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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Dicuno 25 mg film-coated tablets

Dicuno 50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

25 mg: Each tablet contains 25 mg of diclofenac potassium.

50 mg: Each tablet contains 50 mg of diclofenac potassium.

50 mg:

Excipient: colouring agent Ponceau 4R aluminium lake (E 124).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet.

25 mg: Tablets are light red, round and convex tablet with a score on one side. Diameter is 8 mm.

50 mg: Tablets are reddish-brown, round and convex tablet with a score line on one side. Diameter is 10 mm.

The tablet can be divided into equal doses.

4. Clinical particulars

Symptomatic treatment of acute pain of mild to moderate intensity. Symptomatic treatment of acute migraine headaches.

Posology

Adults

25-50 mg 3 times daily. The maximum recommended daily dose is 150 mg. In migraine an initial dose of 50 mg should be taken at the first signs of an impending attack. In cases where relief 2 hours after the first dose is not sufficient, a further dose of 50 mg may be taken. If needed, further doses of 50 mg may be taken at intervals of 4-6 hours, not exceeding a total dose of 150 mg per day.

Impaired hepatic or renal function

Diclofenac is contraindicated in patients with severe hepatic or renal impairment (see section 4.3). Caution and careful monitoring is advised in patients with mild to moderate renal and hepatic impairment (see section 4.4). The lowest effective dose should be given.

Elderly patients

The aim should be to administered the lowest effective dose (see section 4.4).

Paediatric patients

Diclofenac should not be given to children and adolescents under 18 years of age.

Monitoring of treatment

In the case of long-term treatment with diclofenac, laboratory blood values and liver and kidney function should be monitored.

Method of administration

Oral use.

Treatment should begin at the lowest expected effective dose, with subsequent adjustment on the basis of therapeutic response and any side-effects. Undesirable effectsmay 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). With long-term treatment, a low maintenance dose should be aimed for.

To obtain maximal effect, the tablets should not be taken with a meal or directly after a meal.

4.3 Contraindications

• Hypersensitivity to the active substance or any of the excipients, listed in section 6.6.

• Active gastric/duodenal ulcer, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

• History of gastrointestinal bleeding or perforation, related to previous NSAID therapy.

• Conditions giving an increased tendency to bleeding.

• Severe hepatic impairment.

• Hepatic porphyria.

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

• Severe renal impairment (glomerular filtration <30 ml/min).

• The third trimester of pregnancy.

Due to cross-reaction, the medicinal product should not be given to patients, especially asthmatics, who have experienced symptoms of asthma, rhinitis or urticaria after taking aspirin or other nonsteroidal anti-inflammatory drugs.

4.4 Special warnings and precautions for use

Warnings

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal effects

Gastrointestinal bleeding, ulceration or perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The consequences are often more severe in the elderly. When GI bleeding or ulceration occurs in patients receiving diclofenac, treatment should be withdrawn. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild heart failure (NYHA I) as fluid retention and oedema have been reported in association with NSAID therapy.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, 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.

Serious skin reactions

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 the 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. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Other

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur

without earlier exposure to the drug.

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of diclofenac in case of varicella.

As with other NSAIDs, the pharmacodynamic properties of diclofenac mean that it can mask the signs or symptoms of infection.

Precautions

The use of diclofenac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. Elderly patients are also more likely to suffer from impaired renal, heart or liver function.

Gastrointestinal effects

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose of acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).

As with other analgesics, the following applies: if patients with acute abdominal pain are repeatedly given pain relief, this can modify or disguise the pattern of symptoms of associated complications such as perforation.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8).

Effects on the airways

Caution should be exercised when treating patients with asthma, rhinitis,chronic obstructive pulmonary disease or chronic airway inflammation (especially when associated with symptoms of rhinitis) because reactions to NSAIDs, like asthma exacerbation, urticaria or Quinke’s oedema are more common in these patients. This also applies in patients who are allergic to other substances, for example in form of skin reactions, pruritus or urticaria.

Renal effects

Due to reported fluid retention and oedema in association with treatment with NSAIDs, including diclofenac, special care should be taken when patients with impaired heart or kidney function, history of hypertension and elderly are treated. Because of same reason caution should be taken with concomitant treatment with diuretics or nephrotoxic medicines, for example ciclosporin. The risk of fluid retention and of deterioration of renal function must be taken into account in patients who have lost large extracellular volumes during, for example, the perioperative or postoperative phase of major surgical procedures (see also sections 4.3 and 5.2).

