Buprenorphine 0.4 mg sublingual tablets Buprenorphine 2 mg ... · UKPAR Buprenorphine 0.4 mg, 2 mg...

UKPAR Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets PL 40378/0092-0094

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Buprenorphine 0.4 mg sublingual tablets Buprenorphine 2 mg sublingual tablets Buprenorphine 8 mg sublingual tablets

PL 40378/0092-0094

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific Discussion

Page 6

Steps Taken for Assessment

Page 14

Summary of Product Characteristics

Page 15

Patient Information Leaflet

Page 16

Labelling Page 17


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LAY SUMMARY


This is a summary of the Public Assessment Report (PAR) for Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets (PL 40378/0092-0094). It explains how Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets. For practical information about using Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets, patients should read the package leaflet or contact their doctor or pharmacist. The products may be referred to as Buprenorphine sublingual tablets in this report. What are Buprenorphine sublingual tablets and what are they used for? Buprenorphine sublingual tablets are medicines that are used in opioid (narcotic) dependence. Buprenorphine sublingual tablets are used as a part of a medical, social and psychological treatment programme for patients addicted to opiate (narcotic) drugs. Treatment is prescribed and monitored by physicians who are specialists in the treatment of drug dependence. Treatment with Buprenorphine sublingual tablets is intended for use in adults and adolescents over 15 years of age. Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets are identical to Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328; Actavis Group PTC ehf, Iceland), which were granted Marketing Authorisations in the UK on 07 September 2011. How do Buprenorphine sublingual tablets work? The active ingredient, buprenorphine (as buprenorphine hydrochloride), belongs to a group of medicines called opioids (also known as “opiates” or “narcotics”). Opioid analgesics, such as morphine and diamorphine (heroin), are often subject to abuse, which can lead to dependence (addiction). Individuals who are addicted to these drugs need a regular dose to feel ‘normal’, otherwise they will develop withdrawal symptoms within a day or so after the last dose. Buprenorphine sublingual tablets prevent or reduce the unpleasant withdrawal symptoms experienced when an addict stops using opioid drugs. How are Buprenorphine sublingual tablets used? Buprenorphine sublingual tablets can only be obtained on prescription. The medicine should always be taken exactly as prescribed by the doctor. If unsure, the patient should check with the doctor or pharmacist. Buprenorphine sublingual tablets are administered sublingually. This means that the tablets must be placed under the tongue and allowed to dissolve. This is the only way the tablets should be taken. The tablets should not be chewed, crushed or swallowed whole, as they will not work properly and the patient may get withdrawal symptoms. Buprenorphine sublingual tablets should be taken once a day, unless otherwise prescribed by the doctor.


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The doctor will determine the best dose for the patient. During treatment, the doctor may adjust the dose, depending upon the patient’s response. To get the greatest benefit from taking Buprenorphine sublingual tablets, the patient must tell the doctor about all the medicines that are being taken, including alcohol, medicines containing alcohol, street drugs, and any prescription medicine that the patient is taking that has not been prescribed by the treating doctor. Reduced kidney or liver function: If the patient has kidney or liver problems the dose may have to be reduced, so the patient should talk to the treating doctor. Patients who suffer from serious liver insufficiency should not take Buprenorphine sublingual tablets. Treatment duration: The length of treatment will be determined individually by the patient’s doctor. After a time of successful treatment, the doctor may reduce the dose gradually to a lower maintenance dose. Depending on the patient’s condition, the dose of Buprenorphine sublingual tablets may continue to be reduced under careful medical supervision, until eventually it may be stopped. Treatment should not be changed in any way or stopped without the agreement of the treating doctor. The effectiveness of this treatment depends on the dose, in combination with the associated medical, psychological and social treatment. If the patient has the impression that the effect of Buprenorphine sublingual tablets is too strong or too weak, he/she talk to treating doctor or pharmacist. Use in children and adolescents: Buprenorphine sublingual tablets should not be used in children and adolescents below the age of 15 years due to lack of data on safety and efficacy For further information on how Buprenorphine sublingual tablets are used, refer to the package leaflet and Summary of Product Characteristics. What benefits of Buprenorphine sublingual tablets have been shown in studies? The applications for Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets (PL 40378/0092-0094) are considered to be identical to the previously authorised licences for Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328), respectively, with the same benefits and risks. So, no new studies have been provided for Buprenorphine sublingual tablets. However, reference is made to the studies for Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328), respectively. What are the possible side effects from Buprenorphine sublingual tablets? Like all medicines, Buprenorphine sublingual tablets can cause side effects, although not everybody gets them. Some side effects are more likely to occur than others. If the patient develops symptoms of a severe allergic reactions (such as difficulty in breathing, wheezing and swelling of eyes, lips, throat, tongue or hands), medical help should be sought immediately.


