Document: spc-doc_PL 00030-0447 change

• spc-doc_PL 00030-0447
• spc-doc_PL 44673-0160

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Voltarol 12 Hour Emulgel 2.32% Gel or

Voltarol Extra Strength Emulgel 2.32% Gel

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Diethylammonium-{-o-[2,6-dichlorophenyl)-amino]-phenyl}-acetate.

100g of Voltarol® 12 Hour Emulgel 2.32% Gel contains 2.32g of the active substance diclofenac diethylammonium, which corresponds to 2g diclofenac sodium.

Excipients:    Propylene glycol (50 mg/g gel)

Buthylhydroxytoluene (0.2 mg/g gel).

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Gel

White to practically white, soft, homogeneous, cream-like gel.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the local symptomatic relief of pain and inflammation in:

trauma of the tendons, ligaments, muscles and joints, e.g. due to sprains, strains and bruises localised forms of soft tissue rheumatism

4.2 Posology and method of administration

Adults and children aged 14 years and over: Voltarol® 12 Hour Emulgel 2.32% Gel should be rubbed gently into the skin. Depending on the size of the affected site to be treated 2-4g (a circular shaped mass approximately 2.0-2.5cm in diameter) should be applied 2 times daily (preferably morning and evening). The maximum daily dose is 8g. Therefore the maximum weekly dose is 56g.

After application, the hands should be washed unless they are the site being treated.

If symptoms persist after 7 days or get worse at any time, medical advice should be sought.

Not to be used for more than 7 days unless recommended by a doctor.

Use in the elderly: The usual adult dosage may be used.

Children and adolescents: There are insufficient data on efficacy and safety available for the children and adolescents below 14 years of age (see also contraindications section 4.3). In children 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.

4.3 Contraindications

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

Hypersensitivity to diclofenac, acetylsalicylic acid or other non-steroidal antiinflammatory drugs.

Hypersensitivity to any other ingredient of the gel.

Concomitant use of oral NSAID's.

Voltarol® 12 Hour Emulgel 2.32% Gel should not be co-administered with other products containing diclofenac.

During the last trimester of pregnancy.

4.4 Special warnings and precautions for use

The possibility of systemic adverse events from application of Voltarol^® 12 Hour Emulgel 2.32% Gel cannot be excluded if the preparation is used on large areas of skin and over a prolonged period (see the product information on systemic forms of diclofenac).

Voltarol® 12 Hour Emulgel 2.32% Gel should be applied only to intact, non-diseased skin and not to skin wounds or open injuries. It should not be used with occlusion. It should not be allowed to come into contact with the eyes or mucous membranes, and should never be taken by mouth.

Patients with a history of, or active, peptic ulceration. Some possibility of gastro-intestinal bleeding in those with a significant history of this condition has been reported in isolated cases.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac and other NSAIDs can precipitate bronchospasm if administered to patients suffering from or with a previous history of asthma or allergic disease.

Discontinue if rash develops.

Information concerning excipients

Voltarol® 12 Hour Emulgel 2 .32% Gel contains propylene glycol, which may cause mild, localised skin irritation in some people. It also contains butylhydroxytoluene which may cause local skin reactions (e.g. contact dermatitis) or irritation to the eyes and mucous membranes.

4.5 Interaction with other medicinal products and other forms of interaction

Systemic absorption of diclofenac from topical application is very low and no drug interactions during treatment with Voltarol Emulgel have been reported, but the following have been observed with oral forms of diclofenac or other NSAIDs.

Lithium and digoxin: Voltarol may increase plasma concentrations of lithium and digoxin.

Anticoagulants: Although clinical investigations do not appear to indicate that Voltarol has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Antidiabetic agents: Clinical studies have shown that Voltarol can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.

Ciclosporin: Cases of nephrotoxicity have been reported in patients receiving concomitant cyclosporin and NSAIDs, including diclofenac. This might be mediated through combined renal antiprostaglandin effects of both the NSAID and cyclosporin.

Methotrexate: Cases of serious toxicity have been reported when methotrexate and NSAIDs are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSATD.

Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSATD.

