Flamaryx 7,5 mg, 15 mg TABLET

FLAMARYX is indicated for the symptomatic treatment of:

• Rheumatoid arthritis.
• Painful osteoarthritis.
• Ankylosing spondylitis.
• Episodes of acute sciatica.

Use the lowest effective dose for the shortest possible duration of treatment, as the potential for adverse reactions increases with dose and duration of exposure. The maximum daily dose of FLAMARYX is 15 mg.

Adults:

• Acute sciatica: 7,5 mg once daily. If there is no improvement the dose can be increased to 15 mg a day.
• Ankylosing spondylitis: 15 mg once daily. According to the therapeutic response, the dose may be reduced to 7,5 mg/day.
• Osteoarthritis: 7,5 mg once daily. Increase to 15 mg if necessary.
• Rheumatoid arthritis: 15 mg once daily. Reduce dose if possible to 7,5 mg per day (provided therapeutic response is maintained).

Special populations:

• Elderly population: In patients with an increased risk of adverse reactions, e.g. the elderly, a history of gastrointestinal disease or risk factors for cardiovascular disease, the treatment should be started at the dose of 7,5 mg per day (see section 4.4).
• Renal impairment: The dose of FLAMARYX in patients with end stage renal disease on haemodialysis should not be greater than 7,5 mg/day. No dosage reduction is necessary in patients with mild to moderate renal impairment (i.e. in patients with a creatinine clearance of greater than 25 mL/min). In non-dialysed patients with severe renal impairment FLAMARYX is contraindicated (see section 4.3).
• Paediatric population: Safety and efficacy in children under the age of 12 years has not been established.

Method of administration:

Oral administration. The tablet should be taken with a glass of water and together with a meal.

• Hypersensitivity to FLAMARYX or to any ingredients of the formulation (see section 6.1).
• Patients in who attacks of asthma, urticaria, nasal polyps, angioedema or acute rhinitis are precipitated by acetylsalicylic acid/aspirin or by other non-steroidal anti-inflammatory agents.
• Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
• Active peptic ulcer disease.
• Active or history of recurrent gastrointestinal ulceration/haemorrhage/perforations.
• Active inflammatory bowel disease (Crohnu2019s disease or ulcerative colitis).
• History of gastrointestinal perforation, bleeding or perforation (PUBs) related to previous NSAIDs.
• Severe hepatic impairment.
• Severe non-dialysed renal impairment.
• Overt gastrointestinal bleeding, recent cerebrovascular bleeding or established systemic bleeding disorders.
• Heart failure, established ischaemic heart disease and/or cerebrovascular disease (stroke) and peripheral arterial disease.
• Pregnancy and lactation (see section 4.6).
• Use in children under 12 years of age.
• In case of rare hereditary conditions that may be incompatible with an excipient of FLAMARYX, the use of this medicine is contraindicated (see section 4.4).

FLAMARYX may predispose to cardiovascular events, gastrointestinal events, or cutaneous reactions which may be fatal. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal (GI) and cardiovascular risks below). The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, nor should an additional NSAID be added to the therapy because this may increase the toxicity while therapeutic advantage has not been proven. The use of FLAMARYX with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5). FLAMARYX is not appropriate for the treatment of patients requiring relief from acute pain. In the absence of improvement after several days, the clinical benefit of the treatment with FLAMARYX should be reassessed.