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Misusing this medicine by injecting can cause withdrawal symptoms, infections, other skin reactions and potentially serious liver problems. After the first dose of Buprenorphine sublingual tablets, the patient may have some opiate withdrawal symptoms. The frequency of possible side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Rare: may affect up to 1 in 1000 people Very rare: may affect up to 1 in 10,000 people Not known: frequency cannot be estimated from the available data. Very common side effects • not being able to sleep • a general feeling of weakness • withdrawal syndrome Common side effects • headache • fainting • dizziness • anxiety • nervousness • nervousness • constipation • nausea • vomiting • diarrhoea • stomach pain • tearing disorder • runny nose • drowsiness • drop in blood pressure on changing position from sitting or lying down to standing • sweating • back pain • chills • abnormal electrocardiogram Uncommon side effects • hallucinations • severe difficulty in breathing (respiratory depression) • liver problem with or without jaundice • death of the cells of the liver (necrosis of the liver)


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Very rare side effects • hypersensitivity (allergic) reactions have been reported. Symptoms may include skin rash, hives and

itching. Reporting of side effects If any side effects are experienced, the patient should talk to the doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard. The reporting of side effects can help to provide more information on the safety of this medicine. Why are Buprenorphine sublingual tablets approved? No new or unexpected safety concerns arose from these applications. The MHRA, therefore, considered that the benefits of Buprenorphine sublingual tablets outweigh their risks; and the grant of Marketing Authorisations was recommended. What measures are being taken to ensure the safe and effective use of Buprenorphine sublingual tablets? A Risk Management Plan has been developed to ensure that Buprenorphine sublingual tablets are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics and the package leaflet for Buprenorphine sublingual tablets, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well. Other information about Buprenorphine sublingual tablets. Marketing Authorisations were granted in the UK on 01 October 2014. The full PAR for Buprenorphine sublingual tablets follows this summary. For more information about treatment with Buprenorphine sublingual tablets, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in November 2014.


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PL 40378/0092-0094

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 7

Pharmaceutical assessment

Page 8

Non-clinical assessment

Page 11

Clinical assessment

Page 12

Overall conclusion and benefit/risk assessment Page 13


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INTRODUCTION The Medicines and Healthcare products Regulatory Agency (MHRA) granted Aptil Pharma Limited Marketing Authorisations for the medicinal products Buprenorphine sublingual tablets (PL 40378/0092-0094) on 01 October 2014. The products are prescription-only medicines (POM) indicated for substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. The applications were submitted as abridged applications according to Article 10c of Directive 2001/83/EC, as amended, cross-referring to Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328), respectively, which were granted Marketing Authorisations in the UK to Actavis Group PTC ehf on on 07 September 2011, following an Incoming Mutual Recognition procedure wherein Portugal was the Reference Member State and the UK was a Concerned Member State. Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets contain the active ingredient buprenorphine (as buprenorphine hydrochloride). Buprenorphine is an opioid partial agonist/antagonist, which binds to the µ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the µ receptors which, over a prolonged period, might minimise the need of addicted patients for drugs. No new data were submitted nor were necessary to be submitted for these applications, as the data are identical to those of the previously granted cross-reference products.


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PHARMACEUTICAL ASSESSMENT LICENCE NO: PL 40378/0092-0094 PROPRIETARY NAME(S): Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets ACTIVE(S): Buprenorphine (as buprenorphine hydrochloride) COMPANY NAME: Aptil Pharma Limited E.C. ARTICLE: Article 10c of Directive 2001/83/EC, as amended LEGAL STATUS: POM 1. INTRODUCTION These are abridged applications for Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets (PL 40378/0092-0094) submitted under Article 10c of Directive 2001/83/EC, as amended. The applications cross-refer to Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328; Actavis Group PTC ehf., Iceland), which were granted Marketing Authorisations in the UK on 07 September 2011. The applications are considered valid. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1. Name The proposed names of the products are Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets. The products have been named in line with current requirements. 2.2. Strength, pharmaceutical form, route of administration, container and pack sizes Each sublingual tablet contains 0.4 mg, 2 mg or 8 mg of buprenorphine (as buprenorphine hydrochloride). The products are packaged in:

1. Aluminium/aluminium (Al/Al) or Aluminium/polyvinylchloride/polyvinylidene chloride/Perlalux Tristar Ultra (Al/PVC/PVDC/Perlalux Tristar Ultra) blisters, in pack sizes of 1, 7, 20, 24, 28, 48 and 50 sublingual tablets.

2. High-density polyethylene (HDPE) tablet containers with low-density polyethylene (LDPE) plastic caps and dessicant, in pack sizes of 1, 7, 20, 24, 28, 48 and 50 sublingual tablets.

The products are packed with the Patient Information Leaflet into cardboard outer cartons. Not all pack sizes may be marketed. The proposed shelf lives/storage conditions are:

1. 2 years for the products packaged in Al/Al blisters and1 year for the products packaged in Al/PVC/PVDC/Perlalux Tristar Ultra blisters, with the storage conditions ‘Do not store above 25°C. Store in the original package in order to protect from moisture.’

2. 2 years for the products packaged in tablet containers, with the storage conditions ‘Do not store above 30°C. Keep the container tightly closed in order to protect from moisture.

