public assessment report ukpar duloxetine · pdf filethis is a summary of the public...

PAR Duloxetine Distr iquimica 30 mg and 60 mg gastro-resistant capsules, hard PL 21562/0008-0009

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Public Assessment Report

UKPAR

Duloxetine Distriquimica 30 mg gastro-resistant capsules, hard Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard

(duloxetine hydrochloride)

UK Licence Numbers: PL 21562/0008-0009

Distriquimica S.A.


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LAY SUMMARY

Duloxetine Distriquimica 30 mg gastro-resistant capsules, hard Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard

(duloxetine hydrochloride, capsule, hard, 30 mg and 60 mg)

This is a summary of the Public Assessment Report (PAR) for Duloxetine Distriquimica 30 mg gastro-resistant capsules, hard (PL 21562/0008) and Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard (PL 21562/0009). It explains how Duloxetine Distriquimica 30 mg and 60 mg gastro-resistant capsules, hard were assessed and their authorisations recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Duloxetine Distriquimica 30 mg and 60 mg gastro-resistant capsules, hard. The products will collectively be referred to as Duloxetine throughout the remainder of this public assessment report (PAR). For practical information about using Duloxetine, patients should read the package leaflet or contact their doctor or pharmacist. What is Duloxetine and what is it used for? Duloxetine is a ‘generic medicine’. This means that Duloxetine is similar to a ‘reference medicine’ already authorised in the European Union (EU) called Cymbalta. Duloxetine is used in adults to treat:

• depression • generalised anxiety disorder (chronic feeling of anxiety or nervousness) • diabetic neuropathic pain (often described as burning, stabbing, stinging, shooting or aching or

like an electric shock. There may be loss of feeling in the affected area, or sensations such as touch, heat, cold or pressure may cause pain).

How does Duloxetine work? This medicine contains the active ingredient, duloxetine. Duloxetine is a serotonin-noradrenaline re-uptake inhibitor. It works by preventing the neurotransmitters 5-hydroxytryptamine (also called serotonin) and noradrenaline from being taken back up into nerve cells in the brain and spinal cord. Neurotransmitters are chemicals that allow nerve cells to communicate with one another. By blocking their re-uptake, duloxetine increases the amount of these neurotransmitters in the spaces between these nerve cells. Since these neurotransmitters are involved in maintaining high mood and reducing the sensation of pain, blocking their re-uptake into nerve cells can improve the symptoms of depression, anxiety and neuropathic pain. How is Duloxetine used? The pharmaceutical form of Duloxetine is a hard capsule and the route of administration is oral (by mouth). The patient should always take this medicine exactly as their doctor or pharmacist has told them. The patient should check with their doctor or pharmacist if they are not sure. Duloxetine is for oral use. The patient should swallow the capsule whole with a drink of water.


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The usual recommended dosage of Duloxetine is as follows: For depression and diabetic neuropathic pain: The usual dose of Duloxetine is 60 mg once a day, but the patient’s doctor will prescribe the dose that is right for them. For generalised anxiety disorder: The usual starting dose of Duloxetine is 30 mg once a day after which most patients will receive 60 mg once a day, but the patient’s doctor will prescribe the dose that is right for them. The dose may be adjusted up to 120 mg a day based on the patient’s response to Duloxetine. To help the patient to remember to take Duloxetine, they may find it easier to take it at the same times every day. Duloxetine starts to work in most people with depression or anxiety within two weeks of starting treatment, but it may take 2-4 weeks before they feel better. The patient should tell their doctor if they do not start to feel better after this time. The patient’s doctor may continue to give them Duloxetine when they are feeling better to prevent their depression or anxiety from returning. In people with diabetic neuropathic pain it can take some weeks before they feel better. Patients should talk to their doctor if they do not feel better after 2 months. Please read section 3 of the package leaflet for detailed dosing recommendations, the route of administration, and the duration of treatment. This medicine can only be obtained with a prescription. What benefits of Duloxetine have been shown in studies? Because Duloxetine is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Cymbalta. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the possible side effects of Duloxetine? Because Duloxetine is a generic medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with Duloxetine, see section 4 of the package leaflet available on the MHRA website. Why was Duloxetine approved? It was concluded that, in accordance with EU requirements, Duloxetine has been shown to have comparable quality and to be bioequivalent to Cymbalta. Therefore, the MHRA decided that, as for Cymbalta; the benefits are greater than the risks and recommended that they can be approved for use. What measures are being taken to ensure the safe and effective use of Duloxetine? A risk management plan (RMP) has been developed to ensure that Duloxetine is used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics (SmPCs) and the package leaflet for Duloxetine including the appropriate precautions to be followed by healthcare professionals and patients.


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Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Duloxetine The Marketing Authorisations for Duloxetine were granted in the UK on 14 August 2015. The full PAR for Duloxetine follows this summary. For more information about use of Duloxetine, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in September 2015. .


