sanofi-aventis

Oruvail 200mg Prolonged-Release Capsules, Hard.

Each capsule contains 200mg of Ketoprofen.

For a full list of excipients, see Section 6.1.

Prolonged-Release Capsules, Hard.

Having a transparent pink body with opaque white cap with the product name 'Oruvail 200' imprinted on both sections and containing off-white to cream coloured spherical pellets.

Oruvail is recommended in the management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, non-infectious arthropathy, acute articular and periarticular disorders (bursitis, capsulitis, synovitis, tendonitis), sciatica, painful musculoskeletal conditions and management of the pain of dysmenorrhoea.

Oruvail reduces joint paint and inflammation, and facilitates increase in mobility and functional independence. As with other non-steroidal anti-inflammatory agents, it does not cure the underlying disease.

To be taken orally.

Adults Only:

The usual total daily dose is 100 to 200 mg as a single dose to be taken with food.

Elderly:

NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events. It is advisable to reduce the initial dosage and maintain such patients on the minimal effective dose.

Patients with impaired renal function:

It is advisable to reduce the initial dose and maintain such patients on the minimal effective dose. Individual assessment may be considered only after good individual tolerance has been ascertained.

Patients with impaired hepatic function:

These patients should be carefully monitored and kept at the minimal effective daily dosage.

Children:

The safety and effectiveness of Oruvail has not been established.

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

As with other medications, it is generally advisable to initiate ketoprofen therapy at the lower dose and to maintain patients on the lowest effective dosage (see also Section 4.4).

Undesirable effects may be minimised by using the shortest duration necessary to control symptoms (see section 4.4).

• Use in patients hypersensitive (e.g. bronchospasm, asthmatic attacks, rhinitis, urticaria) to ketoprofen, aspirin or any other non-steroidal anti-inflammatory drugs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients.

• Hypersensitivity to any of the excipients of Oruvail 200mg Prolonged Release Capsules.

• Use in patients with active or history of peptic ulcer/hemorrhage.

• Active peptic ulcer, or a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

• Severe heart failure.

• Severe hepatic insufficiency.

• Severe renal insufficiency.

• Third trimester of pregnancy.

Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below). Patients treated with NSAIDS long term should undergo regular medical supervision to monitor for adverse events.

Gastrointestinal bleeding, ulceration and perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.

The risk of gastrointestinal 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 asprin, or other drugs likely to increase gastrointestinal risk (See below and Section 4.5).

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

Some epidemiological evidence suggests that ketoprofen may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially at high doses (see also section 4.2 and 4.3).

Caution should be advised in patients receiving combination 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 asprin (See Section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients receviving Oruvail 200mg Prolonged Release Capsules, the treatment 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 (See Section 4.8). 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. Oruvail 200mg Prolonged Release Capsules should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Ketoprofen should only be used with great caution in the following cases:

NSAIDs shoul dbe given with care to patients with a history of GI disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Brochospasm may be precipitated in patients with a history of, or suffering from, bronchial asthma, allergy to aspirin or related compounds or allergic disease.

Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in assocaiation with NSAID therapy.

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 ketoprofen.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ketoprofen 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).

At the start of treatment, renal function must be carefully monitored in patients with heart failure, cirrhosis and nephrosis, in patients receiving diuretic therapy, in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decomposition.

Clinical studies have shown a few cases in which reversible increases in BUN or serum creatinine occurred during use of ketoprofen, particularly in patients with existing renal damage, or in concurrent diuretic therapy.

In patients with abnormal liver function tests or with a history of liver disease, transaminase levels should be evaluated periodically, particularly during long-term therapy. Rare cases of jaundice and hepatitis have been described with ketoprofen.

Many elderly patients have received the drug for periods of up to a year without development of renal dysfunction. However, care should be taken during use of the drug in patients with severe renal dysfunction and in the elderly particularly during prolonged therapy. Where prolonged therapy is required, patients should be reviewed regularly.

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

As NSAIDS can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.

As with other NSAIDs, in the presence of an infectious disease, it should be noted that the anti-inflammatory, analgesic and the antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever.