• Paediatric population: Children under the age of 12 years u2013 safety and efficacy have not been established (see section 4.3).
• Elderly population: Adverse reactions are often less well tolerated in the elderly or weakened individuals, who therefore require careful monitoring. As with other NSAIDs, particular caution is required in the elderly, in whom renal, hepatic and cardiac functions are frequently impaired. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation (PUBs) which may be fatal.
• Gastrointestinal (GI) effects: Any history of oesophagitis, gastritis and/or peptic ulcer must be sought before starting treatment with FLAMARYX (see section 4.3). Gastrointestinal bleeding, ulceration or perforation, potentially fatal, can occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. The consequences of such events are generally more serious in the elderly. The risk of gastrointestinal bleeding or perforation (PUBs) is higher with increasing doses of FLAMARYX, in patients with a history of ulcers, and the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective medicines (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other medicines likely to increase gastrointestinal risk (see below and section 4.5).
• Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. Patients appear to be at higher 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. FLAMARYX should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If the patient has developed SJS or TEN with the use of FLAMARYX, therapy with FLAMARYX must not be re-started in this patient at any time.
• Functional renal failure: NSAIDs, such as FLAMARYX, may cause a dose dependent inhibition of the synthesis of renal prostaglandins involved in the maintenance of renal perfusion. In patients with decreased renal blood flow and blood volume, taking FLAMARYX may result in the decompensation of latent renal failure. However, renal function returns to its initial status when treatment is stopped. Patients who are dehydrated, have hepatic or renal dysfunction, taking diuretics or have undergone surgery leading to hypovolaemia, are at particular renal decompensation and renal function should be carefully monitored. Patients who have heart failure are at particular renal decompensation (see section 4.3). This particularly concerns patients with the following risk factors where monitoring of diuresis and renal function during treatment is necessary (see sections 4.2 and 4.3):
  • Elderly patients.
  • Dehydrated patients.
  • Concomitant treatment with medicines such as ACE inhibitors, angiotensin-II antagonists, sartans or diuretics (see section 4.5).
  • Hypovolaemia (whatever the cause).
  • Renal failure.
  • Nephrotic syndrome.
  • Lupus nephropathy.
  • Those with congestive heart failure.
  • Liver cirrhosis.
• Cardiovascular and cerebrovascular effects: FLAMARYX may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Caution is advised when FLAMARYX is prescribed to patients with cardiovascular risk factors (e.g. diabetes, smoking hypercholesterolaemia and hypertension) and they should only be treated with FLAMARYX after careful consideration. Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with FLAMARYX therapy due to inhibition of prostaglandin synthesis. In view of FLAMARYXu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients. Clinical monitoring of blood pressure for patients at risk is recommended at baseline and especially during treatment initiation with FLAMARYX. Because of its lack of platelet effects, FLAMARYX is not a substitute for aspirin for cardiovascular prophylaxis (see section 4.5).
• Parameters of liver and renal function: FLAMARYX should be used with caution in patients with:
  • Hepatic impairment - Increases risk of renal decompensation.
  • Renal impairment - Increases risk of renal decompensation. Increases in serum transaminase levels, increases in serum bilirubin or other liver function parameters, as well as increases in serum creatinine and blood urea and other laboratory disturbances, have been reported. In most cases these have been small and transient increases above the normal range. If the abnormality is significant or persistent, FLAMARYX should be stopped and follow up tests carried out. No dose reduction is required in patients with clinically stable liver cirrhosis. Frail or debilitated patients may tolerate side-effects less well and such patients should be carefully supervised. Caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.
• Sodium, potassium and water retention: Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with FLAMARYX. Furthermore, a decrease of the antihypertensive effect of antihypertensive medicines may occur (see section 4.5). Oedema or hypertension may be precipitated or exacerbated. Clinical monitoring is therefore necessary for patients at risk. In view of the productu2019s FLAMARYXu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients (see sections 4.2 and 4.3).
• Hyperkalaemia: Hyperkalaemia can be favoured by diabetes or concomitant treatment known to increase serum potassium levels (see section 4.5). Regular monitoring of potassium values should be performed in such cases.
• Combination with pemetrexed: In patients with mild to moderate renal insufficiency receiving pemetrexed, FLAMARYX should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).
• Underlying infections: FLAMARYX may mask the symptoms of an underlying infectious disease.

Safety and efficacy in pregnancy and lactation has not been established. FLAMARYX is contraindicated during pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo-foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastrochisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The use of FLAMARYX during the third trimester is not recommended because of possible adverse effects on the foetus, such as:

• cardiopulmonary toxicity (premature closure of the ductus arteriosus, which may lead to persistent pulmonary hypertension in the newborn).
• renal dysfunction, which may progress to renal failure with oligohydramnios.

At the end of pregnancy, FLAMARYX may expose the mother and the neonate to the following:

• prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• the onset of labour may be delayed and its duration increased (see section 4.3).

Breastfeeding: FLAMARYX is contraindicated during lactation (see section 4.3). While no specific experience exists for FLAMARYX in humans, NSAIDs are known to pass into motheru2019s milk. Administration is therefore contraindicated in women who are breastfeeding.