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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 10 IV Clinical aspects Page 10 V User consultation Page 15 VI Overall conclusion, benefit/risk assessment and

recommendation Page 15


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Distriquimica S.A, marketing authorisations for the medicinal products Duloxetine Distriquimica 30 mg gastro-resistant capsules, hard (PL 21562/0008) and Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard (PL 21562/0009). The products are prescription-only medicines (POM) indicated in adults for:

• Treatment of major depressive disorder • Treatment of diabetic peripheral neuropathic pain • Treatment of generalised anxiety disorder

These applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, as so-called generic applications. For the reference medicinal products authorised for more than 10 years in the EEA, reference has been made to Yentreve 20 mg hard gastro-resistant capsules and Yentreve 40 mg hard gastro-resistant capsules (EMEA/H/C/000545), which were authorised to Eli Lilly Nederland B.V. on 11 August 2004. The reference medicinal products for these applications are Cymbalta 30 mg Hard gastro-resistant capsules and Cymbalta 60 mg Hard gastro-resistant capsules (EMEA/H/C/000572), which were authorised to Eli Lilly Nederland B.V on 17 December 2004. Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Two bioequivalence studies were submitted to support these applications (one study was conducted in the fed state and the other under fasting conditions). The applicant has stated that the bioequivalence studies were conducted in accordance with the Declaration of Helsinki, the requirements of the U.S Code of Federal Regulations (Title 21, part 56), the Directive 2001/20/EC (Europe) and the Tri-Council Policy Statement (Canada) and in compliance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new non-clinical or clinical data were submitted, which is acceptable given that these applications were based on being a generic medicinal product of an originator product that has been in clinical use for over 10 years. No new or unexpected safety concerns arose during the review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Duloxetine outweigh the risks and Marketing Authorisations were granted.


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II QUALITY ASPECTS II.1 Introduction Each hard gastro-resistant capsule contains 30 mg or 60 mg duloxetine (as duloxetine hydrochloride). Other ingredients consist of the pharmaceutical excipients:

Hypromellose, talc, titanium dioxide, methacrylic acid-ethyl acrylate copolymer dispersion 30% (includes sodium lauryl sulphate and polysorbate 80), triethyl citrate, sugar spheres (maize starch and sucrose) and sucrose.

Capsule contents

Gelatin, titanium dioxide (E171), and FD& C Blue 2/Indigo carmine (E132). The 60 mg capsule shells also contain yellow iron oxide (E172).

Capsule shell

The finished products are packed into: 30 mg:

• Aluminium/aluminium blister foils in pack sizes of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504 (8x63) (hospital pack) capsules.

• PVD/PVDC-/Aluminium blister foils in pack sizes of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504 (4x126) (hospital pack) capsules

• White opaque polyethylene (PE) bottles, containing a desiccant sachet and a polypropylene (PP) cap with a tamper evident ring closure containing 500 capsules (hospital pack).

60 mg: • Aluminium/aluminium blister foils in pack sizes of 7, 10, 14, 20, 28, 30, 50, 56, 60 (2x30), 84

(2x42), 98 (2x49) and 504 (8x63) (hospital pack) capsules. • PVD/PVDC-/Aluminium blister foils in pack sizes of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and

504 (4x126) (hospital pack) capsules. • White opaque polyethylene (PE) bottles, containing a desiccant sachet and a polypropylene (PP)

cap with a tamper evident ring closure containing 500 capsules (hospital pack). Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2 Drug Substance INN: Duloxetine hydrochloride Chemical name: (+)-(S)-N-Methyl-3-(naphtnalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine

hydrochloride Structure:

Molecular formula: C18H20ClNOS Molecular weight: 333.9 Appearance: A white or almost white powder Solubility: Sparingly soluble in water, freely soluble in methanol, practically insoluble in

hexane. Duloxetine hydrochloride is the subject of a European Pharmacopoeia monograph.


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All aspects of the manufacture and control of the active substance, duloxetine hydrochloride, are covered by the European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, hard gastro-resistant capsules containing 30 mg or 60 mg duloxetine (as duloxetine hydrochloride) per capsule that are generic versions of the reference products Cymbalta 30 mg Hard gastro-resistant capsules and Cymbalta 60 mg Hard gastro-resistant capsules. A satisfactory account of the pharmaceutical development has been provided. Comparative in-vitro dissolution and impurity profiles have been provided for the proposed and originator products. All excipients comply with their respective European Pharmacopoeia monograph. Satisfactory Certificates of Analysis and batch analysis data have been provided for the excipients. None of the excipients contain materials of animal or human origin, with the exception of gelatin. A satisfactory declaration of compliance with current TSE/BSE regulations has been provided by the supplier(s) of gelatin. No genetically modified organisms (GMO) have been used in the preparation of these products. Manufacture of the product Satisfactory batch formulae have been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial scale batch size and has shown satisfactory results. Finished Product Specification The finished product specifications proposed are acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of all strengths (30 mg and 60 mg) of the finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years with the storage conditions: 30 mg:

• Aluminium/Aluminium blíster: This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.

• PVD/PVDC-/Aluminium blister foils: Store below 30ºC. Keep the blister in the outer carton in order to protect from light.

• White opaque polyethylene (PE) bottles: This medicinal product does not require any special temperature storage conditions. Keep the bottle tightly closed in order to protect from light.

