Diclofenac Potassium PL 18866-033-4 - GOV.UK

1 PL 18866 /0033-4. Public Assessment Report Diclofenac Potassium 25mg Tablets Diclofenac Potassium 50mg Tablets Diclofenac Potassium PL 18866 /0033. PL 18866 /0034. Rockspring Healthcare Ltd Table of Contents Page Lay Summary 2. Scientific Discussion 3. Overall Conclusion And Risk Benefit/Analysis 10. Steps Taken During Assessment 11. Steps Taken After Assessment 12. Summary of Product Characteristics 13. Labels and Leaflet 39. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 1. PL 18866 /0033-4. Lay Summary The MHRA granted marketing authorisations (licences) to Rockspring Healthcare Ltd for the medicinal products Diclofenac Potassium 25mg and 50mg Tablets on 25/02/2009 (PL 18866 /0033-4). The market authorisations were then transferred to Gentian Generics Ltd (PL 33217/0010-1) on the 14/04/2009. Diclofenac Potassium is a non-steroidal anti-inflammatory drug and is used in the treatment of rheumatoid arthritis, osteoarthritis, low back pain, migraine attacks, acute musculo-skeletal disorders and trauma such as periarthritis (especially frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains, and dislocations, relief of pain in fracture, ankylosing spondylitis, acute gout and relief of orthopaedic, dental and minor surgery, pyrophosphate anthropathy and associated disorders.

2 These products are prescription only medicines. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 2. PL 18866 /0033-4. Scientific Discussion INTRODUCTION. The MHRA granted marketing authorisations (licences) to Rockspring Healthcare Ltd for the medicinal products Diclofenac Potassium 25mg and 50mg Tablets on 25/02/2009 (PL 18866 /0033-4). The market authorisations were then transferred to Gentian Generics Ltd (PL 33217/0010-1) on the 14/04/2009. Diclofenac Potassium is a non steroidal anti-inflammatory drug of the phenylacetic acid class and an inhibitor of cyclo-oxygenase. It is used for the treatment of rheumatoid arthritis, osteoarthritis, low back pain, migraine attacks, acute musculo- skeletal disorders and trauma such as periarthritis (especially frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains, and dislocations, relief of pain in fracture, ankylosing spondylitis, acute gout and relief of orthopaedic, dental and minor surgery, pyrophosphate anthropathy and associated disorders.

3 The drug products were demonstrated to be generic medical products of Voltaren T. 25mg and 50mg tablets respectively, authorised to Novartis in Sweden 19/10/1990, which contain the same amount of active substance under Artcicl of EC directive 2001/83/EC,. The reference products in UK are Cataflam tablets 25mg and 50mg, PL. 00030 / 0054 and PL 00030 / 0055, authorised to Novartis on 25/11/1992. PHARMACEUTICAL ASSESSMENT. DRUG SUBSTANCE. An appropriate specification based on the European Pharmacopoeia has been provided. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Active trimethoprim is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory. Batch analysis data are provided and comply with the proposed specification. Satisfactory certificates of analysis have been provided for working standards used by the active substance manufacturer and finished product manufacturer during validation studies.

4 Appropriate stability data have been generated supporting a retest period of 60 months, with no specific storage instructions. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 3. PL 18866 /0033-4. DRUG PRODUCT. Other Ingredients Silica colloidal anhydrous Sodium starch glycollate Povidone Starch maize Calcium hydrogen phosphate anhydrous Magnesium stearate Tablet Coating: Polyvinyl alcohol partially hydrolysed Titanium dioxide E171. Talc Lecithin Soya E322. Iron Oxide red E172. Iron Oxide yellow E172. Xanthan gum E415. All excipients used comply with their respective European Pharmacopoeial monograph. Magnesium stearate is of animal origin and an acceptable TSE Certificate of Suitability was provided. Dissolution and impurity profiles Dissolution and impurity profiles for both strengths of drug product were found to be similar to those for the reference products. Manufacture A description and flow-chart of the manufacturing method has been provided.

5 In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on batches of each strength. The results are satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System Blister strips made from polyamide/aluminium/PVC (25um/45um/60um) film coupled with 20um aluminium lidding by polyvalent thermal lacquer. The specifications and COA are satisfactory UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 4. PL 18866 /0033-4. PP-containers (Securitainer).

