Public Assessment Report. Scientific discussion. Dicloziaja Diclofenacum diethylammonium Gel, 11,6 mg/g PL/H/0231/001/DC

Transcription

1 Public Assessment Report Scientific discussion Dicloziaja Diclofenacum diethylammonium Gel, 11,6 mg/g Applicant: Ziaja Ltd Zakład Produkcji Leków Sp. z o.o. Date: This module reflects the scientific discussion for the approval of Dicloziaja. 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 (CZ, LT, SK and PL) have granted a marketing authorisation for Dicloziaja, Diclofenac diethylamine, gel, 11,6 mg/g, from Ziaja Ltd Zakład Produkcji Leków Sp. z o.o. The product is indicated for hyperaemic agent for percutaneous heat stimulation treatment. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10a (well-established use application) of Directive 2001/83/EC. Diclofenac is a potent non-steroidal, analgesic and anti-inflammatory drug that has been in clinical for the treatment of acute and chronic rheumatic disorders and nonrheumatic, inflammative, painful swelling and injury. Pharmacological classification Pharmacotherapeutic group: anti-inflammatory preparations, non steroids for topical use Hyperaemic agent for percutaneous heat stimulation treatment ATC code: MO2 AA 15 Claimed indication and recommendation for use The indications of Dicloziaja gel are as follows: posttraumatic tendinitis and inflammation of ligaments, muscles and joints (after contortion, strains or contusions); - back pain; - localised inflammation of soft tissues (such as tendinitis or athlete's elbow); - localised and mild symptoms of osteoarthritis. II. QUALITY ASPECTS II.1 Introduction The pharmaceutical form of the drug product is a gel for cutaneous use packed in aluminium tube internally coated with epoxide-phenol lacquer with membrane and with sealing latex ring; closed with polyethylene screw cap. The excipients of the drug product are: carbomer 5984, sodium hydroxide, macrogol cetostearyl ether 20, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, paraffin liquid light, perfum cream PO, water purified. II Drug Substance The active substance diclofenac diethylamine is not monographed in the Ph.Eur. but it is described in the British Pharmacopoeia (BP). The BP monograph states that: It is a white to light beige, crystalline powder, sparingly soluble in water and in acetone; freely soluble in ethanol (96%) and in methanol; practically insoluble in 1m sodium hydroxide. It melts at about 154, with decomposition. Synthesis, specifications and analytical methods for the active substance are all satisfactorily described. 2/5

3 All issues relating to the Applicant s Part and the Restricted Part of the Active Substance Master File have been resolved. II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis results show that the finished products meet the specifications proposed. A shelf - life of 3 years with the label storage condition: Store below 25 ºC. Do not refrigerate or freeze is accepted. Proposed in-use shelf-life of 2 years is accepted. III. NON-CLINICAL ASPECTS No new non-clinical data have been provided. The pharmacodynamic, pharmacokinetic and toxicology of diclofenac is well established and the non-clinical dossier is based on a review of published literature. The non-clinical overview has been written by a suitably qualified person. The overview comprised a thorough review of pharmacology and toxicology of diclofenac with 62 publications up to year Considering data presented in ERA, diclofenac is not expected to pose a risk to the environment. IV. CLINICAL ASPECTS IV.1 Introduction For the first time the preparation containing diclofenac as an active substance was registered in an oral formulation (as a brand - Voltaren) in Japan in Later on diclofenac as a tablet was introduced in the market also in USA in 1990s, in Europe in 1978 and in Poland in 1996 (also as a brand - Voltaren). In Poland, Voltaren as gel was registered for the first time in 1989 and in other countries in 2000s. The clinical overview has been written by a suitably qualified person. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics Diclofenac has well known pharmacokinetic properties. Topical diclofenac, applied in the form of gel, penetrates the skin and reaches highly effective concentrations in the subcutis, fascial, tendons, ligaments and muscles in the amounts that are sufficient to exert therapeutic effects in the absence of high plasma concentrations and consequently, systemic adverse effects. Compared with the parenteral formulation the systemic availability of diclofenac from both topical preparations is limited. In general, the rate of penetration and absorption of topical diclofenac is related to the permeability and hydration of the skin, showing large inter-individual variation. Diclofenac binds extensively to plasma proteins (>99%), reaching systemic circulation it is rapidly 3/5