Hepatic effects

As with other NSAIDs, serious hepatic damages have been reported in association with diclofenac treatment (see section 4.8).

Patients with impaired liver function should be carefully monitored when treated with diclofenac as the condition may be exacerbated. Caution is called for when using Diclofenac in patients with hepatic porphyria, since it may trigger an attack.

As with other NSAIDs the level of one or several liver enzyme values can be elevated in association with treatment with diclofenac. As safety precaution, liver function should be regularly controlled in long term treatment with diclofenac. The treatment should be discontinued if abnormal liver enzyme values remain or worsen, or if signs of liver effects or other symptoms occur (for example eosinophilia, rash).

Hepatitis may appear without prodromal symptoms.

Treatment with NSAIDs in patients with chronic liver disease should if possible be avoided due to possible increased risk of GI bleeding.

Haematologic effects

As other NSAIDs, diclofenac can temporarily inhibit thrombocyte aggregation. Patients with disturbances in hematopoiesis and coagulation should therefore be carefully monitored. In long term treatment blood status should be regularly controlled.

Other

Patients with SLE should be kept under careful monitoring when treated with diclofenac.

Patients who are being treated with oral anticoagulants or antidiabetics should be monitored with respect to overdose in the event of concomitant treatment with diclofenac. Laboratory tests should be carried out in order to check that the desired effect of anticoagulants is maintained. Isolated cases of hypoglycaemia and of hyperglycaemic effects that require dose adjustment of antidiabetic agents have been reported.

NSAIDs can inhibit the diuretic effect and enhance the potassium-sparing effect of diuretics, which makes it necessary to check serum potassium levels.

50 mg:

This product contains colouring agent Ponceau 4R aluminium lake (E 124) that may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4). NSAID preparations inhibit platelet aggregation and damage the mucous membrane of the gastrointestinal tract.

Anticoagulants

NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4). Diclofenac can inhibit the metabolism of warfarin and in this way increase levels of warfarin in plasma. The risk of haemorrhaging is higher in patients who are taking anticoagulants and being treated concomitantly with diclofenac. There is a serious risk of bleeding stomach ulcer with the concomitant administration of NSAID preparations and anticoagulants. This combination should be avoided.

Heparin (parenteral administration)

An increased risk of bleeding (inhibition of platelet function and increased gastrointestinal side effects of NSAIDs).

Pentoxifylline

Increased risk of bleeding: increased clinical monitoring and check of bleeding times are recommended.

Zidovudine

Increased risk of bleeding in HIV-positive haemophiliac patients.

Antihypertensive agents

Anti-inflammatory agents of the NSAID type counteract the antihypertensive effects of beta-blockers and ACE inhibitors. It may be necessary, therefore, to adjust the dose of antihypertensive agents. Concomitant treatment with NSAIDs and ACE inhibitors increases the risk of acute renal insufficiency.

Angiotensin II antagonists

NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g.dehydrated patients or elderly patients) when angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Other NSAIDs

Concomitant systemic administration of other NSAIDs should in general be avoided due to the increased risk of undesirable effects.

Quinolones

Convulsions may occur as a consequence of interactions between quinolones and NSAIDs. They can occur in patients with or without a previous history of epilepsy or convulsions. For this reason care should be taken when considering the administration of quinolones to patients already taking NSAIDs.

Oral antidiabetics

Clinical trials have shown that diclofenac does not influence the effect of antidiabetic agents, although there have been isolated reports of hypoglycaemia and hyperglycaemia that have required dose adjustment.

Corticosteroids

Concomitant treatment with diclofenac with corticosteroids can increase the risk of gastrointestinal bleeding.

Phenytoin

When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Pharmacokinetic interactions

Effects of diclofenac on the pharmacokinetics of other drugs:

Methotrexate

NSAIDs inhibit the tubular secretion of methotrexate, leading to increased plasma concentrations. High-dose treatment with methotrexate should be avoided with concomitant diclofenac treatment. Care should be observed during concomitant low-dose treatment and patients should be monitored with respect to methotrexate-related toxicity.

Lithium

Diclofenac reduces the renal clearance of lithium by about 20% and thus increases serum lithium levels. It may be necessary to adjust the lithium dose. The combination should be avoided unless frequent checks of serum lithium can be carried out at the time of the introduction and the discontinuation of the treatment.