Other NSAIDs and steroids: Co-administration of Voltarol with other systemic NSAIDs and steroids may increase the frequency of unwanted effects. Concomitant therapy with aspirin lowers the plasma levels of each, although no clinical significance is known.

Diuretics: Various NSAIDs are liable to inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, hence serum potassium should be monitored.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.

Anti-hypertensives: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

4.6 Fertility, pregnancy and lactation

Fertility

Treatment with Voltarol® 12 Hour Emulgel 2.32% Gel is unlikely to have an adverse effect on fertility because the systemic exposure to diclofenac after application of Voltarol® 12 Hour Emulgel 2.32% Gel is low.

Pregnancy

The systemic concentration of diclofenac is lower after topical administration, compared to oral formulations. With reference to experience from treatment with NSAIDs with systemic uptake, the following is recommended:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to:

-    cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

-    renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

The mother and the neonate, at the end of pregnancy, to:

-    possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

-    inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, diclofenac is contraindicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. However, at therapeutic doses of Voltarol® 12 Hour Emulgel 2.32% Gel no effects on the suckling child are anticipated. Because of a lack of controlled studies in lactating women, the product should only be used during lactation under advice from a healthcare professional. Under this circumstance, Voltarol® 12 Hour Emulgel 2.32% Gel should not be applied on the breasts of nursing mothers, nor elsewhere on large areas of skin or for a prolonged period of time (see section 4.4).

4.7    Effects on ability to drive and use machines

Voltarol® 12 Hour Emulgel 2.32% Gel has no or negligible influence on the ability to drive and use machines.

4.8    Undesirable effects

Undesirable effects include mild and passing skin reactions at the site of application. In very rare instances, allergic reactions may occur.

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: very common (> 1/10) common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following additional side-effects have been observed with oral forms of diclofenac.

Gastro-intestinal tract

Occasional: Epigastric pain, other gastro-intestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia).

Rare: Gastro-intestinal bleeding, peptic ulcer (with or without bleeding or perforation), bloody diarrhoea.

In isolated cases: Lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations of ulcerative colitis or Crohn's proctocolitis, colonic damage and stricture formation), pancreatitis, aphthous stomatitis, glossitis, oesophageal lesions, constipation.

Central Nervous System:

Occasional: Headache, dizziness, or vertigo.

Rare: Drowsiness, tiredness.

In isolated cases: Disturbances of sensation, paraesthesia, memory disturbance, disorientation, disturbance of vision (blurred vision, diplopia), impaired hearing. Tinnitus, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions. Taste alteration disorders.

Skin:

Occasional: Rashes or skin eruptions.

Rare: Urticaria.

In isolated cases: Eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, (acute toxic epidermolysis), photosensitivity reactions, erythroderma (exfoliative dermatitis), loss of hair, purpura including allergic purpura.

Kidney:

In isolated cases: Acute renal failure, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.

Liver:

Occasional: Elevation of serum aminotransferase enzymes (ALT, AST).

Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.

Blood:

In isolated cases: Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

Hypersensitivity:

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of rare cases of anaphylactic/anaphylactoid systemic reactions including hypotension, and respiratory tract reactivity comprising

asthma, aggravated asthma, bronchospasm or dyspnoea. (See also “Skin”).

Other organ systems:

Rare: Oedema

Isolated cases: Impotence (association with diclofenac is doubtful), palpitation, chest pain, hypertension.

4.9 Overdose

The low systemic absorption of topical diclofenac renders overdose very unlikely.

However undesirable effects, similar to those observed following an overdose of Voltarol tablets, can be expected if Voltarol® 12 Hour Emulgel 2.32% Gel is inadvertently ingested (e.g. 1 tube of 50 g contains the equivalent of 1 g diclofenac sodium.)

