Idea Transcript
Public Assessment Report Decentralised Procedure AKIS 25 MG/ML SOLUTION FOR INJECTION AKIS 50 MG/ML SOLUTION FOR INJECTION AKIS 75 MG/ML SOLUTION FOR INJECTION AKIS 25 MG/ML SOLUTION FOR INJECTION IN PREFILLED SYRINGE AKIS 50 MG/ML SOLUTION FOR INJECTION IN PREFILLED SYRINGE AKIS 75 MG/ML SOLUTION FOR INJECTION IN PREFILLED SYRINGE Diclofenac sodium Procedure No: UK/H/3585/001/DC UK/H/3585/002/DC UK/H/3585/003/DC UK/H/3585/004/DC UK/H/3585/005/DC UK/H/3585/006/DC UK Licence No: PL 21039/0018 PL 21039/0019 PL 21039/0020 PL 21039/0021 PL 21039/0023 PL 21039/0024 IBSA Farmaceutici Italia Srl
PAR Akis 25, 50, 75 mg/ml Solution for Injection
UK/H/3585/001-6/DC
LAY SUMMARY On 7 November 2012, Belgium, Cyprus, Czech Republic, Germany, Greece, France, Hungary, Italy, Poland, Slovakia, Spain and the UK agreed to grant Marketing Authorisations to IBSA Farmaceutici Italia Srl for the medicinal products Akis 25, 50 and 75 mg/ml Solution for Injection (PL 21039/0018-20; UK/H/3585/001-3/DC) and Akis 25, 50 and 75 mg/ml Solution for Injection in prefilled syringe (PL 21039/0021, 0023-4; UK/H/3585/004-6/DC). The licences were granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After a national phase, Marketing Authorisations were granted in the UK on 23 January 2013. These products contain the active ingredient diclofenac sodium, which is a non-steroidal antiinflammatory drug (NSAID). These drugs are used to reduce pain and inflammation. These products are used to treat a number of painful conditions, including: Flare-ups of joint or back pain Attacks of gout Pain caused by kidney stones Pain caused by injuries, fractures or trauma It is also used to treat pain following an operation. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking these products outweigh the risks and Marketing Authorisations were granted.
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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TABLE OF CONTENTS Module 1: Information about initial procedure
Page 4
Module 2: Summary of Product Characteristics
Page 5
Module 3: Patient Information Leaflets
Page 6
Module 4: Labelling
Page 7
Module 5: Scientific Discussion
Page 10
I Introduction II About the Product III Scientific Overview and Discussion III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall conclusions Module 6
Steps taken after initial procedure
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
UK/H/3585/001-6/DC
Module 1 Type of Application
Akis 25, 50 and 75 mg/ml Solution for Injection Akis 25, 50 and 75 mg/ml Solution for Injection in prefilled syringe Hybrid, Article 10(3)
Active Substances
Diclofenac sodium
Form
Solution for injection
Strength
25, 50 and 75 mg/ml
MA Holder
IBSA Farmaceutici Italia Srl, Via Martiri di Cefalonia 2, 26900 Lodi (Italy)
Reference Member State (RMS)
UK
Concerned Member States (CMS)
Belgium, Cyprus, Czech Republic, Germany, Greece, France, Hungary, Italy, Poland, Slovakia, Spain
Procedure Number
UK/H/3585/001-6/DC
Timetable
Day 210 – 7 November 2012
Product Name
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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Module 2 Summary of Product Characteristics The current approved UK versions of the Summaries of Product Characteristics (SmPCs) for these products are available on the MHRA website.
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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Module 3 Patient Information Leaflet The current approved UK version of the Patient Information Leaflet (PIL) for these products is available on the MHRA website.
