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MHRA PAR, VOLTAROL ACTIVE 4% CUTANEOUS SPRAY, PL 00030/0445 1

Public Assessment Report

Decentralised Procedure

Voltarol Active 4% cutaneous spray

PL 00030/0445

Novartis Consumer Health UK Limited


It should be noted that this Marketing Authorisation was transferred from ECONOMED GmbH (PL 31527/0001) to Novartis Consumer Health UK Limited (PL 00030/0445) on 5 October 2010, following a Change of Ownership. In addition, a variation to change the name of the product in the UK from KWIS Spray Gel 4% Cutaneous Spray, Solution to Voltarol Active 4% cutaneous spray was granted on 12 August 2011. The following report was published on 3 September 2008 and, therefore, refers to the original Marketing Authorisation details, however, Annex 1 (page 30) contains the updated Marketing Authorisation information.

LAY SUMMARY The Medicines Healthcare products Regulatory Agency granted ECONOMED GmbH a Marketing Authorisation (licence) for the medicinal product KWIS Spray Gel 4% Cutaneous Spray, Solution. This is a pharmacy-only medicine for the relief of acute pain and swelling affecting small or medium-sized joints and surrounding tissues. KWIS Spray Gel 4% Cutaneous Spray, Solution contains the active ingredient diclofenac sodium, which belongs to a group of drugs called non-steroidal anti-inflammatory drugs (NSAID). No new or unexpected safety concerns arose from this application and it was therefore judged that the benefit of taking KWIS Spray Gel 4% Cutaneous Spray, Solution outweighs the risks; hence a Marketing Authorisation has been granted.


TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 9 Module 4: Labelling Page 13 Module 5: Scientific Discussion Page 17 1 Introduction Page 17 2 Quality aspects Page 19 3 Pre-clinical aspects Page 20 4 Clinical aspects Page 22 5 Overall conclusions Page 28 Module 6 Steps taken after initial procedure Page 29 Annex 1 0


Module 1

Product Name

KWIS Spray 4% Cutaneous Spray, Solution

Type of Application

Full Dossier, Article 8.3

Active Substance

Diclofenac Sodium

Form

Cutaneous Spray, Solution

Strength

4% (40mg/g)

MA Holder

ECONOMED GmbH

RMS

UK

CMS

Germany

Procedure Number

UK/H/1221/001/DC

End of Procedure Day 182 – 3rd July 2008


Module 2 Summary of Product Characteristics

The UK Summary of Product Characteristics (SPC) for KWIS Spray Gel 4% Cutaneous Spray, Solution are as follows: 1 NAME OF THE MEDICINAL PRODUCT

KWIS Spray Gel 4% cutaneous spray, solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1g of solution contains 40 mg of diclofenac sodium. Each pump stroke delivers 8 mg of diclofenac sodium. Excipients: Propylene glycol 150 mg/g Soy bean lecithin 100 mg/g For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cutaneous spray, solution. A golden-yellow, transparent solution (pH value: 6.5–7.6), which turns to a gel-like consistency after administration.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

For the local symptomatic relief of mild to moderate pain and inflammation following acute blunt trauma of small and medium-sized joints and periarticular structures.

4.2 Posology and method of administration

For cutaneous use only. Adults Sufficient solution of KWIS Spray Gel should be sprayed onto the skin of the affected site. Depending on the size to be treated 4–5 pump strokes (0.8–1.0 g of spray containing 32–40 mg of diclofenac sodium) should be applied 3 times a day at regular intervals. The maximum single dose of 1.0 g of the product should not be exceeded. The maximum daily dose is 15 pump strokes (3.0 g of spray containing 120 mg of diclofenac sodium). KWIS Spray Gel should be massaged gently into the skin. After this the hands should be washed unless they are the site to be treated. After application some minutes for drying should be allowed before dressing or binding the treated area. The treatment may be discontinued when the symptoms (pain and swelling) have subsided. Treatment should not be continued beyond 7 days without review. The patient is requested to consult the doctor if no improvement is seen after 3 days. Elderly The posology is the same as for adults. Children There is no experience in children, therefore KWIS Spray Gel is not recommended for use in children below 15 years of age Patients with hepatic or renal insufficiency For the use of KWIS Spray Gel in patients with hepatic or renal insufficiency see section 4.4.

4.3 Contraindications

• Hypersensitivity to the active substance, peanut, soya or to any of the excipients. Hypersensitivity to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs)

• Patients with or without asthma in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents.

• The last trimester of pregnancy.

• Application to the breast area of breast-feeding mothers


4.4 Special warnings and precautions for use Contact with eyes and mucous membranes as well as oral use should be avoided. KWIS Spray Gel should only be administered onto intact skin, not on open wounds or diseased skin areas. Patients should be warned against excessive exposure to sunlight in order to reduce the incidence of photosensitivity. If any rash develops administration should be discontinued. Not for use with occlusive dressings. The concomitant use of KWIS Spray Gel with oral NSAIDs should be cautioned as the incidence of systemic undesirable effects may increase (see section 4.5). Where KWIS Spray Gel is applied to a relatively large area of skin (i.e. more than 600 square centimetres of the body surface) and over a prolonged period (i.e. more than 4 weeks), the possibility of systemic undesirable effects cannot be completely excluded (for example, there is the potential for hypersensitivity, asthmatic and renal adverse reactions). Bronchospasm may be precipitated in patients suffering from or with previous history of bronchial asthma or allergenic disease. KWIS Spray Gel should only be used with caution in patients with a history of peptic ulcer, hepatic or renal insufficiency, or bleeding diathesis, or inflammatory bowel disease, as isolated cases with topical diclofenac have been reported. KWIS Spray Gel contains propylene glycol which may cause skin irritation. KWIS Spray Gel contains peppermint oil which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

The systemic availability of diclofenac from this pharmaceutical presentation is very low. Hence the risk of interactions with other medicinal products is small. Concurrent acetylsalicylic acid or other NSAIDs may result in an increased incidence of adverse reactions (see section 4.4).

