Clotam^® Rapid.

Tolfenamic acid 200 mg.

Tablets.

Acute migraine.

For oral administration.

To be taken preferably with or after food.

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

ADULTS

Migraine - acute attacks:

200mg when the first symptoms of migraine appear. The treatment can be repeated once after 1-2 hours if a satisfactory response is not obtained.

CHILDREN

A paediatric dosage regimen has not yet been established.

ELDERLY

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Hypersensitivity to tolfenamic acid or to any of the excipients.

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

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

Severe heart failure, hepatic failure and renal failure (see 4.4 Special warnings and precautions for use).

During the last trimester of pregnancy (see 4.6 Pregnancy and lactation).

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

In all patients:

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see 4.2 Posology and administration, and GI and cardiovascular risks below).

The use of Clotam Rapid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see 4.5 Interaction with other medicinal products and other forms of interaction).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see 4.2 Posology and administration).

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, renal and hepatic impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also 4.3 Contraindications).

Cardiovascular and cerebrovascular effects:

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

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tolfenamic acid.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tolfenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and 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 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 4.3 Contraindications), 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 aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5 Interaction with other medicinal products and other forms of interaction).

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

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 aspirin (see 4.5 Interaction with other medicinal products and other forms of interaction).

When GI bleeding or ulceration occurs in patients receiving tolfenamic acid, the treatment should be withdrawn.

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 4.8 Undesirable effects).

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see 4.8 Undesirable effects).

Dermatological:

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 4.8 Undesirable effects). 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. Clotam Rapid should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility:

The use of tolfenamic acid 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 tolfenamic acid should be considered.

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see 4.4 Special warnings and precautions for use).

Anti-hypertensives:

Reduced anti-hypertensive effect.

Diuretics:

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides:

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium:

The effect of lithium may be increased due to decreased elimination of lithium.

Methotrexate:

Decreased elimination of methotrexate.

Ciclosporin:

Increased risk of nephrotoxicity.

Mifepristone:

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

Corticosteroids:

Increased risk of gastrointestinal ulceration or bleeding (see 4.4 Special warnings and precautions for use).

Anti-coagulants:

NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see 4.4 Special warnings and precautions for use). In patients treated with anti-coagulants, close monitoring of blood coagulation is recommended.

Quinolone antibiotics:

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

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

Increased risk of gastrointestinal bleeding (see 4.4 Special warnings and precautions for use).

Tacrolimus:

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine:

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy:

Congenital abnormalities have been reported in association with NSAID administration in man, however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see 4.3 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Lactation:

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See 4.4 Special warnings and special precautions for use, regarding female fertility.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Tolfenamic acid is well tolerated at the recommended dosage.

The following side effects have been observed:

Gastrointestinal:

The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see 4.4 Special warnings and precautions for use). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see 4.4 Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity:

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see 4.4 Special warnings and precautions for use).

Other adverse reactions reported less commonly include:

Renal:

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. Harmless dysuria in the form of smarting during urination may occur occasionally, most commonly in males. The occurrence is correlated with the concentration of a metabolite and is most probably due to a local irritating effect of the urethra. Increased consumption of liquid or reduction of the dose diminishes the risk of smarting. The urine may, due to coloured metabolites, become a little more lemon coloured.

Hepatic:

Abnormal liver function, hepatitis and jaundice.

Neurological and special senses:

Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see 4.4 Special warnings and precautions for use), depression, confusion, allucinations, tinnitus, vertigo, tremor, euphoria, dizziness, malaise, fatigue and drowsiness.

Haematological:

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological:

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measure

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

NSAID with anti-inflammatory, analgesic, and antipyretic effects. Tolfenamic acid is a prostaglandin synthesis inhibitor and a leukotriene synthesis inhibitor.

Tolfenamic acid is absorbed quickly and almost completely after oral administration.

Hepatic first pass metabolism is as low as 15% (bioavailability 85%). Maximum plasma concentrations are reached after about 1-1½ hours. The half-life in plasma is about 2 hours. Tolfenamic acid is extensively bound to plasma proteins (99%). It is metabolised in the liver and tolfenamic acid as well as the metabolites is conjugated with glucuronic acid. About 90% of a given dose of tolfena-mic acid is excreted in the urine as glucuronic acid conjugates, and about 10% is excreted in the faeces. Enterohepatic circulation exists.

The therapeutic index for tolfenamic acid is high, and gastrointestinal ulceration and kidney changes have only been seen with oral doses approximately 6-10 times the maximum therapeutic dose recommended for tolfenamic acid. In human volunteers, tolfenamic acid did not affect renal function.

Maize starch; Sodium starch glycollate (Type A); Macrogol 6000; Alginic acid; Cellulose, microcrystalline; Croscarmellose sodium; Silica, colloidal anhydrous; Sodium stearyl fumarate.

None known.

Five years.

Store below 25°C.

Blister card:

HDPE tablet container with LDPE closure.

Pack sizes: 3, 10 and 30 tablets.

None.

A/S GEA Farmaceutisk Fabrik

Edvard Thomsens Vej 14

2300 Copenhagen S

Denmark

PL 04012/0043

25 April 1997

31 October 2011