The packaging, proposed shelf-life and storage conditions are consistent with the details registered for the cross-reference product. 2.3. Legal status On approval, the products will be available as prescription-only medicines (POM). 2.4. Marketing Authorisation Holder/Contact Persons/Company Aptil Pharma Limited 9th Floor, CP House 97-107 Uxbridge Road Ealing, London W5 5TL


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The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV has been provided. 2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference products and evidence of Good Manufacturing Practice (GMP) compliance has been provided. 2.6. Qualitative and quantitative composition The proposed compositions are consistent with the details registered for the cross-reference products. 2.7. Manufacturing process The proposed manufacturing process is consistent with the details registered for the respective cross-reference products and the maximum batch sizes are stated. 2.8. Finished product/shelf-life specification The proposed finished product specifications are consistent with the details registered for the respective cross-reference products. 2.9. Drug substance specification The proposed drug substance specifications are consistent with the details registered for the cross-reference products. 2.10. TSE Compliance With the exception of lactose monohydrate, none of the excipients contain materials of animal or human origin. The supplier of lactose monohydrate has confirmed that the milk used in the production of lactose anhydrous is sourced from healthy animals under the same conditions as that intended for human consumption. In addition, the supplier has confirmed that no ruminant material of any kind is used during the production of lactose monohydrate. This is consistent with the cross-reference products. 2.11. Bioequivalence No bioequivalence data are required to support these simple abridged applications because the proposed products are manufactured to the same formula and utilise the same processes as the reference products Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328; Actavis Group PTC ehf., Iceland). 3. EXPERT REPORT The applicant cross-refers to the data for Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328; Actavis Group PTC ehf., Iceland) to which these applications are claimed to be identical. This is acceptable. 4. PRODUCT NAME & APPEARANCE See Section 2.1 for details of the proposed product names. The appearance of each product is identical to the respective cross-reference product. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPCs) The proposed SmPCs are consistent with the details registered for the cross-reference products. 6. PATIENT INFORMATION LEAFLET (PIL) AND LABELLING

The PIL has been prepared in line with the details registered for the cross-reference products. PIL


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User-testing of the PIL for Buprenorphine 0.4 mg, 2 mg and 8 mg sublingual tablets (PL 40378/0092-0094) has been accepted based on the bridging report provided by the applicant making reference to the successful user-testing of the PIL for Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328) as the ‘parent PIL’.

The proposed text is consistent with that for the cross-reference products. The Marketing Authorisation holder has committed to submitting mock-ups to the relevant regulatory authorities for approval before marketing any pack size.

Carton and label

7. CONCLUSION The data submitted with the applications are acceptable. The grant of Marketing Authorisations is recommended.


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NON-CLINICAL ASSESSMENT As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no new non-clinical data have been supplied and none are required. Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As the applications are identical versions of already authorised products, it is not expected that environmental exposure will increase following approval of the Marketing Authorisations for the proposed products. The grant of Marketing Authorisations is recommended.


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CLINICAL ASSESSMENT

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no new clinical data have been supplied and none are required. The Marketing Authorisation Holder has provided details of a suitable pharmacovigilance system that fulfils the requirements and provides adequate evidence that they have the services of a qualified person responsible for pharmacovigilance, and have the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. An acceptable Risk Management Plan (RMP) has been submitted. Routine risk minimisation is provided through the Summary of Product Characteristics and the Patient Information Leaflet and this is sufficient. The grant of Marketing Authorisations is recommended.


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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The data for these applications are consistent with those previously assessed for the cross-reference products and as such have been judged to be satisfactory. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY These applications are identical to the previously granted licences for Buprenorphine 0.4mg, 2mg and 8mg Sublingual Tablets (PL 30306/0376 and PL 30306/0327-0328; Actavis Group PTC ehf., Iceland). SAFETY No new safety data were supplied or required for these applications. Buprenorphine has a well-established safety profile. No new or unexpected safety concerns arose from these applications. PRODUCT LITERATURE The SmPCs and PIL are satisfactory, and consistent with those for the cross-reference products. The labelling complies with statutory requirements and is satisfactory. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the cross-reference products. Extensive clinical experience with buprenorphine is considered to have demonstrated the therapeutic value of the compound. The benefit/risk assessment is, therefore, considered to be positive.


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PL 40378/0092-0094

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation applications on 20 December 2012.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 21 January 2013.

3 Following assessment of the applications the MHRA requested further information relating to the dossiers on 24 April 2013, 17 July 2013, 11 April 2014, 11 September 2014 and 15 September 2014.

4 The applicant responded to the MHRA’s request, providing further information on the 27 June 2013, 31 October 2013, 22 July 2014, 12 September 2014 and 18 September 2014.

5 The applications were granted on 01 October 2014.


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SUMMARY OF PRODUCT CHARACTERISTICS

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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PATIENT INFORMATION LEAFLET

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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LABELLING The Marketing Authorisation Holder has submitted the text version only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. Buprenorphine 0.4 mg sublingual tablets:


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Buprenorphine 2 mg sublingual

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Buprenorphine 8 mg sublingual tablets:


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