4.6 Pregnancy and lactation There are no adequate data from the use of KWIS Spray Gel in pregnant and breast-feeding women. Studies in animals have shown reproductive toxicity, however, no evidence of a malformative effect was observed with diclofenac (see 5.3). The potential risk for humans is unknown. Use in pregnancy: During the last trimester of pregnancy, the use of prostaglandin synthetase inhibitors may result in: - pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with preterm closing of the

ductus arteriosus) - renal insufficiency in the foetus with oligohydramnios - inhibition of uterine contractions and prolongation of pregnancy and delivery - increased possibility of bleeding in the mother and child. Therefore, during the first six months of pregnancy, KWIS Spray Gel should not be used unless clearly necessary and must not be applied to a large area of the skin (i.e. more than 600 square centimetres of the body surface). It must not be used for long-term treatment (> three weeks). KWIS Spray Gel is contraindicated (see section 4.3) during the last trimester of pregnancy. Use during lactation: It is not expected that any measurable amount of diclofenac will occur in breast milk following topical application. However, NSAIDs are excreted in human milk. Therefore KWIS Spray Gel is not recommended for use in breast-feeding mothers. An application to the breast area of breast-feeding mothers is contraindicated.

4.7 Effects on ability to drive and use machines

KWIS Spray Gel has negligible influence on the ability to drive and use machines. Patients who experience dizziness or other central nervous disturbances while taking NSAIDs should refrain from driving or operating machinery, but this would be very unlikely using topical preparations.

4.8 Undesirable effects

Skin disorders are commonly reported. Skin: Application site reactions, rashes, pruritus and urticaria, drying, reddening, burning sensations, contact dermatitis. In a clinical trial 236 patients with ankle distortions were treated with 4–5 pump strokes of KWIS Spray Gel t.i.d. (120 patients) or placebo (116 patients) for 14 days. The following adverse drug reactions were reported:


System Organ class

Very common (≥ 1/10)

Common(≥ 1/100, <1/10)

Uncommon (≥1/1,000, <1/100)

Rare (≥1/10,000,

<1/1,000

Very Rare (<1/10,000) not known (cannot be

estimated from the available

data)

Skin and subcutaneous tissue disorders

Pruritus 0.9 % Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration. The total single dose of product should not exceed 1.0 g (equivalent to 5 pump strokes) of spray. Nevertheless during long term treatment (> three weeks) and/or when treating large areas (i.e. more than 600 square centimetres of the body surface) there is a possibility of systemic adverse reactions. Reactions like abdominal pain, dyspepsia, gastric and renal disorders may occur. In patients using topical NSAID preparations asthma has been reported rarely. In isolated cases generalised skin rash, hypersensitivity reactions such as angioedema and photosensitivity reactions have been reported.

4.9 Overdose

During recommended use there is practically no risk due to overdose. If accidentally KWIS Spray Gel has been administered orally symptomatic treatment should be given.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiinflammatory preparations, non-steroids for topical use. ATC code: M02AA 15 Sodium diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has also analgesic properties. The inhibition of prostaglandin synthesis is considered to be an essential part of its mode of action.

5.2 Pharmacokinetic properties

After cutaneous application of 1.5 g KWIS Spray Gel a rapid onset of diclofenac absorption can be observed leading to measurable plasma levels of about 1 ng/ml as early as 30 minutes and to maximum levels of about 3 ng/ml at about 24 hours after application. The achieved systemic concentrations of diclofenac are about 50 times lower than those achieved following oral administration of equivalent amounts of diclofenac. Systemic plasma levels are not supposed to contribute to the efficacy of KWIS Spray Gel. Diclofenac is extensively bound to plasma proteins (about 99 %).

5.3 Preclinical safety data

In rabbit skin, KWIS Spray Gel is classified as non-irritant. Non-clinical data based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential of diclofenac reveal no special hazard for humans beyond those already outlined in other sections of the SPC. In animal studies, chronic toxicity of diclofenac following systemic administration mainly took the form of gastrointestinal lesions and ulcers. In a 2-year toxicity study, rats treated with diclofenac showed a dose-dependent increase in thrombotic occlusion of the cardiac vessels. In rats and rabbits oral doses of diclofenac were not teratogenic but caused embryotoxicity at maternally toxic doses. Diclofenac did not affect fertility in rats but inhibited ovulation in rabbits and reduced implantation in rats.


In rats, diclofenac resulted in dose-dependent constriction of the fetal ductus arteriosus, dystocia and delayed parturition (see section 4.3). Doses below the materno-toxic threshold had no influence on the postnatal development of the progeny.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Isopropyl alcohol Soybean lecithin Ethanol Disodium phosphate dodecahydrate Sodium dihydrogen phosphate dihydrate Disodium edetate Propylene glycol Peppermint oil (contains menthol and cineole) Ascorbyl palmitate Hydrochloric acid 10% (w/w) for pH adjustment Sodium hydroxide 10% (w/w) for pH adjustment Purified water.

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

3 years After first opening: 6 months

6.4 Special precautions for storage

Store in the original package. 6.5 Nature and contents of container

Glass bottle (Type III Ph.Eur.) with metering pump and protection cap. Pack sizes of 12.5 g solution (15 ml bottle) and 25 g solution (30 ml bottle). Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements. 7 MARKETING AUTHORISATION HOLDER

ECONOMED GmbH Industriestraße 32 74909 Meckesheim GERMANY

8 MARKETING AUTHORISATION NUMBER(S)

PL 31527/0001 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 29/08/2008 10 DATE OF REVISION OF THE TEXT

29/08/2008

11 DOSIMETRY (IF APPLICABLE) 12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF

APPLICABLE)