Ciclosporin and tacrolimus

A relatively high frequency of nephrotoxicity (increasing levels of serum creatinine) with increasing blood pressure has been observed during concomitant treatment with diclofenac and ciclosporin (for rheumatoid arthritis). It is probable that the risk is present during concomitant treatment with tacrolimus. The dose of diclofenac should be halved if combination treatment is given.

Digoxin

Trials in healthy subjects show that the introduction of diclofenac in persons being treated with digoxin results in increased plasma levels of digoxin. Plasma digoxin levels should be monitored when instituting diclofenac and when discontinuing treatment, since adjustment of the dose may be necessary.

Effects of other drugs on the pharmacokinetics of diclofenac:

Drugs that inhibit or induce the enzyme CYP2C9

The metabolism of diclofenac is catalysed by the enzyme CYP2C9. Concomitant treatment with drugs (such as fluconazole) that inhibit this enzyme probably lead to higher concentrations of diclofenac in plasma. Drugs such as rifampicin, carbamazepine and barbiturates, which induce CYP2C9 activity, can reduce the plasma concentration of diclofenac to subtherapeutic levels. Diazepam, which is metabolised via CYP2C9, increases the plasma concentration of diclofenac by 50-100%.

Colestipol and colestyramine

Concomitant administration of diclofenac with colestipol or colestyramine reduces the absorption of diclofenac by about 30% (colestipol) and 60% (colestyramine). These agents should be given separated by a period of several hours.

4.6 Fertility, pregnancy and lactation

Fertility

As with other NSAIDs, the use of Diclofenac may impair femalefertility and isnot recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigationof infertility, withdrawal of Diclofenac should be considered.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal 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 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 postimplantation 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 organogenic 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 after very low doses.

• Inhibition of uterine contractions resulting in delayed or prolonged labour.

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

Breast-feeding

Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Diclofenac should not be administered during breastfeeding in order to avoid undesirable effects in the infant.

4.7 Effects on ability to drive and use machines

The ability to react may be reduced in certain patients treated with diclofenac. This should be born in mind when increased concentration is required, e.g.when driving a car.Patients who experience dizziness, drowsiness, fatigue or visual disturbances, while taking NSAIDS should refrain from driving or operating machinery.

Gastrointestinal problems can occur at the start of treatment in approximately 10% of patients. These undesirable effects normally disappear after a few days, even if treatment is continued.

Peptic ulcers, perforation of GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Such problems can occur at any time during treatment, with or without warning symptoms and with or without previous history of disease.

Diclofenac temporarily inhibits platelet aggregation, which may lead to increased risks in patients with various bleeding conditions.

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed.

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).

The frequency classification of adverse effects is following:

• 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), not known (cannot be estimated from the available data)

The following undesirable effects include those reported with either short-termor long-term use:

Blood and lymphatic system
Very rare	Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), Agranulocytosis
Immune system disorders
Rare Very rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common Rare Very rare	Headache, dizziness. Somnolence. 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 Very rare	Vertigo. 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 Very rare	Asthma (including dyspnoea). Pneumonitis.
Gastrointestinal disorders
Common Rare Very rare	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia. Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding or perforation). Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, Stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancereatitis.
Hepatobiliary disorders
Common Rare Very rare	Transamines increased. Hepatitis, jaundice, liver disorder. Fulminant hepatitis, hepatic necrosis, hepatic failure
Skin and subcutaneous tissue disorders
Common Rare Very rare	Rash. Urticaria. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

4.9 Overdose

Doses more than 300 mg could be toxic. Administration of 50 mg to children aged 1-3 years gave no or only mild intoxication. Administration of 150 mg followed by activated charcoal tablets to a 2-year-old gave mild intoxication. Administration of 325 mg to an adult gave moderate intoxication. Administration of 2.8 g during one week resulted in intestinal perforation of an adult, 2 g to an adult gave renal effects.

Symptoms

Nausea, vomiting, abdominal pain, gastrointestinal haemorrhage, diarrhea. Dizziness, somnolence, headache, tinnitus, anxiety, hallucinations, convulsions (in children also myoclonic seizures), unconsciousness. Renal effects. Liver effects. Tendency to oedema, possibly also metabolic acidosis. Further, hypotension, respiratory depression, and cyanosis might occur.