60 mg: • Aluminium/Aluminium blíster: This medicinal product does not require any special storage

conditions.


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• PVD/PVDC-/Aluminium blister foils: Store below 30°C. • White opaque polyethylene (PE) bottles: This medicinal product does not require any special

storage conditions. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of these applications from a pharmaceutical viewpoint.


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III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of duloxetine are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. Impurities Based on the maximum daily dose of 120mg per day; the proposed impurity limits are all in compliance with the requirements of ICHQ3B(R2) - Impurities in New Drug Products and / or the limits set in the Ph Eur monograph. There are no toxicology issues with the specification limits proposed. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Duloxetine 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.6 Discussion on the non-clinical aspects No new non-clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. There are no objections to the approval of these applications from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction The clinical pharmacology of duloxetine is well-known. With the exception of data from the bioequivalence studies detailed below, no new pharmacodynamics or pharmacokinetic data are provided or are required for these applications. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of duloxetine. Based on the data provided, Duloxetine can be considered bioequivalent to Cymbalta 30 mg Hard gastro-resistant capsules and Cymbalta 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V).


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IV.2 Pharmacokinetics In support of these applications, the applicant submitted the following bioequivalence studies: STUDY 1 A laboratory-blinded, randomised, two-sequence, two-period, crossover, single-dose bioequivalence study to compare the pharmacokinetics of the applicant’s test product Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard (Distriquimica S.A) versus the reference product, Cymbalta 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V), in healthy adult subjects under fasting conditions. The study compared the proposed 60 mg capsules and Cymbalta 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V). The subjects were administered a single dose (60 mg) of either the test or the reference product under fasting conditions. Blood samples were collected for plasma levels before dosing and up to and including 60 hours after each administration. The washout period between the treatment phases was 7 days. The pharmacokinetic results are presented below:

The 90% confidence intervals for AUC and Cmax were within the acceptance range of 80.00 to 125.00 %. Bioequivalence between the 60 mg test product and 60 mg reference product has been adequately demonstrated, under fasting conditions.


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STUDY 2 A laboratory-blinded, randomised, two-sequence, two-period, crossover, single-dose bioequivalence study to compare the pharmacokinetics of the applicant’s test product Duloxetine Distriquimica 60 mg gastro-resistant capsules, hard (Distriquimica S.A) versus the reference product, Cymbalta 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V), in healthy adult subjects under fed conditions. The study compared the proposed 60 mg capsules and Cymbalta 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V). After a supervised overnight fast, subjects received a standardised high-fat, high-calorie meal, thirty minutes before drug administration. Thirty minutes after the start of breakfast, the subjects were administered a single dose (60 mg) of either the test or the reference product. Blood samples were collected from each subject in each period at pre-dose and at intervals up to up to 60 hours following drug administration. The washout period between the treatment phases was 7 days. The pharmacokinetic results are presented below:

The 90% confidence intervals for AUC and Cmax were within the acceptance range of 80.00 to 125.00 %. Bioequivalence between the 60 mg test product and 60 mg reference product has been adequately demonstrated, under fed conditions. Overall bioequivalence has been demonstrated between the applicant’s 60 mg capsules and the 60 mg reference product, under fasting and fed conditions. A biowaiver for the 30 mg capsules has been proposed and is acceptable since the proposed capsules: - are manufactured by the same manufacturer and using the same manufacturing process, - have the same qualitative composition, - have quantitatively proportional compositions, - contain identical pellets, - have in vitro dissolution data that are similar to the test biobatch data, thus confirming the adequacy of waiving additional bioequivalence testing. In addition the pharmacokinetics of the originator formulation exhibits linear pharmacokinetics with respect to dose and duration of treatment. A biowaiver for the 30 mg strength is, therefore, fully supported, according to the guideline on investigation of bioequivalence and the guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms.


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As the 30 mg and 60 mg strengths of the product meet the criteria specified in the guideline on investigation of bioequivalence, the extrapolation of results and conclusions from the bioequivalence study on the 60mg strength to the 30 mg is justified. Therefore, bioequivalence has been shown between the applicant’s 30 mg and 60mg capsule strengths and their respective reference products. IV.3 Pharmacodynamics No new pharmacodynamic data were submitted and none were required for an application of this type. IV.4 Clinical efficacy No new efficacy data were submitted and none were required for an application of this type. IV.5 Clinical safety No new safety data were submitted and none were required for these applications. IV.6 Risk Management Plan (RMP) and Pharmacovigilance System The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), 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 Duloxetine. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary table of safety concerns:


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Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns. IV.7 Discussion on the clinical aspects With the exception of the bioequivalence studies, no new clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. Bioequivalence has been demonstrated between the applicant’s test products Duloxetine Distriquimica 30 mg and 60 mg gastro-resistant capsules, hard (Distriquimica S.A) and the reference products, Cymbalta 30 mg and 60 mg Hard gastro-resistant capsules (Eli Lilly Nederland B.V). The grant of marketing authorisations is recommended for these applications. V User consultation The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the package leaflet was English. The results show that the package leaflet meets the criteria for readability, as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with duloxetine 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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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Duloxetine is presented below:


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