Module 3

PATIENT INFORMATION LEAFLET


Module 4 Labelling

Text to appear on carton


Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for KWIS 4 % Spray Gel, for the local symptomatic relief of mild to moderate pain and inflammation following acute blunt trauma of small and medium-sized joints and peri-articular structures is approvable. This is a decentralised application for Diclofenac sodium 4 % Spray Gel, submitted under Article 8(3) of Directive 2001/83/EC (as amended). The RMS is the UK and the only CMS is Germany. The medicinal product is already authorised in the UK under the name ‘Diclofenac Sodium 4 % Spray Gel’ with the marketing authorisation holder MIKA Pharma GmbH and the licence number PL 18017/0001-2 and has been authorised in other European member states during the mutual recognition procedures, UK/H/0562 and UK/H/0563. Diclofenac is one of the most widely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and is regarded as an effective analgesic across a range of conditions affecting the musculo-skeletal system. Diclofenac was first marketed in 1974 and has been available for cutaneous use since 1986. Diclofenac is available in the sodium salt form, as a 3 % gel in Solaraze® (used twice daily in the treatment of actinic keratosis), however it is more commonly used for the relief of pain in musculoskeletal conditions in the form of diclofenac diethylammonium salt 1.16 % (Voltarol Emulgel®, Novartis), used three to four times daily. Diclofenac Sodium 4% Spray Gel has been approved in 17 member states through two mutual recognition procedures, UK/H/0562/001 and UK/H/0563/001. The data in this application includes additional safety data from one pharmacodymamic study and three safety studies in addition to the data submitted during the aforementioned mutual recognition procedures. The Applicant, Economed GmbH, seeks a marketing authorisation for a topical formulation of diclofenac sodium administered as a cutaneous spray. The following indication is sought: For the local symptomatic relief of mild to moderate pain and inflammation following acute blunt trauma of small and medium-sized joints and periarticular structures such as trauma of the tendons, ligaments, muscles and joints e.g. due to sprains and strains. The application is in accordance with Article 8(3) (dossier with administrative, quality, pre-clinical and clinical data) of Directive 2001/83/EC (as amended). The submitted documentation in relation to the proposed product is of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory quality, non-clinical and clinical overviews have been submitted. They represent an adequate summary of the dossier. It is not anticipated that that marketing of this product will change the overall use pattern of the existing market, as it is anticipated that the gel formulation will replace and/or reduce the use of other Diclofenac Sodium formulations, therefore the absence of an environmental risk assessment is acceptable.


A document relating to a Pharmacovigilance system has been provided. The Applicant has not provided a Risk Minimisation plan, justifying the absence on the basis of the extensive use of diclofenac spray gel. The RMS has been assured that acceptable standards of GMP are in place for this product type at the site responsible for the manufacture and assembly of this product. For the manufacturing site within the Community, the RMS has accepted a copy of the current manufacturing authorisation issued by inspection services of the competent authority as certification that acceptable standards of GMP are in place at that site. The Applicant states that the clinical studies included in the application meet the ethical requirements of Directive 2201/20./EC. No PIL User testing has been performed as the product is not intended to be marketed at this time. The marketing authorisation holder has provided a commitment to update the marketing authorisation with a package leaflet in compliance with Article 59 of Council Directive 2001/83/EC and that the leaflet shall reflect the results of consultation with target patient groups, before the product is marketed. II. ABOUT THE PRODUCT

Name of the product in the Reference Member State

KWIS Spray Gel 4% Cutaneous Spray, Solution

Name(s) of the active substance(s) (INN) Diclofenac sodium Pharmacotherapeutic classification (ATC code)

M02AA15, Topical products for joint and muscular pain, anti-inflammatory preparations, non-steroids for topical use

Pharmaceutical form and strength(s) Cutaneous spray, solution, 4% (40mg/g)

Reference numbers for the Mutual Recognition Procedure UK/H/1221/01/DC Reference Member State United Kingdom Member States concerned Germany Marketing Authorisation Number(s) PL 31527/0001 Name and address of the authorisation holder Economed GmbH, Industriestraβe 32, D-

74909 Meckesheim, Germany


III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance General Information Nomenclature INN Diclofenac sodium Chemical names 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid monosodium salt [O-(2,6-dichloroanilino)phenyl]-acetic acid sodium salt Sodium 2-[(2,6-dichlorophenyl)amino]phenyl-acetate (Ph.Eur.) CAS number 15307-79-6 Laboratory code GP 45840 (Sodium Salt, Ciba Geigy)

Structure

NHCl

Cl

CO Na+

O

Molecular formula: C14H10Cl2NNaO2 Molecular mass: 318.14

General properties

Diclofenac sodium is a white to yellowish white, practically odourless, sieved or milled powder, which is weakly hygroscopic. The structure has no centre of chirality. Diclofenac sodium is sparingly soluble in water, soluble in methanol and ethanol, slightly soluble in acetone, insoluble in chloroform and in ether. Diclofenac sodium is the subject of a European Pharmacopoeia monograph. Manufacture An Active Substance Master File (ASMF) has been provided covering the manufacture and control of the drug diclofenac sodium. The drug substance specification complies with the Ph.Eur. monograph. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Active diclofenac sodium is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory. Batch analysis data have been 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. Appropriate stability data have been generated supporting a re-test period of 5 years. P Medicinal Product Other ingredients consist of pharmaceutical excipients namely; isopropyl alcohol, soybean lecithin, ethanol, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, disodium edentate, propylene glycol, peppermint oil, ascorbyl palmitate, sodium hydroxide, hydrochloric acid and purified water. All the ingredients used comply with their respective European Pharmacopoeial monograph. Satisfactory certificates of analysis have been provided for all excipients. The development of the product has been described, the choice of excipients is justified and their functions explained. Impurity profile The specified impurities are as listed in the Ph. Eur monograph for diclofenac sodium. Given that the product has been on the market in the UK for some years, that the impurity profile of diclofenac sodium is well-known and that levels of impurities in batch analyses are low, this was satisfactory. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Validations of the analytical methods have been presented. Process validation has been carried out on nine batches of the product. The batch analysis results show that the finished products meet the specifications proposed. Certificates of analysis have been provided for any working standards used. Container Closure System The product is packed into amber Ph.Eur Type III glass bottles of 30mL or 15mL with metering pump and protection cap for the pack sizes 25g and 12.5g respectively, not all pack sizes may be marketed. Specifications and a certificate of analysis for the packaging type used have been provided. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 3 years (unopened) and 6 months after first opening, which is satisfactory. Storage conditions are ““Store in original package”. Conclusion It is recommended that a Marketing Authorisation is granted for this application. III.2 Non clinical aspects A non-clinical overview, has been written by a suitably qualified person. This consists of a review of published literature on the pharmacology and toxicology of diclofenac sodium. In addition, preclinical studies performed with the proposed formulation are also discussed. These consist of a local tolerance study in mini-pigs, phototoxicity and photosensitation studies in guinea pigs.