4 metabolised, and is eliminated via the renal and biliary routes. The plasma elimination halflife of oral diclofenac is 1-2 hours, for topically administered diclofenac it is prolonged. To demonstrate that Dicloziaja gel is similar to two reference products marketed in Poland, the skin penetration of diclofenac from Dicloziaja gels were therefore compared to that of Naklofen gel (manufactured by Krka) and Voltaren Emulgel (manufactured by Novartis, Germany) in an in vitro study. The objective of this work was to measure over time and to compare, under strictly standarized in vitro experimental conditions, to compare the ex vivo skin penetration and permeation of diclofenac from three topical preparations with diclofenac. The studies were conducted in compliance with OECD guidelines. IV.3 Pharmacodynamics Diclofenac is a potent non-steroidal, analgesic and anti-inflammatory drug that has been in clinical use since 1974 for the treatment of acute and chronic rheumatic disorders and nonrheumatic, inflammative, painful swelling and injury. Its clinical use is well established and well documented. Currently, the drug is available in various administration forms in order to provide flexibility in individualised therapy. The main mechanism of action of NSAIDs like diclofenac is attributed to inhibition of prostaglandin (PG) synthesis. Investigations both in vitro and in vivo have shown that, in the family of NSAIDs, diclofenac, on a molar basis, is one of the most effective inhibitors of cyclooxygenase (i.e. of PG synthesis), and thus has marked anti-inflammatory, analgesic, anti-oedematous, and antipyretic properties. Further mechanisms have been identified, such as interactions with other mediators and enzyme systems, effects on immune reactions, and inhibition of the synthesis of oxygen radicals. IV.4 Clinical efficacy The efficacy and safety of diclofenac has been confirmed in numerous clinical trials. The results of these studies have showed that the effectiveness of topical diclofenac was equal to or higher than other topical NSAIDs, and superior or equivalent to oral diclofenac. Topical diclofenac has been used for many years as an adjunctive external drug in the symptomatic treatment of traumatic soft tissue injury and disorders (e.g. pain due to acute distortions and strains, sprains and contusions). In many countries worldwide it has become a standard therapy. There are a considerable number of clinical trials on the efficacy of topical diclofenac available. IV.5 Clinical safety Topical preparations, containing diclofenac, may cause adverse effects at the site of application. The adverse reactions are usually mild and transient. Allergic reactions and asthma can occur in very rare cases. Generalised skin rash, hypersensitivity reactions, such as angioedema and photosensitivity reactions have been reported in isolated cases. Pharmacovigilance system On the day 106 the Applicant submitted the Summary of the PharmacoVigilance System Master File which is considered satisfactory. EudraVigilance code of The PharmacoVigilance System Master File Location: MFL /5

5 Risk Management Plan Considering that Diclofenac Ziaja is the well established-used application form dossier the MAH has submitted the assessment of the justification for not submitting a risk management plan which is satisfactory. Periodic Safety Update Report (PSUR) The applicant has applied for a PSUR submission scheme of 3 years upon approval as: EU HBD 1977/05//11 DLP 09/ /2015 PSUR-cycle is applied for, to harmonise with a substance Birthdate and related Data Lock Point (DLP). The suggestion scheme and this period should be followed. The next DLP is September The PSUR is not entirely expected to cover the period from the date of granting Marketing Authorisation. If needed it will be expected as soon as the Marketing Authorisation is granted. Diclofenac was assessed during P-RMS allocated procedure number DK/H/PSUR/0022/002. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION 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 PIL 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. Therapeutic indications were agreed as follows: Adolesncents over 14 years, for short-term treatment in: - local symptomatic relief of pain in acute strains, sprains or contusions following blunt trauma Adults - Posttraumatic tenditis and inflammation of ligaments, muscles and joints (after contortion, strains or contusions); - Back pain; - Localised inflammation of soft tissues (such as tenditis or athlete s elbow); - Localised and mild symptoms of osteoarthritis. The risk/benefit ratio is considered positive and Dicloziaja 11,6 mg/g, gel was recommended for approval. 5/5