Public Assessment Report. Scientific discussion. Diliban Retard Tramadol/Paracetamol IS/H/0168/001/DC. Date:

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1 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Diliban Retard Tramadol/Paracetamol IS/H/0168/001/DC Date: This module reflects the scientific discussion for the approval of Diliban Retard. The procedure was finalised at For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Diliban Retard 75 mg/650 mg prolonged-release tablets, from Labopharm. The product is indicated for: the symptomatic treatment of moderate to severe pain in adults and adolescents over the age of 12 years. 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. Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure non selective agonists of the,, and opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be onetenth to one-sixth that of morphine. The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects, and includes cyclooxygenase (COX) inhibition, nitric oxide (NO) synthesis blockade, and interaction with many neurotransmitter systems, in particular the serotonergic system, as well as interaction with many neurotransmitter systems such as opioidergic, noradrenergic and cholinergic systems. ATC code: N02A X 52. No discussion in CMDh took place. Diliban Retard combination tablets have a different pharmaceutical form than the reference product which is a film-coated tablet. The Diliban Retard combination is a bi-layered tablet, which consists of both an immediate-release (paracetamol) and a prolonged-release (tramadol and paracetamol) layer. The tablet is designed to provide rapid onset of effective analgesia for a full 12-hour period, thereby providing a controlled release of the active ingredients over an extended period. Contramid is a technology developed by Labopharm for the formulation and manufacturing of solid, prolonged-release oral dosage forms. The Labopharm dossier relies mostly on the results of the pre-clinical and clinical data for the Reference Product but includes additional pre-clinical and clinical studies. Two toxicology studies were conducted with Contramid and a bioequivalence study which supports the development of its prolonged release, twice daily tablet formulation with demonstration of bioequivalence between immediate-release Zaldiar administered every 6 hours, and Diliban Retard, administered every 12 hours. A Phase III placebo-controlled clinical study (efficacy and safety) has also been conducted by Labopharm in a representative pain model (moderate to severe acute low back pain) to confirm that Diliban Retard provides pain relief when administered in accordance with the dosing instructions. The Labopharm dossier includes a complete Module 3. The submission under Article 10(3) is justified. PAR Scientific discussion 2/7

3 II. QUALITY ASPECTS II.1 Introduction Each prolonged-release tablet contains 75 mg tramadol hydrochloride and 650 mg paracetamol. The tablets are bi-layered biconvex oval shaped film-coated tablets, consisting of an immediate-release layer (light peach) and a prolonged-release layer (white to off-white). The tablets are embossed DDS 082 on the face of light peach layer. The tablets contain the following excipients: Tablet core: Microcrystalline cellulose Croscarmellose sodium Silica colloidal anhydrous Sodium stearyl fumarate Sunset yellow E110 Hydroxypropyl distarch phosphate (E1442) Copovidone Pregelatinised maize starch Hypromellose type 2208 Film-coating: Polydextrose Hypromellose Talc Maltodextrin Medium chain triglycerides The tablets are packaged into PVC/PE/PCTFE (Aclar ) blisters with aluminium backing foil and HDPE bottles with PP cap. II.2 Drug Substance The active substances specifications include relevant tests and the acceptance limits have been appropriately justified. The analytical methods applied are suitably described and validated. The active substances have been granted Certificates of Suitability of the European Pharmacopoeia 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. All the excipients except Contramid (Hydroxypropyl distarch phosphate) are described in the Ph.Eur and comply with the relevant monographs. Hydroxypropyl distarch phosphate and the colouring and coating agents comply with in-house monographs. PAR Scientific discussion 3/7

4 The pharmaceutical development of the drug product has been well described. It is a modified release product where Tramadol is included in the controlled release layer and paracetamol in both immediate and controlled layer. The application is a hybrid and the pharmaceutical strength is double that of the reference product. The aim was to develop once a day tablet that covers dosage of two immediate release tablets of the reference product. Manufacturing process consists of making immediate release layer and controlled release layer and compress together to form a bi-layer tablet. Tablets are then coated before packaging and release. The manufacturing process has been sufficiently described and critical steps were 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 in the commercial packaging and data presented support the shelf life claimed in the SPC (3 years). The pharmaceutical quality of the products has been adequately demonstrated. 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. III. NON-CLINICAL ASPECTS III.1 Introduction Abridged applications avoid the need for repetitive tests on animals and humans. However, two toxicology studies were conducted with Contramid an excipient used in the formulation for Diliban Retard. III.2 Pharmacology Pharmacodynamic, pharmacokinetic and toxicological properties of tramadol and paracetamol are well known. As tramadol and paracetamol are widely used, well-known active substances, the applicant has not provided additional studies on the active substances. Overview based on literature review is, thus, appropriate. However, Diliban Retard contains the excipient Contramid in the formulation and two toxicology studies conducted with Contramid are presented, a Bacterial Reverse Mutation Assay and an Acute Oral Toxicity Study of Contramid in Albino Rats. Further studies are not required. PAR Scientific discussion 4/7