The pharmacological, pharmacokinetic and toxicological properties of diclofenac are well known. As diclofenac is a well known active substance, the assessment concentrates on the new non-clinical data submitted New non-clinical studies A dermal toxicity study (study ID TDS-943) in mini-pigs was conducted, consisting of five groups (5/sex/group treated), one of which was a control group. Animals were dosed dermally by spraying over the dose site, 3 times a day with Diclofenac Sodium Spray Gel 4% and vehicle at doses of 0, 2.4, 4, and 8 mg/kg/day for 90 days.

Skin encrustation and minimal to mild subacute inflammation were noted at the application site and considered test article-related. In addition, single or very low incidences of dermal irritation (very slight to well-defined erythema) were observed in the vehicle and Diclofenac Sodium Spray Gel 4% treated groups. In half of the pigs that exhibited erythema, the erythema appeared shortly after razor burn was noted and may have been related to the razor burn. Erythema in the remainder of the pigs had no apparent relationship to razor burn but was of short duration and was considered not to be test article-related. No macroscopic or microscopic findings adverse treatment-related effects were noted. Phototoxicity

The phototoxic properties of Diclofenac Sodium 4% Spray Gel in comparison to Voltaren® Emulgel following dermal administration and UV irradiation to guinea pigs (exposure time of 72 h) were examined. Female guinea pigs were allocated to 7 groups (5 animals/group).

Diclofenac Sodium 4% Spray Gel (2ml/80 mg), Voltaren® Emulgel (2g/20 ml), and vehicle control were applied to the application site (Day 1) and left on the skin for 72 h. The patches were removed (Day 4), and the animals were exposed to UV irradiation for 20 min using a mercury lamp. Animals in the positive control group received 8-methoxypsoralen (40 mg/kg) p.o. 30 min before UV irradiation. Skin reactions were evaluated 4, 24 and 48 h after completing the irradiation. Both erythema and edema were graded on scales on 1 (slight) to 4 (maximum). This study was GLP compliant. Diclofenac Sodium 4% Spray Gel (2 mL/80mg) and Voltaren® Emulgel (2 g/20mg Diclofenac Sodium equivalent) did not show any phototoxic effects. A phototoxic effect was observed in the positive control group at 40 mg 8-methoxypsoralen. Photosensitizing The photosensitizing properties of Diclofenac Sodium 4% Spray Gel (0.5 ml/20 ml) in comparison to Voltaren® Emulgel (0.5 g/5 mg) following dermal administration to female guinea pigs were examined. A dose of 0.5 mL Diclofenac Sodium 4% Spray Gel or 0.5 g for Voltaren® Emulgel was selected for this study because a higher dose of 2 mL or 2 g resulted in mortality in a pilot photosensitivity study (% mortality at the end of Stage 1 in the pilot study: Group 3, 60%; Group 5, 40%; Group 7, 40%; Group 9, 20%). A positive control group was also included. The vehicle control, mid-dose diclofenac, and high-dose diclofenac) were applied to gauze patches (3 x 3.5 cm), which were applied to the application site (Day 1) and left on the skin for 72 h. The patches were removed (Day 4), and the animals were exposed to UV irradiation


for approx. 10 min using a mercury lamp. The procedure was repeated immediately: test item applied to neck on Day 4, and removal of patches followed by UV irradiation on Day 7.

In addition, four adjuvant injections were made to the 4 corners of the application site at 48 h intervals (Days 0, 2 and 4). For the second stage of induction (Stage 2), the skin was shaved on Day 10, patches with test item were applied to the neck on Day 11, patches were removed and the animals were exposed to UV irradiation on Day 14. For the challenge stage (Stage 3), the flank regions were depilated on Day 28 and patches were applied to the flanks on Day 32; test items to the left flank and placebo to the right flank. On Day 35, the patches were removed and the animals were exposed to UV irradiation. Skin reactions were evaluated 24 h after the end of each treatment period (Stages 1, 2 and 3). Both erythema and edema were graded on scales on 1 (slight) to 4 (maximum). This study was GLP compliant.