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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Module 4 Labelling
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
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Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the member states considered that the applications for Akis 25, 50 and 75 mg/ml Solution for Injection (PL 21039/001820; UK/H/3585/001-3/DC) and Akis 25, 50 and 75 mg/ml Solution for Injection in prefilled syringe (PL 21039/0021, 0023-4; UK/H/3585/004-6/DC) could be approved. These applications were submitted via the Decentralised Procedure, with the UK as Reference Member State (RMS), and Belgium, Cyprus, Czech Republic, Germany, Greece, France, Hungary, Italy, Poland, Slovakia and Spain as Concerned Member States (CMS). These are prescription-only medicines that are effective in acute forms of pain, including renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute trauma and fractures, and post-operative pain. These products contain the active substance diclofenac sodium. Diclofenac is a phenylacetic acid derivative and belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) that also exhibit analgesic and antipyretic properties. NSAIDs are inhibitors of the enzyme cyclo-oxygenase and directly inhibit the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. These were applications submitted according to Article 10(3) of Directive 2001/83/EC, as amended - hybrid applications because of the different route of administration and different strength in comparison with the originator product. These applications state the originator product as Voltarol 75 mg/3 ml (PL 00101/0466), for which a licence was first granted to Ciba-Geigy Plc in August 1981. After a subsequent change of ownership approved in July 1997, the current marketing authorisation holder is Novartis Pharmaceuticals UK Limited. 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. In support of these applications, the applicant submitted two bioavailability studies, two efficacy/safety studies and one tolerability study with efficacy data. The studies were conducted in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for these product types at all sites responsible for the manufacture, assembly and batch release of these products. The RMS and CMS considered that the applications could be approved with the end of procedure (Day 210) on 7 November 2012. After a subsequent national phase, the licences were granted in the UK on 23 January 2013.
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
II.
UK/H/3585/001-6/DC
ABOUT THE PRODUCTS
Name of the products in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form and strength(s) Reference numbers for the Mutual Recognition Procedure Reference Member State Member States concerned
Marketing Authorisation Number(s) Name and address of the authorisation holder
Akis 25, 50 and 75 mg/ml Solution for Injection Akis 25, 50 and 75 mg/ml Solution for Injection in prefilled syringe Diclofenac sodium Non-steroidal anti-inflammatory/anti-rheumatic drugs (M01 AB05) 25, 50 and 75 mg/ml solution for injection and 25, 50 and 75 mg/ml solution for injection in prefilled syringe UK/H/3585/001-6/DC United Kingdom Belgium, Cyprus, Czech Republic, Germany, Greece, France, Hungary, Italy, Poland, Slovakia and Spain PL 21039/0018-21 and 23-4 IBSA Farmaceutici Italia Srl, Via Martiri di Cefalonia 2, 26900 Lodi (Italy)
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
III
UK/H/3585/001-6/DC
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS S. Active substance – Diclofenac sodium rINN: Diclofenac sodium Chemical name: Sodium 2-[(2,6-diclorophenyl)amino] phenyl acetate Structure:
Molecular formula: Molecular weight: Appearance: Solubility:
C14H10Cl2NNaO2 318.1 g/mol White to slightly yellowish crystalline powder Sparingly soluble in water, freely soluble in methanol, soluble in alcohol, slightly soluble in acetone
With the exception of stability, all aspects of the manufacture and control of the active ingredient are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. Appropriate stability data have been generated to support a suitable retest period when stored in the proposed packaging. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients hydroxypropylbetadex, polysorbate 20 and water for injections. All excipients are controlled to their respective European Pharmacopoeia monographs. No excipients are sourced from animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate globally acceptable and stable products that were available in volumes of 1ml in a water-based solution. A satisfactory account of the pharmaceutical development has been provided. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the finished products. The manufacturing process has been validated using commercial and pilot-scale batches and has shown satisfactory results.