Fertility: FLAMARYX can inhibit cyclooxygenase / prostaglandin synthesis, which may impair fertility and is not recommended in women attempting to conceive. FLAMARYX may delay ovulation. In women who have difficulties conceiving, or who are undergoing investigation of infertility, FLAMARYX should be stopped (see section 4.4).

Patients should not operate machinery or drive a vehicle if they experience drowsiness, blurred vision or any other central nervous system effect. FLAMARYX may cause side effects, such as visual disturbances including blurred vision, dizziness, drowsiness, vertigo and other central nervous system disturbances (see section 4.8) and therefore affect the ability to drive a vehicle or use machinery. Caution is advised before driving a vehicle or operating machinery until the effects of FLAMARYX are known.

b. Tabulated list of adverse reactions

System Organ Class Frequency Side effects

Blood and lymphatic system disorders Frequent Anaemia, Less frequent Thrombocytopenia, agranulocytosis, leucopoenia, abnormal blood count (including differential white cell count), neutropenia, eosinophilia Concomitant administration of a potentially myelotoxic medicine in particular methotrexate, appears to be a predisposing factor to the onset of cytopenia.

Immune system disorders Less frequent Hypersensitivity reactions including anaphylaxis, angioedema and bronchospasm (especially if patient is aspirin-sensitive and has FLAMARYX should be withdrawn immediately) Frequency unknown Anaphylactoid reactions

Psychiatric disorders Less frequent Altered mood, confusional state, insomnia, nightmares Frequency unknown Disorientation

Nervous system disorders Frequent Headache, dizziness, light-headedness Less frequent Drowsiness, somnolence Frequency unknown Insomnia, nightmares, cerebrovascular incidents (strokes).

Eye disorders Less frequent Visual disturbances (such as blurred vision), conjunctivitis

Ear and labyrinth disorders Less frequent Vertigo, tinnitus

Cardiac disorders Less frequent Oedema, palpitations, elevated blood pressure (hypertension), congestive cardiac failure Frequency unknown Dysrhythmia tachycardia, congestive cardiac failure, myocardial infarction, cardiovascular thrombotic events

Vascular disorders Less frequent Elevated blood pressure (hypertension), flushing Frequency unknown Aggravated hypertension

Respiratory, thoracic and mediastinal disorders Less frequent Bronchospasm, asthma in individuals allergic to aspirin or other NSAIDs

Gastrointestinal disorders Frequent Dyspepsia, diarrhoea, nausea, vomiting, abdominal pain Less frequent Peptic ulcers, perforation or gastrointestinal bleeding (sometimes fatal), perforation or ulceration (is generally more serious in the elderly), melaena, haematemesis, ulcerative stomatitis, induction or exacerbation of colitis, stomatitis gastritis, eructation oesophagitis, flatulence, constipation, exacerbation of Crohnu2019s disease Frequency unknown Pancreatitis The most commonly observed adverse events are gastrointestinal in nature.

Hepato-biliary disorders Less frequent Hepatitis, abnormal liver function test (e.g., raised transaminases or bilirubin

Skin and subcutaneous tissue disorders Less frequent Pruritus, rash, Less frequent Angioedema urticaria, photosensitivity, bullous reactions, including erythema multiforme and Stevens-Johnson syndrome, toxic epidermal necrolysis

Renal and urinary disorders Less frequent Nephrotic syndrome, glomerulonephritis, interstitial nephritis and papillary necrosis, acute renal failure, (particularly in patients with risk factors u2013 see section 4.4), sodium and water retention, hyperkalaemia (see sections 4.4 and 4.5), abnormal renal function test (increased serum creatinine and/or serum urea), micturition disorders including acute urinary retention

Reproductive system and breast disorders Less frequent Delayed ovulation

General disorders and administration site conditions Frequent Peripheral oedema.

Symptoms: Symptoms following acute NSAID (such as FLAMARYX) overdose are usually limited to lethargy, drowsiness, nausea, vomiting and epigastric pain, which may be reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs (such as FLAMARYX) and may occur following an overdose.

Treatment of overdosage:

• Treatment is symptomatic and supportive as there is no known antidote. Absorption should be reduced by:
• Activated charcoal if patient presents 1 to 2 hours after overdose
• Cholestyramine