing knowledge of the complaint, etc.)

• How has the test group been recruited? Are they new users or patients, parents or carers?

• Is it clear how many people were involved in the test/test rounds?

• Is that number sufficient? (The PL should be tested in minimum 2 rounds of 10 participants each)

• Questionnaire

Comments/further details The text is easily understandable to the respondent. Given questions are open and do not require a long list of answers.

• Time aspects

Comments/further details_ Each interview lasted not longer than 45 minutes.

• Procedural aspects

Rounds of testing including pilot ___3____

Comments/further details Testing was undertaken in the English. Experienced and appropriately trained interviewers personally interview all study subjects. The testing was conducted in 3 rounds including the pilot test.

• Interview aspects

Comments/further details Interviews were done with one subject at a time, in a private, quiet location. Clear instructions for the test instructors were given.

2EVALUATION OF RESPONSES

• Evaluation system

Comments/further details_ The assessment was based on a check list covering the following 2 basic areas: finding the information and understanding the information.

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• Question rating system

Comments/further details The search for information was graded as “simple”, “easy”,“moderate” and “difficult”.

The understanding of information was evaluated as “Correct answer”, “Wrong answer”.

3DATA PROCESSING

Comments/further details_The data were recorded and processed satisfactory.

• QUALITY ASPECTS

• Evaluation of diagnostic questions

Comments/further details In both rounds 90% of participants were able to find each item of information and to show that they had understood correctly all questions.

Comments/further details The evaluation system is satisfactory.

• DIAGNOSTIC QUALITY/EVALUATION

Comments/further details No changes were suggested on the basis of the quantitative and qualitative results of the combined first and second rounds.

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Trumpa kokybinės dalies apžvalga

Vaistinio preparato rinkodaros teisės suteikimo paraiška pateikta pagal direktyvos 2001/83/EB 10 str. 1d. “generinis” . Vaistinio preparato veiklioji medžiaga loperamido hidrochloridas aprašytas

Europos Farmakopėjoje. Veikliosios medžiagos gamintojas pateikė galiojantį loperamido kokybės atitikties Europos Farmakopėjai sertifikatą. Gatavo produkto gamintojo veikliosios medžiagos loperamido hidrochlorido specifikacija yra tinkamos kokybės. Galutinio produkto sudėtyje esančios pagalbinės medžiagos yra saugios ir plačiai naudojamos farmacinėje pramonėje. Galutinio produkto specifikacijos kokybė yra tinkama ir atitinka ES gairių reikalavimus. Galutinio produkto kokybei kontroliuoti analizės procedūros yra parinkotos tinkamai ir validuotos. Vaistinio preparato 3 metų tinkamumo laikas ir laikymo sąlygos yra patvirtintos stabilumo tyrimų duomenimis. Šiam vaistiniam preparatui jokių specialių laikymo sąlygų nereglamentuojama.

Pareiškėjas visus klausimus dėl vaistinio preparato kokybės išsprendė, todėl esminių prieštaravimų dėl vaistinio preparato kokybės nėra.

Trumpa klinikinės dalies apžvalga

Pareiškėjas vaistinio preparato veiksmingumą ir saugumą pagrindė klinikinio farmakokinetikos tyrimu, kuriame palyginus šio vaistinio preparato ir originalaus vaisto Imodium farmakokinetikos rezultatus, išgėrus 4 mg loperamido dozę, esminių skirtumų nenustatyta. Vaistiniuo preparato indikacijos, dozavimo rekomendacijos bei saugumo informacija iš esmės nesiskiria nuo originalaus vaistinio preparato Imodium.

Procedūros eigoje pareiškėjas visus klausimus dėl saugumo ir veiksmingumo išsprendė, todėl nėra priežąsčių, kurios neleistų suteikti rinkodaros teisės.

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