Diclofenac Sodium 4% Spray Gel (0.5 mL/20mg) and Voltaren Emulgel (0.5 g/5mg Diclofenac Sodium equivalent) did not show any photosensitizing properties under test conditions. A photosensitizing effect was observed in the positive control group treated with 2,2’-thiobis (4,6-dichlorophenol). Conclusion In the 90-day dermal toxicity study in mini-pigs, encrustation and inflammation of skin was noted at the application site in pigs treated with Diclofenac Sodium Spray Gel 4%, no other treatment-related findings were seen. Diclofenac Sodium Spray Gel 4%, showed no phototoxic or photosensitizing properties. There are no objections to approval of Diclofenac Spray Gel 4% from a non-clinical point of view. III.3 Clinical aspects Pharmacokinetics Diclofenac is well absorbed after oral administration and undergoes first-pass metabolism in the liver, only 60% of the absorbed dose reaching the general circulation. In the plasma, the drug is extensively protein bound (>99%). Quantitatively for topical applications of diclofenac (5g of 1% gel administered twice daily) it is estimated that the maximum plasma level is about 10%, and total AUC amounts correspond to 25 to 50% of the values seen after parenteral administration. The pharmacokinetics of diclofenac are well described in the literature. The Applicant has undertaken two pharmacokinetic studies which together demonstrate that diclofenac in the spray-gel formulation permeates through the skin to the target tissues in significantly greater amounts than is distributed to the systemic circulation. The amount of diclofenac that enters the systemic circulation is similar for both diclofenac 4% spray gel and Voltarol emulgel (containing diclofenac diethyammonium that is equivalent to 1% diclofenac sodium). The pharmacokinetic information proposed in the product information is adequate. Pharmacodynamics No new pharmacodymamic studies have been undertaken the pharmacology of diclofenac sodium, an NSAID, is well established. Diclofenac inhibits prostaglandin synthesis through inhibition of cyclo-oxygenase (COX). Diclofenac is a more potent inhibitor of COX-2 than COX-1 and has anti-inflammatory, analgesic and antipyretic activity. Some of the


metabolites of diclofenac have anti-inflammatory activity but are less potent than diclofenac. 4¢-Hydroxy-diclofenac, the major metabolite in man, has anti-inflammatory, analgesic and antipyretic activity but is 15-60 times less potent than diclofenac. Clinical efficacy The Applicant has submitted scientific literature and the results of a pivotal study to support this application. Study 9702 SUV P 9902 This was a double-blind, randomised, placebo-controlled, multi-centre study to assess the efficacy and safety of diclofenac 4% spray gel in the treatment of ankle injury. Main criterion for inclusion. Acute unilateral and uncomplicated ‘ankle distortion’ – swelling not less than 12 mm compared to the contralateral ankle. Endpoint. Objective measurement of swelling (50% decrease by day 10), marked with tattooing points and based on the ITT population. Further efficacy objectives were the decrease of spontaneous pain VAS and symptoms, pain on active movement, tenderness, the consumption of analgesics and global assessments of therapeutic efficacy by investigator and patients. Duration. Two weeks, measurements at days 3/4, 7/8, 10/11 and 14 +/- 1. Dose. Four to five actuations of the pump tds, corresponding to between 96 –160 milligrams diclofenac sodium or placebo (diclofenac spray gel vehicle) Results. One centre (centre 9) including 40 (20 active, 20 placebo) patients was excluded, having shown signs of false documentation. In the circumstances and as justified in the study final report it appears reasonable to exclude this group from the ITT efficacy analysis. Five other patients were excluded to leave the ‘Full Analysis Set’ with 97 patients on the active, and 94 on placebo. There was a trend towards less swelling in those patients on the ‘active’ medication at baseline, so this assessment was evaluated as relative change calculated as a percentage. The defined primary criterion response expressed as a decrease in swelling of at least 50% during 10 days of treatment for the ‘Full Analysis Set’ was reached in 87 of 97 patients (89.7%) treated with diclofenac spray gel compared to 74 of 94 treated with placebo (78.7%, p = 0.029 (one-tail) and p = 0.0467 (two-tail)). At each visit, there was also a statistically significant difference in favour of the diclofenac spray gel in terms of decrease in swelling. In all of the other efficacy measurements, there was either a clear trend or statistically significant difference favouring the test product over the placebo treatment. The active treatment was NOT associated with a decreased consumption of rescue medication.


The safety analysis was also conducted with the exclusion of the 40 patients from one centre, as it was concluded that these patients did not actually exist and had not received any trial medication. Seven adverse events occurred in six patients on diclofenac while eight events occurred in eight patients taking placebo. One patient from each group was prematurely withdrawn, moderate stomach pain being reported in one patient who had also resorted to taking oral diclofenac, whilst a case of flu occurred in the placebo group. Laboratory tests, including a minority of patients tested for the presence of blood in the stool, showed no clinically significant occurrences. The review of the literature presented in the clinical overview is cursory and is little more than a presentation of study summaries, and from this the quality is poor. However although the literature cited covers a wide range of study designs, and differing indications, formulations and dose, there is adequate evidence of the efficacy of topical formulations of diclofenac in the relief of pain and swelling. The original primary endpoint in the pivotal efficacy study that was undertaken to demonstrate that the results in the literature could be considered applicable to this formulation of diclofenac sodium used swelling as a primary endpoint, currently pain is considered to be the endpoint of choice. The clinical overview states that a post-hoc analysis of the results for the secondary endpoint spontaneous pain (measured by visual analogue scale) was conducted. A number needed to treat (NNT) analysis was undertaken the results of which were a relative benefit of 1.9 and a NNT of 3.9 and is comparable with that seen in the literature. In conclusion it is judged that the results of the efficacy study are sufficient to justify the use of literature to support the efficacy for this formulation. Clinical safety The Applicant has submitted safety data from eight studies, including 3 local tolerability studies and a study to assess systemic safety issues. A total of 524 subjects received diclofenac sodium 4% spray gel as part of its clinical development. Systemic Safety Study Study TD-04-01: This study compared the effects of 120mg/day diclofenac sodium 4% spray gel compared to 200 mg/day celecoxib, 1000 mg.day naproxen and placebo on prostaglandin synthesis in patients with acute gastro-duodenal injury. It was a single centre, randomised, double-blind, double-dummy, placebo controlled 3-way crossover study with a 14-21 day washout period between treatments. Following an overnight fast, qualifying subjects provided three blood samples for COX-1 (Thromboxane B2 assay), COX-2 (lipopolysaccharide stimulated prostaglandin E2 assay) and diclofenac plasma assays, and immediately underwent gastro-duodenal endoscopy at the baseline visit of each study period. Patients without significant endoscopic findings were dosed with double-blind study medication for 15 days. On return to the study site, blood samples and assays were repeated and patients underwent endoscopy and gastric biopsy for determination of gastric mucosal prostaglandin synthesis.


