Voltarol Pain-Eze Tablets

Document: spc-doc_PL 44673-0162 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Voltarol Pain-eze Tablets Or

Voltarol Joint Pain 12.5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5mg diclofenac potassium. For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

White capsule-shaped film-coated tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Short term relief of headache, dental pain, period pain, rheumatic pain, muscular pain and backache and the symptoms of colds and flu, including fever.

4.2 Posology and method of administration

Adults and children aged 14 years and over:

Initially two tablets, followed by one or two tablets every 4 to 6 hours as needed. No more than 6 tablets (75 mg) should be taken in any 24 hour period.

Voltarol Pain-eze Tablets should not be used for longer than 3 days. If symptoms persist or worsen consult your doctor.

The tablets should be swallowed whole with a drink of water.

Children and Adolescents:

Voltarol Pain-eze Tablets are not to be used in children and adolescents under 14 years of age.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use).

4.3 Contraindications

• Known hypersensitivity to diclofenac or to any of the excipients. Patients in whom attacks of asthma, urticaria, angioedema, or acute rhinitis are precipitated by aspirin or other non-steroidal anti-inflammatory drugs such as ibuprofen.

• Gastric or intestinal ulcer, bleeding or perforation.

• Pregnancy or breastfeeding (see section 4.6 Pregnancy and lactation).

• Severe hepatic or renal failure (see section 4.4 Special warnings and special precautions for use).

• Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease

• Concomitant use of anticoagulants and antiplatelets (see section 4.5 Interactions)

• Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see section 4.5 Interactions)

4.4 Special warnings and precautions for use

Warnings

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occur in patients receiving diclofenac, the medicinal product should be withdrawn.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (see section 4.8 Undesirable effects). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur in rare cases without earlier exposure to diclofenac.

In common with other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Precautions

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and Cardiovascular risks below).

The concomitant use of diclofenac with systemic NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.

Caution is indicated in the elderly. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.

Voltarol Pain-eze Tablets contain lactose and therefore are not recommended for patients with rare hereditary problems of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAIDs therapy (see Renal effects below).

Pre-existing asthma

In patients with asthma, seasonal allergic rhinitis, swelling of nasal mucosa (i.e. nasal polypus), chronic obstructive pulmonary disease or chronic infection of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs such as asthma exacerbations (so-called intolerance to analgesics / analgesics-asthma), angioedema or urticaria are more frequent than in other patients.

Gastrointestinal effects

As with all NSAIDs, close medical surveillance is imperative and caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly.

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Close medical surveillance should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) should only be treated with diclofenac after careful consideration.

As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically. Patients should be advised to seek further medical advice if symptoms persist or do not improve within the recommended duration of treatment.

Clinical trial and epidiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150 mg daily) and in long-term treatment. Available data do not suggest an increased risk with use of low dose diclofenac (up to 75 mg/day) up to 3 days for relief of pain or fever.

Hepatic effects

Close medical surveillance is required when prescribing diclofenac to patients with impaired hepatic function, as their condition may be exacerbated.

As with other NSAIDs, values of one or more liver enzymes may increase. In the case of diclofenac being prescribed for a prolonged period, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), diclofenac should be discontinued. Hepatitis may occur without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects

Caution is called for in patiens with impaired renal function, particularly the elderly and patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function and in those patients with substantial extracellular volume depletion.

As fluid retention and oedema have been reported in association with NSAID therapy, particular caution is called for in elderly patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pretreatment state.

Haematological effects

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.

Dermatological effects

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Voltarol Pain-eze Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will state:

Read the enclosed leaflet before taking this medicine.

Do not take if you:

• have or have ever had a stomach ulcer, perforation or bleeding

• are allergic to diclofenac or any other ingredient of the product, acetylsalicylic acid, ibuprofen or other related painkillers

• are taking other NSAID painkillers, or aspirin

• are pregnant or breastfeeding

Speak to a pharmacist or your doctor before taking this product if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, liver, heart, kidney or bowel problems

• are intolerant to some sugars

• are on a controlled potassium diet • are a smoker

If symptoms persist or worsen, consult your doctor.

4.5 Interaction with other medicinal products and other forms of interaction

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

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and special precautions for use).

Other NSAIDs: including cyclooxygenase-2 selective inhibitors and corticosteroids:

Co-administration of diclofenac with aspirin or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and special precautions for use).