6 The container is white, tubular, made from polypropylene and the cap is white LDPE, both comply with Ph Eur Section (Plastic Containers and Closures). Supplier's data confirm compliance with EU food contact regulations, Directive 90/128, FDA, and BGA. It also contains desiccant (silica gel) in HDPE canister, complying with FDA food contact requirements. The specifications and COA are satisfactory. Stability Satisfactory stability data that met current requirements were provided supporting a shelf-life of 3 years with no specific storage instructions. ASSESSOR'S OVERALL CONCLUSIONS ON QUALITY AND ADVICE. Marketing Authorisations were granted. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 5. PL 18866 /0033-4. PRE-CLINICAL ASSESSMENT. No pre-clinical data were submitted with this application and none were required, UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 6. PL 18866 /0033-4. MEDICAL ASSESSMENT. CLINICAL PHARMACOLOGY.

7 PHARMACODYNAMICS. Diclofenac is a phenylacetic acid derivative, one of the group of non-steroidal anti- inflammatory drugs whose action is mediated by inhibition of enzymes of the cyclo- oxygenase type which are essential for the production of prostaglandins. Reduced prostaglandin synthesis is believed to be responsible for the anti-inflammatory and analgesic activities. As with other NSAIDs Diclofenac has been found to be an effective analgesic across the range of musculo-skeletal pathologies. Diclofenac Potassium tablets contain the Potassium salt of Diclofenac , a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties. Diclofenac is a potent inhibitor of prostaglandin biosynthesis and a modulator of arachidonic acid release and uptake. Diclofenac Potassium tablets have a rapid onset of action and are therefore suitable for the treatment of acute episodes of pain and inflammation. In migraine attacks Diclofenac Potassium tablets have been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.

8 PHARMACOKINETICS. Absorption Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption. Peak plasma concentration after one 50 mg sugar-coated tablet was mol/l after 20-60 minutes. The plasma concentrations show a linear relationship to the size of the dose. Diclofenac undergoes first-pass metabolism and is extensively metabolised. Distribution Diclofenac is highly bound to plasma proteins ( ), chiefly albumin ( ). Elimination The total systemic clearance of Diclofenac in plasma is 263 56 ml/min (mean SD). The terminal half-life in plasma is 1 2 hours. Repeated oral administration of Diclofenac Potassium tablets for 8 days in daily doses of 50 mg does not lead to accumulation of Diclofenac in the plasma. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 7. PL 18866 /0033-4. Approx. 60% of the dose administered is excreted in the urine in the form of metabolites, and less than 1% as unchanged substance.

9 The remainder of the Bioequivalence Study A comparative bioavailability study (EC/ ) was performed comparing the plasma levels of Diclofenac Potassium after administration of the two products:2x Diclofenac Potassium 50mg Tablets, batch No 56288 (Delta) and 2xVoltaren Rapid 50mg Tablets. This study was a single dose (2x50mg), randomised, two-way cross-over study, performed on minimum of 24 health volunteers (male and females). A total of 26. volunteers entered the study and 26 completed the study. The wash period was one week (accepted, given t is hours). The blood samples were taken at 0, , , , , 1, 2, 3, 4, 6, 8, 10, after the drug intake. The ratio AUCt / AUC is not estimated as the data do not include AUCt. The samples were analysed by the validated [for selectivity, linearity (20-3000ng/ml, R > ), accuracy (CV< ), specificity and LOQ of 20ng/ml)] HPLC. analysis at UV detection at 280nm, after drug precipitation and extraction from the biological sample with methanol/water (50:50) mixture.

10 Pharmacokinetic parameters of Diclofenac Potassium 50mg Tablets vs Voltaren Rapid 50 mg tablets are presented below: Pharmacokinetic parameters Diclofenac Voltaren Rapid Ratio* Ratio at 90%. Potassium 50mg 50mg (Novartis) Test/Ref CI of the ratio (Delta) Reference Test AUC ( ) 3653 3780 C max (ng/ml) 3274 3347 Tmax** (h) T / (h) * The ratio and the 90% confidence interval for the ratio are found after logarithmic transformation. ** Non-parametric median The results from the statistical analysis show that the AUC ratio between (90%CI) comply with the NfG ( ) requirement of (90% CI). The Cmax value of is just outside the acceptance criteria but within the criteria in the protocol .This may be accepted with the medical justification. From the data obtained it is concluded that two formulations are bioequivalent with respect to the rate and extent of absorption. UKPAR Rockspring Healthcare, Diclofenac Potassium 25 and 50mg Tablets 8. PL 18866 /0033-4. Safety and Efficacy The clinical expert report satisfactorily reviewed the bibliographic data on safety and efficacy of Diclofenac Potassium and was written by a suitably qualified person.