Forty-five subjects were to be enrolled. At least 24 subjects in the diclofenac/celecoxib/placebo crossover and at least 10 subjects in the naproxen/celecoxib/placebo crossover were required to complete the study. Fifty-one subjects were randomised into the study and received at least one dose of study medication. 39 subjects completed the study and were analysed (26 diclofenac/celecoxib/placebo, and 13 naproxen/celecoxib/placebo crossover).

Diclofenac spray gel had no effect on gastric prostaglandin synthesis, prostaglandin levels were significantly higher compared to celecoxib and naproxen.

No subjects developed ulcers. Only one subject developed an erosion while taking Diclofenac Sodium 4% Spray Gel (3.8%) compared to 7 (17.9%) for placebo, 4 (10.3%) for Celecoxib, and 10 (76.9%) for Naproxen, the majority of erosions were non-haemorrhagic.. Local tolerability investigations

Study PK 1-33: Skin assessments were performed by the investigators and subjects in this study to compare the local tolerability between Diclofenac Sodium 4% Spray Gel and Voltaren

® Emulgel (each

equivalent to 60 mg diclofenac sodium). Skin assessments of erythema, itching and burning arising at the application site were made out throughout the study in regular intervals. Good local tolerability was found in both treatment groups. For Diclofenac Sodium 4% Spray Gel, mild (4 cases) and moderate (1 case) erythema were seen in 2 subjects after the last drug application of the multiple-dose treatment; while for Voltaren

® Emulgel mild erythema (3

cases) were seen in 2 subjects after the single-dose application and mild itching was reported in one subject. None of these cases were regarded as adverse events. Study MD 0102: Skin assessments were performed in this study for the topical application of Diclofenac Sodium 4% Spray Gel by investigators using a 5 point scale ranging from 0 (no erythema, itching, or pain) to 4 (severe erythema and very severe itching or burning). No skin assessments were performed for the oral comparator, Voltaren 50 mg enteric coated tablets. The investigators reported only stage 1 (very slight erythema - barely perceptible) on the third day of administration in 3 subjects. In addition to skin assessments performed in studies PK 1-33 and MD 0102 results from 3 studies specifically designed to investigate local tolerability are presented (TD 04-06, TD 04-08 and TD 04-09). Study TD 04-06: Maximum use tolerance study. This study was designed to investigate the effect of long-term (28-days) use of diclofenac 4% spray gel (40 mg three times a day) on the skin. It was a single centre, open-label, repeat dose study. Subjects were instructed to apply five sprays of the diclofenac spray gel to the knee every 6 hours for 28 consecutive days. Detailed dermatological assessments were performed by trained individuals at weekly intervals. Sixty-two healthy volunteers were enrolled of whom sixty completed the study the median age was 62-years.


The primary safety endpoint was the percentage of subjects discontinuing form the study due to an application site reaction. A total of 40 application site reactions were recorder for 29 subjects, 25 were reported through dermatological findings versus subject reported. All reactions were rated as mild. 20 subjects had unresolved reactions by the end of the study or at the time of discontinuation. The most frequent observed (>10%) application site reactions were desquamation, dryness, erythema and follicular reaction. The most frequent subject-reported reactions were pruritis (9.7%), pain (3.2%) and parasthesia (3.2%). Two subjects were discontinued at week 3 due to application site reactions. Study TD-04-08: Human Repeat Insult Patch Study This was a repeat-dose, multiple treatment, randomised, assessor blinded study to determine the sensitisation potential of diclofenac 4% spray gel undertaken in 251 healthy volunteers (205 completed) There were three study phases, a 22-day induction phase, a 10-14 day rest phase and a 48-hour challenge phase. Following completion of the challenge phase, treatment was reapplied approximately 1 month later to subjects meeting the criteria for potential sensitisation. During the induction phase treatments were applied under occlusion to the same intra-scapular sites (days 1, 3, 5, 8, 10, 12, 15, 17 and 19). The application sites were evaluated for irritation on days 3, 5, 8, 10, 12, 15, 17, 19 and 22 by a qualified assessor who was blinded to the treatment applied to each site. During the challenge phase treatment was applied to previously unexposed areas under occlusion and removed 48-hours later, dermal reactions were evaluated immediately and 48-hours after removal of the patch. This was repeated during the rechallenge phase with the addition of a treatment under a semi-occlusive patch. Data was available from 230 subjects during the induction phase and 210 during the challenge phase. The mean irritancy scores for the challenge phase are presented below:

Confirmed sensitisation was observed in a single subject. Overall the characteristics of reactions during the challenge phase were more indicative of irritation as opposed to sensitisation. TD 04-09: 21 Day Cumulative Irritation Assay This study was performed to determine the irritancy potential of Diclofenac Sodium 4% Spray Gel compared to vehicle control and the marketed products Arthricare For Women Multi-Action (a preparation containing 0.025% capsaicin in addition to vitamins A and E available in the US) P P, and Speed StickP �P Regular Deodorant (US proprietary solid anti-perspirant,) as well as 0.2% sodium lauryl sulfate (SLS) as a positive control and saline as a negative control.


Each treatment and patch was applied to the same intra-scapular site (selected randomly) 5 days weekly, Monday through Friday, as follows: Days 1-5, 8-12, and 15-19. Including weekends, the total length of exposure to each treatment was 21 days. On Days 2-5, 8-12, 15-19, and 22, the application site was evaluated by a qualified skin assessor (at approximately the same time each day). The skin assessor was blinded as to the treatment applied to each site. If possible, each subject’s skin assessments were made by the same assessor throughout the study. A total of 41 subjects were exposed to medication of whom 37 subjects had irritation data. Diclofenac Sodium 4% Spray Gel was similarly irritating to vehicle and the Speed Stick P ® P

but was less irritating than SLS and ArthricareP� The overall safety profile of diclofenac sodium 4% spray gel is acceptable. There is a very low potential for systemic side effects and local tolerability appears satisfactory. Further reassurance is provided by the pharmacovigilance data that the Applicant has submitted. Pharmacovigilance system The RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan The applicant considers the submission of a risk management plan unnecessary, since the product is a well-established drug. The RMS agrees that no EU risk management plan is necessary. BENEFIT RISK ASSESSMENT Overall the benefit/risk assessment for KWIS 4% spray gel is considered favourable and approval is recommended.


IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT The important quality characteristics of KWIS Spray Gel 4% Cutaneous Spray, Solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. The efficacy data are presented in the form of a literature review and a single efficacy study, despite the differences in patient populations and study designs the results of the study are consistent with those in the presented literature and are sufficient to provide evidence that topical presentations of diclofenac, including this formulation are efficacious in the relief of pain and swelling following joint injury. The applicant has undertaken a comprehensive safety review including safety studies specifically addressing local tolerance and systemic safety, and a review of adverse reactions reported through pharmacovigilance systems. Based on the results of the studies, that show local tolerance is at least as good as similar preparations, that there is a low potential for sensitisation and systemic effects and on the review of pharmacovigilance data the safety profile is considered to be acceptable. No new or unexpected safety concerns arise from this application.

The SPC, PIL and labelling are satisfactory. The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with diclofenac sodium is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


Module 6

Steps taken after procedure

The following table lists some non-safety updates to the Marketing Authorisation for this product that have been approved by the MHRA since the product was first licensed. The table includes updates that are detailed in the annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

Date submitted

Application type

Scope Outcome

06/04/2011 Type IB variation

To change the name of the product in the UK from KWIS Spray Gel 4% Cutaneous

Spray, Solution to Voltarol Active 4% cutaneous spray

Approved 12/08/2011

14/11/2011 Type IB variation

To update section 5.1 (Pharmacodynamic properties) of the SmPC in order to support the dual action effect claim (in the UK only) as per the reference product SmPC. Consequently, the Patient Information Leaflet and product labels have also been updated.

Approved 01/02/2012


Annex 1 As these variations were classified as Type IB variations, no assessment reports were produced during the assessment process. Following approval of these variations on 12 August 2011 and 1 February 2012 the following updated SmPC, PIL and labels have been incorporated into Marketing Authorisation for Voltarol Active 4% cutaneous spray.


SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Voltarol Active 4% cutaneous spray

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1g of solution contains 40 mg of diclofenac sodium. Each pump stroke delivers 8 mg of diclofenac sodium. Excipients: Propylene glycol 150 mg/g Soy bean lecithin 100 mg/g For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cutaneous spray, solution. A golden-yellow, transparent solution (pH value: 6.5–7.6), which turns to a gel-like consistency after administration.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the local symptomatic relief of mild to moderate pain and inflammation following acute blunt trauma of small and medium-sized joints and periarticular structures.

4.2 Posology and method of administration

For cutaneous use only. Adults and adolescents aged 14 years and over Sufficient solution of Voltarol Active 4% cutaneous spray should be sprayed onto the skin of the affected site. Depending on the size to be treated, 4–5 pump strokes (0.8–1.0 g of spray containing 32–40 mg of diclofenac sodium) should be applied 3 times a day at regular intervals. The maximum single dose of 1.0 g of the product should not be exceeded. The maximum daily dose is 15 pump strokes (3.0 g of spray containing 120 mg of diclofenac sodium). Voltarol Active 4% cutaneous spray should be massaged gently into the skin. After this the hands should be washed unless they are the site to be treated. After application some minutes for drying should be allowed before dressing or binding the treated area. The treatment may be discontinued when the symptoms (pain and swelling) have subsided. Treatment should not be continued beyond 7 days without review. The patient is requested to consult the doctor if no improvement is seen after 3 days. Children and adolescents There are insufficient data on efficacy and safety available for children and adolescents below 14 years (see also contraindication section 4.3. In adolescents aged 14 years and over, if this product is required for more than 7 days for pain relief or if the symptoms worsen the patient/parents of the adolescent is/are advised to consult a doctor. Elderly The posology is the same as for adults.


Patients with hepatic or renal insufficiency For the use of Voltarol Active 4% cutaneous spray in patients with hepatic or renal insufficiency see section 4.4.

4.3 Contraindications

• Hypersensitivity to the active substance, peanut, soya or to any of the excipients. Hypersensitivity to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs)

• Patients with or without asthma in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents.

• The last trimester of pregnancy. • Application to the breast area of breast-feeding mothers. • Use in children and adolescents less than 14 years is contraindicated.

4.4 Special warnings and precautions for use

Contact with eyes and mucous membranes as well as oral use should be avoided. Voltarol Active 4% cutaneous spray should only be administered onto intact skin, not on open wounds or diseased skin areas. Patients should be warned against excessive exposure to sunlight in order to reduce the incidence of photosensitivity. If any rash develops administration should be discontinued. Not for use with occlusive dressings. The concomitant use of Voltarol Active 4% cutaneous spray with oral NSAIDs should be cautioned as the incidence of systemic undesirable effects may increase (see section 4.5). Where Voltarol Active 4% cutaneous spray is applied to a relatively large area of skin (i.e. more than 600 square centimetres of the body surface) and over a prolonged period (i.e. more than 4 weeks), the possibility of systemic undesirable effects cannot be completely excluded (for example, there is the potential for hypersensitivity, asthmatic and renal adverse reactions). Bronchospasm may be precipitated in patients suffering from or with previous history of bronchial asthma or allergenic disease. Voltarol Active 4% cutaneous spray should only be used with caution in patients with a history of peptic ulcer, hepatic or renal insufficiency, or bleeding diathesis, or inflammatory bowel disease, as isolated cases with topical diclofenac have been reported. Voltarol Active 4% cutaneous spray contains propylene glycol which may cause skin irritation. Voltarol Active 4% cutaneous spray contains peppermint oil which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

The systemic availability of diclofenac from this pharmaceutical presentation is very low. Hence the risk of interactions with other medicinal products is small. Concurrent acetylsalicylic acid or other NSAIDs may result in an increased incidence of adverse reactions (see section 4.4).