Selective serotonin reuptake inhibitors (SSRIs) and anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and special precautions for use).

Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. Monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Caution is recommended when NSAIDs are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.

Ciclosporin and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin or tacrolimus.

Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

4.6 Pregnancy and lactation

Pregnancy

The use of diclofenac in pregnant women has not been studied. Therefore, Voltarol Pain-eze Tablets should not be used during pregnancy except on the advice of a doctor.

Lactation

Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Voltarol Pain-eze Tablets should not be administered during breast feeding in order to avoid undesirable effects in the infant.

Fertility

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered.

4.7 Effects on ability to drive and use machines

Usually there is no effect at the recommended low-dose and short duration of treatment. However patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac should refrain from driving or using machines.

4.8 Undesirable effects

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Available data do not suggest an increased risk with use of low dose diclofenac (up to 75 mg/day) for up to 3 days treatment for the relief of pain or fever.

Table1

Blood and lymphatic system disorders
Very rare:	Thrombocytopenia, leukopenia, anaemia (including haemolytic anaemia and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare:	Hypersensitivity, anaphylactic and anaphylactoid reaction (including hypotension and shock).
Very rare:	Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare:	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common:	Headache, dizziness.
Rare:	Somnolence.
Very rare:	Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
Eye disorders
Very rare:	Visual disturbance, vision blurred, diplopia.
Ear and labyrinth disorders
Common:	Vertigo.
Very rare:	Tinnitus, hearing impaired.
Cardiac disorders
Very rare:	Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare:	Hypertension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare:	Asthma (including dyspnoea).
Very rare:	Pneumonitis.
Gastrointestinal disorders
Common:	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare:	Gastritis, gastrointestinal haemorrhage, Haematemesis, diarrhoea, hemorrhagic melaena, gastrointestinal ulcer (with or without bleeding or perforation).
Very rare:	Colitis, (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatobiliary disorders
Common:	Transaminases increased.
Rare:	Hepatitis, jaundice, liver disorder.
Very rare:	Fulminant hepatitis
Skin and subcutaneous tissue disorders
Common:	Rash.
Rare:	Urticaria.
Very rare:	Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.

Renal and urinary disorders
Very rare:	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Rare:	Oedema.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment. (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).

4.9 Overdose

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdose can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures

Management of acute poisoning with NSAIDs essentially consists of supportive measures and symptomatic treatment. These should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to the high protein binding and extensive metabolism.

Activated charcoal may be considered in case of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) in case of a potentially life-threatening overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, acetic acid derivatives and related substances (ATC code M01A B05).

Voltarol Pain-eze Tablets contain diclofenac potassium, a non-steroidal antiinflammatory drug (NSAID) with pronounced analgesic, anti-inflammatory and antipyretic properties. Inhibition of prostaglandin biosynthesis is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain and fever.

Diclofenac potassium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.

5.2 Pharmacokinetic properties

Absorption

Diclofenac is rapidly and completely absorbed. Following ingestion of two 12.5 mg coated tablets, mean peak plasma concentrations of 2.15 pmol/L are attained after approximately 30 minutes (median Tmax).

The amount absorbed is in linear proportion to the size of the dose.

Since about half of diclofenac is metabolised during its first passage through the liver (“first pass” effect), the area under the concentration curve is about half as large following oral administration as it is following a parenteral dose of equal size.

Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.

Distribution

99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution is 0.12 to 0.17 L/kg.

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.

Biotransformation

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min. The terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. A fifth metabolite, 3’-hydroxy-4’-methoxy-diclofenac, has a much longer plasma half-life. This metabolite is virtually inactive.

About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

No relevant age-dependent differences in the drug’s absorption, metabolism, or excretion have been observed.

In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

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

Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity, and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses. There was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core: silica, lactose, maize starch, sodium starch glycolate, polyvidone, microcrystalline cellulose, magnesium stearate.

Coating: hypromellose, titanium dioxide (E171), microcrystalline cellulose, stearic acid.

6.2 Incompatibilities

Not applicable

6.3

Shelf life

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/Polychlorotrifluoroethylene/PVC - Alu blister packs. Polyamide/ALU/PVC - Alu blister packs.

Pack size: 10 or 18 tablets, not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

GlaxoSmithKline Consumer Healthcare (UK) Trading Limited,

980 Great West Road Brentford Middlesex TW8 9GS United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 44673/0162

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

30/08/2016