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
UK/H/3585/001-6/DC
Finished Product Specifications The finished product specifications are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Container-Closure System The finished products are packaged in the following packaging and pack sizes. Akis 25, 50 and 75 mg/ml Solution for Injection Transparent Type I glass ampoules, with an administration kit consisting of: one empty 2ml syringe, one 27-gauge grey needle for subcutaneous injection and one 21-gauge green needle for intramuscular injection. The finished product is contained in pack sizes of 1, 3 and 5 ampoules (with an identical number of administration kits). Akis 25, 50 and 75 mg/ml Solution for Injection in prefilled syringe Transparent Type I glass prefilled syringes, with an isoprene-bromobutyl blend tip cap, chlorobutyl rubber plunger and plunger rod made of polystyrene. Also included in the pack are one 27-gauge grey needle for subcutaneous injection and one 21-gauge green needle for intramuscular injection. The finished product is contained in pack sizes of 1, 3 and 5 ampoules (with an identical number of each needle type). Not all pack sizes may be marketed. However, the marketing authorisation holder has committed to submitting mock-ups to the relevant authorities before marketing any pack size. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning the use of Type I glass, medical devices quality management and Type I rubber closures. Stability of the product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years, with the storage conditions “Store below 25°C. Do not refrigerate or freeze. Store in original package to protect from light”. Additionally, after use the instructions are, “The medicinal product must be used immediately after opening any remaining solution must be discarded.” Bioequivalence/bioavailability In support of these applications, the applicant submitted two bioavailability studies, two efficacy/safety studies and one tolerability study with efficacy data. The studies were conducted in accordance with Good Clinical Practice (GCP). Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PILs and labels are acceptable from a pharmaceutical perspective. 22
PAR Akis 25, 50, 75 mg/ml Solution for Injection
UK/H/3585/001-6/DC
A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The results show that the patients/users are able to act upon the information that it contains. Marketing Authorisation Application (MAA) forms The MAA forms are satisfactory from a pharmaceutical perspective. Quality Overall Summary (Expert report) The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of Marketing Authorisations is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of diclofenac sodium are well-known, no further non-clinical studies are required and none have been provided. The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products’ pharmacology and toxicology. Suitable justification has been provided for the non-submission of an environmental risk assessment. As these products are intended for substitution with products that are currently marketed, no increase in environmental burden is expected. There are no objections to the approval of these products from a non-clinical viewpoint. III.3 CLINICAL ASPECTS Clinical Pharmacololgy The following two bioavailability studies were submitted. BIOAVAILABILITY STUDY-CRO-PK-04-118 An open-label, randomised, two-period, two-treatment, two-sequence, single-dose, crossover study to compare the bioavailability following subcutaneous and intramuscular administration of 75 mg Akis Solution for Injection (test) versus intramuscular administration of 75 mg Voltarol Solution for Injection (reference) in healthy volunteers. The results for intramuscular administration of test product versus reference product are presented below for the active substance diclofenac:
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PAR Akis 25, 50, 75 mg/ml Solution for Injection
UK/H/3585/001-6/DC
The results for subcutanous administration of test product versus intramuscular administration of the reference product are presented below for the active substance diclofenac:
The results showed that the proposed diclofenac 75 mg/ml product administered subcutaneously was bioequivalent to the reference product Voltarol administered intramuscularly. The Cmax was marginally higher with the proposed diclofenac 75 mg/ml product administered intramuscularly, in comparison with the reference product Voltarol administered intramuscularly. However, additional supportive data on the efficacy of the proposed product administered intramuscularly is provided in the further studies. BIOAVAILABILITY STUDY-CRO-PK-08-812 An open-label, randomised, three-period, three-treatment, six-sequence, single-dose, crossover study to assess the bioavailability and dose linearity of the test products 25, 50 and 75 mg/ml diclofenac sodium administered subcutaneously in healthy volunteers. The results of the pharmacokinetic parameters for each strength are presented below: Treatment Diclofenac 25 mg/mL (D1)
Cmax (ng/ml) 1090.0 (±264.6)
Tmax (h) 0.41 (±0.09)
AUC0-t (ng/mL*h) 1313.6 (±220.0)
AUC0-∞ (ng/mL*h) 1344.1 (±217.8)
T1/2 (h) 1.16 (±0.25)
Diclofenac 50 mg/mL (D2) Diclofenac 75 mg/mL (D3)
1648.9 (±355.6) 1851.1 (±576.2)
0.60 (±0.14) 0.84 (±0.37)
2539.6 (±417.8) 3761.9 (±567.6)
2573.2 (±420.1) 3796.9 (±566.1)
1.48 (±0.31) 1.85 (±0.39)
MRT (h) 1.16 (±0.16) 1.50 (±0.24) 1.95 (±0.37)
The descriptive statistical assessment performed using an analysis of variance (ANOVA) is presented below: Comparison
Parameter
Range
PE
90% CI
AUC0-t
Period effect p-values 0.9423
D1 vs. D2
80125%
103.46%
100.23106.78%
D2 vs. D3
AUC0-t
0.9423
101.00%
AUC0-t
0.9423
D1 vs. D2
Cmax
0.7727
D2 vs. D3
Cmax
0.7727
97.85104.25% 101.23107.85% 118.29145.26% 123.21151.69%