4.6 Pregnancy and lactation

There are no adequate data from the use of Voltarol Active 4% cutaneous spray in pregnant and breast-feeding women. Studies in animals have shown reproductive toxicity, however, no evidence of a malformative effect was observed with diclofenac (see 5.3). The potential risk for humans is unknown.


Use in pregnancy: During the last trimester of pregnancy, the use of prostaglandin synthetase inhibitors may result in: - pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with preterm

closing of the ductus arteriosus) - renal insufficiency in the foetus with oligohydramnios - inhibition of uterine contractions and prolongation of pregnancy and delivery - increased possibility of bleeding in the mother and child. Therefore, during the first six months of pregnancy, Voltarol Active 4% cutaneous spray should not be used unless clearly necessary and must not be applied to a large area of the skin (i.e. more than 600 square centimetres of the body surface). It must not be used for long-term treatment (> three weeks). Voltarol Active 4% cutaneous spray is contraindicated (see section 4.3) during the last trimester of pregnancy. Use during lactation: It is not expected that any measurable amount of diclofenac will occur in breast milk following topical application. However, NSAIDs are excreted in human milk. Therefore Voltarol Active 4% cutaneous spray is not recommended for use in breast-feeding mothers. An application to the breast area of breast-feeding mothers is contraindicated.

4.7 Effects on ability to drive and use machines

Voltarol Active 4% cutaneous spray has negligible influence on the ability to drive and use machines. Patients who experience dizziness or other central nervous disturbances while taking NSAIDs should refrain from driving or operating machinery, but this would be very unlikely using topical preparations.

4.8 Undesirable effects

Skin disorders are commonly reported. Skin: Application site reactions, rashes, pruritus and urticaria, drying, reddening, burning sensations, contact dermatitis. In a clinical trial 236 patients with ankle distortions were treated with 4–5 pump strokes of Voltarol Active 4% cutaneous spray 4% t.i.d. (120 patients) or placebo (116 patients) for 14 days. The following adverse drug reactions were reported:

System Organ class

Very common (≥ 1/10)

Common

(≥ 1/100, <1/10)

Uncommon (≥1/1,000, <1/100)

Rare (≥1/10,000,

<1/1,000

Very Rare (<1/10,000) not known (cannot be estimated from the available

data) Skin and subcutaneous tissue disorders

Pruritus 0.9 % Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration. The total single dose of product should not exceed 1.0 g (equivalent to 5 pump strokes) of spray.


Nevertheless during long term treatment (> three weeks) and/or when treating large areas (i.e. more than 600 square centimetres of the body surface) there is a possibility of systemic adverse reactions. Reactions like abdominal pain, dyspepsia, gastric and renal disorders may occur. In patients using topical NSAID preparations asthma has been reported rarely. In isolated cases generalised skin rash, hypersensitivity reactions such as angioedema and photosensitivity reactions have been reported.

4.9 Overdose During recommended use there is practically no risk due to overdose. If Voltarol Active 4% cutaneous spray has been accidentally administered orally, symptomatic treatment should be given.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiinflammatory preparations, non-steroids for topical use. ATC code: M02AA 15 Sodium diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has also analgesic properties. Diclofenac is a potent inhibitor of prostaglandin bio-synthesis and modulator of arachidonic acid release and uptake.

5.2 Pharmacokinetic properties

After cutaneous application of 1.5 g Voltarol Active 4% cutaneous spray, a rapid onset of diclofenac absorption can be observed leading to measurable plasma levels of about 1 ng/ml as early as 30 minutes and to maximum levels of about 3 ng/ml at about 24 hours after application. The achieved systemic concentrations of diclofenac are about 50 times lower than those achieved following oral administration of equivalent amounts of diclofenac. Systemic plasma levels are not supposed to contribute to the efficacy of Voltarol Active 4% cutaneous spray. Diclofenac is extensively bound to plasma proteins (about 99 %).

5.3 Preclinical safety data

In rabbit skin, Voltarol Active 4% cutaneous spray is classified as non-irritant. Non-clinical data based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential of diclofenac reveal no special hazard for humans beyond those already outlined in other sections of the SPC. In animal studies, chronic toxicity of diclofenac following systemic administration mainly took the form of gastrointestinal lesions and ulcers. In a 2-year toxicity study, rats treated with diclofenac showed a dose-dependent increase in thrombotic occlusion of the cardiac vessels. In rats and rabbits oral doses of diclofenac were not teratogenic but caused embryotoxicity at maternally toxic doses. Diclofenac did not affect fertility in rats but inhibited ovulation in rabbits and reduced implantation in rats. In rats, diclofenac resulted in dose-dependent constriction of the fetal ductus arteriosus, dystocia and delayed parturition (see section 4.3). Doses below the materno-toxic threshold had no influence on the postnatal development of the progeny.


6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Isopropyl alcohol Soybean lecithin Ethanol Disodium phosphate dodecahydrate Sodium dihydrogen phosphate dihydrate Disodium edetate Propylene glycol Peppermint oil (contains menthol and cineole) Ascorbyl palmitate Hydrochloric acid 10% (w/w) for pH adjustment Sodium hydroxide 10% (w/w) for pH adjustment Purified water.

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

3 years After first opening: 6 months

6.4 Special precautions for storage

Store in the original package. 6.5 Nature and contents of container

Glass bottle (Type III Ph.Eur.) with metering pump and protection cap. Pack sizes of 12.5 g solution (15 ml bottle) and 25 g solution (30 ml bottle). Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Novartis Consumer Health UK Limited Wimblehurst Road

West Sussex RH12 5AB UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00030/0445

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 29/08/2008


10 DATE OF REVISION OF THE TEXT

01/02/2012


PATIENT INFORMATION LEAFLET


LABELLING

Label:


Carton:

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