Treatment

If justified: emptying of the stomach, charcoal. Antacids if required, which may be supplemented with sucralfate. Ensure efficient diuresis. Symptomatic treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Non-steroidal antiinflammatory/antirheumatic drugs (NSAIDs), acetic acid derivatives and related substances. ATC Code: M01AB05

Dicuno contains the potassium salt of diclofenac, a non-steroidal substance with anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin synthesis has been shown experimentally to be an important component of the mechanism of action. Prostaglandins play a prominent role in inflammation, pain and fever. This means that diclofenac also inhibits platelet aggregation. Diclofenac exhibits anti-inflammatory and analgesic properties in rheumatic diseases, clinically manifested as relief of symptoms such as pain when resting and in motion, early morning stiffness and swollen joints. These properties are also manifested as improvement in function. Diclofenac has been shown in clinical trials to relieve pain and reduce blood volumes in primary dysmenorrhoea.

Diclofenac inhibits renal prostaglandin synthesis. This effect is not significant in patients with normal renal function. The inhibition of prostaglandin synthesis can, however, lead to acute renal insufficiency, fluid retention and heart failure in patients with chronic renal, cardiac or liver insufficiency and with conditions that change plasma volume (see section 4.3).

5.2 Pharmacokinetic properties

Diclofenac is rapidly and completely absorbed from diclofenac potassium tablets.Peak plasma concentration after one 50 mg tablet was approximately 1 µg/ml (approximately 4 µmol/l) after 20-60 minutes. The rate of absorption may be diminished for diclofenac upon administration with food.

The peak concentration of diclofenac in the synovial fluid is reached 2-4 hours after peak plasma concentration. Half-life in synovial fluid is 3-6 hours. The concentration of active substance is higher in the synovial fluid than in plasma just 4-6 hours after intake and remains higher for up to 12 hours.

Diclofenac has a serum protein binding rate of 99.7% and binds primarily to albumin (99.4%).

The active substance is eliminated from plasma with a total clearance of 263 ± 56 ml/min. The half-life is 1-2 hours.

The biotransformation of diclofenac involves simple and multiple hydroxylation and glucuronidation. Approximately 60% of the dose is eliminated in urine in the form of metabolites. Less than 1 % is excreted unchanged. The rest of the dose is eliminated as metabolites in bile and faeces.

The pharmacokinetic properties are unchanged following repeated administration. No accumulation occurs in the recommended dosage interval.

The age of the patient has no effect on the absorption, metabolism or excretion of diclofenac.

In patients with impaired kidney function, no accumulation of the unchanged active substance has been seen following a single dose. With a creatinine clearance of less than 10 ml/min, the theoretical plasma level of metabolites at steady state is approximately four times as high as in healthy volunteers.

The metabolites are excreted in bile.

In patients with impaired liver function (chronic hepatitis, uncompensated cirrhosis), the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical safety data

Based on conventional studies on safety pharmacology, genotoxicity and carcinogenic potential, the preclinical data do not show any particular hazards for man exceeding those already described in other sections of the SPC. In animal studies, the chronic toxicity of diclofenac took the form mainly of lesions and ulcers in the gastro-intestinal tract. In a two-year toxicity study, a dose-dependent increase in the incidence of thrombosis of the heart was observed in diclofenac-treated rats.

In experimental animal studies on reproductive toxicity, diclofenac caused an inhibition of ovulation in rabbits as well as impairment of implantation and early embryonic development in rats. Gestation period and parturition time were prolonged by diclofenac. The embryotoxic potential of diclofenac was studied in three animal species (rat, mouse, rabbit). Fetal demise and growth retardation occurred at maternotoxic dose levels.Doses below the materno-toxic threshold had no influence on the postnatal development of the progeny.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline (maize)

Calcium hydrogen phosphate dihydrate

Starch, pregelatinized

Croscarmellose sodium

Silica, colloidal anhydrous

Magnesium stearate

Tablet coating:

Polyvinyl alcohol

Macrogol

Talc

Titanium dioxide (E 171)

Iron oxide, red (E 172)

Iron oxide, yellow (E 172)

25 mg: Iron oxide, black (E 172)

50 mg:Ponceau 4R aluminium lake (E 124)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C.

25 mg: 10, 20, 30, 50 and 100 tablets in blister (PVC/PVdC/Al).

50 mg: 30, 50 and 100 tablets in blister (PVC/PVdC/Al).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Vitabalans Oy

Varastokatu 8

FI-13500 Hämeenlinna

FINLAND

Tel: +358 (3) 615600

Fax: +358 (3) 6183130

8. MARKETING AUTHORISATION NUMBER(S)

<To be completed nationally>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<To be completed nationally>

10. DATE OF REVISION OF THE TEXT

13 April 2016