In the event of accidental ingestion, resulting in significant systemic adverse effects, general therapeutic measures normally adopted to treat poisoning with non-steroidal anti-inflammatory medicines should be used. Gastric lavage and the use of activated charcoal should be considered, especially within a short time of ingestion.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Topical products for joint and muscular pain. Antiinflammatory preparations, non-steroids for topical use, ATC code: M02A A15 Mechanism of action and pharmacodynamic effects:

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) with pronounced analgesic, anti-inflammatory and antipyretic properties. Inhibition of prostaglandin synthesis is the primary mechanism of action of diclofenac. Voltarol® 12 Hour Emulgel 2.32% Gel is an anti-inflammatory and analgesic preparation designed for topical application. In inflammation and pain of

traumatic or rheumatic origin, Voltarol® 12 Hour Emulgel 2.32% Gel relieves pain, decreases swelling, and shortens the time to return to normal function.

In one ankle sprain study (VOPO-P-307), Voltarol® 12 Hour Emulgel 2.32% Gel significantly decreased pain on movement scores versus placebo treated subjects within three days of starting treatment, including a subgroup of patients with severe pain. In addition treatment with Voltarol® 12 Hour Emulgel 2.32% Gel also significantly improved ankle joint function within 3 days of beginning treatment.

Due to an aqueous-alcoholic base the gel also exerts a cooling effect.

5.2 Pharmacokinetic properties Absorption

The quantity of diclofenac absorbed through the skin is proportional to the size of the treated area, and depends on both the total dose applied and the degree of skin hydration. After topical application to approximately 400 cm of skin, the extent of systemic exposure as determined by plasma concentration of Voltarol® 12 Hour Emulgel 2.32% Gel (2 applications/day) was equivalent to diclofenac 1.16% gel (4 applications/day). The relative bioavailability of diclofenac (AUC ratio) for Voltarol® 12 Hour Emulgel 2.32% Gel versus tablet was 4.5% on day 7 (for equivalent diclofenac sodium dose). Absorption was not modified by a moisture and vapour permeable bandage.

Distribution

Diclofenac concentrations have been measured from plasma, synovial tissue and synovial fluid after application of topical diclofenac to hand and knee joints. Maximum plasma concentrations were approximately 100 times lower than after oral administration of the same quantity of diclofenac. 99.7 % of diclofenac is bound to serum proteins, mainly albumin (99.4 %).

Diclofenac penetrates inflamed areas, preferentially distributing to and persisting in deep inflamed tissues such as joints, where it is found in concentrations up to 20 times higher than in plasma.

Biotransformation

Biotransformation of diclofenac involves partly glucuronidation of the intact molecule, but mainly single and multiple hydroxylation resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of the phenolic metabolites are biologically active, however, to a much smaller extent than diclofenac.

Elimination

The total systemic clearance of diclofenac from plasma is 263 ± 56 ml/min. The terminal plasma half-life is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a longer half-life but is virtually inactive. Diclofenac and its metabolites are excreted mainly in the urine.

Characteristics in patients

No accumulation of diclofenac and its metabolites is to be expected in patients suffering from renal impairment. In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical safety data

Voltarol® 12 Hour Emulgel 2 .32% Gel was well tolerated in a variety of studies. There was no potential for phototoxicity and diclofenac-containing gel caused no skin sensitisation or irritation.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Butylhydroxytoluene

Carbomers

Cocoyl caprylocaprate Diethylamine Isopropyl alcohol Liquid paraffin Macrogol cetostearyl ether Oleyl alcohol Propylene glycol Perfume eucalyptus sting Purified water

6.2 Incompatibilities

None Stated

6.3 Shelf life

Three years

6.4 Special precautions for storage

Do not store above 30°C.

Voltarol® 12 Hour Emulgel 2.32% Gel should be kept out of reach and sight of children.

6.5 Nature and contents of container

Aluminium laminated tube [low density polyethylene / aluminium / high density polyethylene (internal layer)] fitted with a high density polyethylene shoulder and closed by a moulded seal. The tube is closed with a polypropylene screw cap, incorporating a moulded feature used to insert, twist and remove the seal before first use.

Pack sizes: 20g, 30g, and 50g Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Novartis Consumer Health UK Ltd.

Trading as Novartis Consumer Health Watchmoor Park, Camberley Surrey GU15 3YL UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 00030/0447

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 20/03/2013

10 DATE OF REVISION OF THE TEXT

20/03/2013