Public Assessment Report Scientific Discussion Oxydol Prolonged
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Public Assessment Report Scientific discussion Oxydol prolonged release hard capsules 10 mg, 20 mg, 40 mg, 80 mg Oxycodone HCl IS/H/0196/001-004/DC This module reflects the scientific discussion for the approval of Oxydol. The procedure was finalised at 9 January 2013. For information on changes after this date please refer to the module ‘Update’. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Oxydol prolonged release hard capsules 10 mg, 20 mg, 40 mg, 80 mg from Ethypharm. The product is indicated for severe pain, which can be adequately managed only with opioid analgesics. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(3) of Directive 2001/83/EC. Oxycodone hydrochloride (oxycodone, ATC code: N02 AA05) is a semi-synthetic opioid analgesic. Oxycodone has affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs. Oxycodone is an opioid agonist at these receptors with no antagonistic effect. Its therapeutic effect is mainly analgesic but it also possesses anxiolytic and sedative properties and has a higher absolute bioavailability than morphine. Oxydol is a slow release formulation which allows more controlled plasma exposure and minimises the peaks and troughs in plasma concentration associated with immediate release dosing. No discussions were held with CMDh during the procedure. II. QUALITY ASPECTS II.1 Introduction Oxydol, prolonged release hard capsules (10 mg, 20 mg, 40 mg, 80 mg) are packaged in PVC / Aluminium blisters. Oxycodone hydrochloride capsules 10 mg are size 4 capsules containing white spherical microgranules. The capsules have opaque yellow body and cap with a black inscription “OCR” on the body and “10” on the cap. Oxycodone hydrochloride capsules 20 mg are size 4 capsules containing white spherical microgranules. The capsules have opaque green body and cap with a black inscription “OCR” on the body and “20” on the cap. Oxycodone hydrochloride capsules 40 mg are size 2 capsules containing white spherical microgranules. The capsules have opaque white body and cap with a black inscription “OCR” on the body and “40” on the cap. Oxycodone hydrochloride capsules 80 mg are size 0 capsules containing white spherical microgranules. The capsules have opaque pink body and cap with a black inscription “OCR” on the body and “80” on the cap. Capsule content: Sugar spheres (containing sucrose and maize starch) Hypromellose Polyacrylate dispersion 30% Talc Capsule shell: Black Printing Ink: PAR Scientific discussion 2/6 Shellac Black iron oxide (E172) Oxydol 10 mg (Yellow): Gelatin, Titanium dioxide (E 171), Yellow iron oxide (E 172) Oxydol 20 mg (Green): Gelatin, Indigo carmine (E132), Black iron oxide (E172), Titanium dioxide (E 171), Yellow iron oxide (E 172) Oxydol 40 mg (White): Gelatin, Titanium dioxide (E 171) Oxydol 80 mg (Pink): Gelatin, Titanium dioxide (E 171), Red iron oxide (E 172) II.2 Drug Substance The drug substance is oxycodone hydrocloride, an established active substance of chemical origin. It is monographed in the European Pharmacopoeia (n°1793). Oxycodone hydrochloride (INN) is hygroscopic and white or almost white powder. It is freely soluble in water, sparingly soluble in anhydrous ethanol, practically insoluble in toluene. The active substance specification includes relevant tests and the acceptance limits have been appropriately justified. The analytical methods applied are suitably described and validated as demonstrated with compliance to the Ph.Eur. as CEP for the active substance confirms. Stability studies have been conducted and the data provided is sufficient to support the proposed retest period. II.3 Medicinal Product The development of the drug product formulation is well described. The excipients used in the product are all standard in the manufacture prolonged release hard capsules and are compliant with European Pharmacopoeia (or equivalent) requirements. The non-standard manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the finished products specifications are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SPC; 3 years with special storage condition “Store below 30°C”. The pharmaceutical quality of Oxydol has been adequately shown. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. Oxycodone Ethypharm PR capsules were included in CHMP assessment of the effects of alcohol on the dissolution of modified release opioids and reformulation was not considered necessary with an appropriate statement in the SmPC. PAR Scientific discussion 3/6 III. NON-CLINICAL ASPECTS III.1 Introduction Abridged applications avoid the need for repetitive tests on animals and humans. III.2 Pharmacology, Pharmacokinetics & Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of oxycodone are well known. As oxycodone 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. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.3 Ecotoxicity/environmental risk assessment (ERA) Since Oxydol 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.4 Discussion on the non-clinical aspects Oxydol is a hybrid to OxyContin®. Abridged applications avoid the need for repetitive tests on animals and humans. There are no objections to approval of Oxydol from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction Abridged applications avoid the need for repetitive tests on animals and humans apart from a conduction of bioequivalence studies to confirm that the applied product is bioequivalent to the reference medicinal product. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics Biowaiver Single dose bioequivalence studies for the 40 mg strength and a multiple dose studies for the 20 mg strength were submitted. A biowaiver for the 10 mg, 20 mg and 80 mg strengths is appropriate. The pharmacokinetics is linear for the proposed dosing range (10 mg – 80 mg). All of the remaining criteria for a biowaiver have been met i.e.: the products are manufactured by the same manufacturing process; the qualitative composition of the different strengths is the same; the composition of the strengths are quantitatively proportional; and in vitro dissolution profiles are comparable. PAR Scientific discussion 4/6 Bioequivalence studies To support the application, the applicant has submitted as report three bioequivalence studies with a positive outcome. Type of BE Study Strength Study Code Outcome tested A single-dose, fed state, naltrexone cover 40 mg OXY/98014/005 Passed A single-dose, fasting state, naltrexone 40 mg OXY/98014/007 Passed cover A multiple-dose, fasting state, naltrexone 20 mg OXY/98014/008 Passed cover Statements of GCP and GLP compliance are provided. A statement is provided to confirm that the bioequivalence study OXY/98014/008 carried out outside the European Union meets the ethical requirements of the European Union Directive 2001/20/EC. OXY/98014/005 The study was an open label, randomised, single dose, 2-period, 2-sequence, crossover bioequivalence study comparing two 40 mg oxycodone formulations in 24 healthy adult subjects under fed conditions. The study was conducted under standardised conditions. Oxycodone was measured in human plasma using a validated HPLC/MS/MS method. The test to reference ratio of geometric LSmeans and corresponding 90% confidence interval for the Cmax, AUC0-t and AUC0-∞ were all within the acceptance range of 80.00% to 125.00%. OXY/98014/007 The study was an open label, randomised, single dose, 2-period, 2-sequence, crossover bioequivalence study comparing two 40 mg oxycodone formulations in 23 healthy adult subjects under fasting conditions. The study was conducted under standardised conditions. Oxycodone was measured in human plasma using a validated HPLC/MS/MS method. The test to reference ratio of geometric LSmeans and corresponding 90% confidence interval for AUC0-t and AUC0-∞ were all within the acceptance range of 80.00 to 125.00% but was slightly outside the acceptance range for Cmax (0.7812- 0.9928) when all subjects were included. However, when one subject experiencing vomiting was excluded the Cmax was found within the acceptance range of 80.00% to 125.00%. Oxydol is considered essentially similar to OxyContin®. Overall the risk/benefit ratio is considered positive for the Oxydol 40 mg prolonged release capsules. OXY/98014/008 The study was a randomised, multiple dose, 2-period,