5 The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.3 Ecotoxicity/environmental risk assessment (ERA) Since Diliban Retard is intended for 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 Diliban Retard 75 mg/650 mg prolonged-release tablets, from Labopharm is similar to Zaldiar (37.5 mg/325 mg film-coated tablets) by Grunenthal GmbH. Abridged applications avoid the need for repetitive tests on animals and humans but two toxicology studies were conducted with Contramid. Further studies are not required. 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. To supplement the application a Phase III efficacy and safety study was performed where the test product was compared to a placebo. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. The SmPC is in line with the text of the reference product. IV.2 Pharmacokinetics Comparisons Diliban Retard vs Zaldiar, fasting conditions A single oral dose of Diliban Retard (1300 mg acetaminophen/150 mg tramadol HCl) was equivalent to the same dose of Zaldiar administered as two doses 6 hours apart, with respect to Cmax (i.e. Cmax 0-36h) and AUCs for tramadol and O-desmethyltramadol and with respect to AUC only for acetaminophen. Cmax of acetaminophen was 20% lower following administration of Diliban Retard than after administration of Zaldiar. The time to Cmax after the first dose, tmax, of acetaminophen was similar between Diliban Retard and Zaldiar. On the other hand, tramadol and O-desmethyltramadol tmax (following first dose) were longer for Diliban Retard than for Zaldiar. The t½,z of tramadol and O-desmethyltramadol were similar after administration of Diliban Retard and Zaldiar whereas t½,z of acetaminophen was about 1 hour longer for Diliban Retard than for Zaldiar. Effects of food on Diliban Retard Food intake did not affect Cmax and AUC of acetaminophen, tramadol or O-desmethyltramadol after single dose treatment with Diliban Retard. PAR Scientific discussion 5/7

6 Food intake resulted in a significantly longer tmax of acetaminophen (about 2 hours), tramadol (about 1 hour) and O-desmethyltramadol (about 1 hour) after a single oral dose of Diliban Retard, which may indicate that the rates of absorption of acetaminophen and tramadol were slower in the fed and fasting states. The t½,z of acetaminophen, tramadol and O-desmethyltramadol for a single oral dose of Diliban Retard were similar in fed and fasting states. The data indicate that Diliban Retard can be taken without regard to food but that it should be taken in a consistent manner every 12 hours. Repeated administration Steady state for plasma concentrations of acetaminophen, tramadol and O-desmethyltramadol was reached on Day 4 or earlier following repeated administration of Diliban Retard and Zaldiar. Repeated twice daily administration of Diliban Retard (1300 mg acetaminophen/ 150 mg tramadol HCl) was equivalent, with respect to AUCss 0-24h and Cmax ss 0-24h, to the same daily doses of Zaldiar administered as four doses 6 hours apart, for tramadol and O- desmethyltramadol, and with respect to AUCss 0-24h, but not Cmax ss0-24h of acetaminophen. Indeed, Cmax,ss 0-24h of acetaminophen for Diliban Retard was approximately 20% lower than for Zaldiar. The time to Cmax for each dosing interval on Day 5, tmax,ss, of acetaminophen was similar between Diliban Retard and Zaldiar. However, tramadol and O-desmethyltramadol tmax,ss were longer for Diliban Retard than for Zaldiar. The Cmin ss 0-24h of acetaminophen wasapproximately 30% lower for Diliban Retard than for Zaldiar. For tramadol and O- desmethyltramadol, the Cmin ss 0-24h following administration of Diliban Retard were similar to those for the reference product. The %PTF of acetaminophen was lower for Diliban Retard than for Zaldiar whereas the %PTF of tramadol and O-desmethyltramadol were similar between the test and reference products. The %SWING of acetaminophen and tramadol were higher for Diliban Retard than for Zaldiar. For O-desmethyltramadol, the %SWING was higher for Diliban Retard than for Zaldiar. This study confirms that the Test product (Diliban Retard, tramadol/paracetamol 75/650 mg tablets, manufactured by Labopharm Inc, Canada) is bioequivalent to the Reference formulations (Zaldiar 37.5/325mg tablets, Grünenthal) with respect to rate and extent of availability, and is well tolerated. Bioequivalence has been shown. Food has very little effect on bioavailability. The differences in Cmax and tmax found for paracetamol are explained by the different release properties of the test and reference products. IV.3 Pharmacodynamics To supplement the application a Phase III clinical efficacy and safety study was performed where the test product was compared to a placebo in a representative pain model (moderate to severe acute low back pain) to confirm that Diliban Retard provides pain relief when administered in accordance with the dosing instructions. The superiority over placebo was demonstrated. The study was done according to Note for guidance on modified release oral and transdermal dosage forms: Section II (pharmacokinetic and clinical evaluation), CPMP/EWP/280/96. PAR Scientific discussion 6/7

7 IV.4 Clinical efficacy No new clinical efficacy studies apart from the Phase III placebo-controlled study were presented and no further studies are required for this application. IV.5 Clinical safety No new clinical safety studies apart from the Phase III placebo-controlled study were presented and no further studies are required for this application. IV.6 Risk Management Plan The MAH did not submit a risk management plan which was acceptable at the time. IV.7 Discussion on the clinical aspects Diliban Retard 75 mg/650 mg prolonged-release tablets, from Labopharm are bioequivalent to two (2) Zaldiar 37.5 mg/325 mg film-coated tablets by Grunenthal GmbH. Abridged applications avoid the need for repetitive tests on animals and humans but the application was supplemented with a Phase III placebo-controlled study The application contains an adequate review of published clinical data and the bioequivalence has been shown between Diliban Retard and Zaldiar. V. USER CONSULTATION No full user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Zaldiar 37.5 mg/325 mg film-coated tablets. The report for the parent leaflet was submitted and accepted in the MRP renewal of Zaldidar (22 June 2007). The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the risk-benefit ratio for application for Diliban Retard 75 mg/650 mg prolonged-release tablets, from Labopharm in the symptomatic treatment of moderate to severe pain in adults and adolescents over the age of 12 years is considered positive and marketing authorisation can be recommended. The marketing authorisation has been granted pursuant to Article 10(3), hybrid application, of Directive 2001/83/EC. There was no discussion in CMDh. There are no specific obligations and/or follow-up measures. PAR Scientific discussion 7/7