If visual disturbances such as blurred vision occur, treatment should be discontinued.

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

Not recommended drug associations

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Other NSAIDS (including cyclooxygenase-2 selective inhibitors) and high dose salicylates: avoid concomitant use of two or more NSAIDs. Increased risk of gastrointestinal ulceration and bleeding.

Lithium: Risk of elevation of lithium plasma levels, sometimes reaching toxic levels due to decreased lithium renal excretion. Where necessary, plasma lithium levels should be closely monitored and the lithium dosage levels adjusted during and after NSAID therapy.

Methotrexate at doses greater than 15mg/week:

Increased risk of haematologic toxicity of methotrexate, particularly if administered at high doses (> 15 mg/week), possibly related to displacement of protein-bound methotrexate and to its decreased renal clearance. In patients receiving ketoprofen therapy previously, treatment by ketoprofen should be interrupted for at least 12 hours before administration of methotrexate. When ketoprofen is to be administered following the end of methotrexate therapy, a period of at least 12 hours should also be observed before initiation of treatment.

Drug associations requiring precautions for use

Diuretics: reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Patients and particularly dehydrated patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated before initiation coadministration therapy and renal function monitored when treatment is started (see section 4.4 Special warnings and special precautions for use).

Methotrexate at doses lower than 15mg/week:

During the first weeks of combination treatment, full blood count should be monitored weekly. If there is any alteration of the renal function or if the patient is elderly, monitoring should be done more frequently.

Pentoxifylline: There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Drug associations to be taken into accountAnti-hypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors): Risk of decreased antihypertensive potency (inhibition of vasodilatator prostaglandins by NSAIDs).

ACE inhibitors and Angiotensin II Antagonists: In patients with compromised renal function (e.g. dehydrated patients or elderly patients the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure.

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Cardiac glycosides: NSAIDS may exacerbate cardiac failure, reduced GFR and increase plasma cardiac glycoside levels.

Cyclosporin: increased risk of nephrotoxicity with NSAIDS.

Oral hypoglycemic agents: inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Selective Serotonin Reuptake Inhibitors (SSRIs): increased risk of gastrointestinal bleeding (See Section 4.4).

Probenecid: Concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen.

Thrombolytics: Increased risk of bleeding.

4.6.1 Pregnancy

During the first and second trimester:

In mice and rats, there is no evidence of teratogenic or embroyotoxicity. In the rabbit, slight embryotoxicity related to maternal toxicity has been reported.

As the safety of ketoprofen in pregnant women has not been evaluated, it is recommended to avoid ketoprofen during the first two trimesters of pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.

During the third trimester of pregnancy:

All prostaglandin synthetase inhibitors including ketoprofen may induce cardiopulmonary and renal toxicity in the foetus. At the end of the pregnancy, prolonged bleeding time in both the mother and child may occur. Therefore, ketoprofen is contraindicated during the last trimester of pregnancy.

No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.

Patients should be warned about the potential for somnolence, dizziness or convulsions, and advised not to drive or operate machinery if these symptoms occur.

Cardiovascular disorders such as hypertension and vasodilation.

Gastrointestinal effects 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 section 4.4). , 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.

General disorders such as headache, weight gain, taste perversion.

Haematology disorders such as thrombocytopenia, anaemia due to bleeding, agranulocytosis and bone marrow aplasia.

Hearing disorders such as tinnitus.

Hypersensitivity reactions include dermatological reactions such as rash, pruritus, urticaria and angioedema. Respiratory reactions such as asthmatic attack, bronchospasm (particularly in patients with known hypersensitivity to aspirin and other NSAIDs) and anaphylactic reactions (including shock).

Liver disorders such as elevation of transaminases levels, rare cases of hepatitis.

Peripheral and central nervous system reactions include dizziness, paresthesia and convulsions.

Psychiatric disorders include somnolence and mood disorders.

Renal disorders such as abnormal renal function tests, acute renal failure, interstitial nephritis, nephrotic syndrome.

Skin reactions include photosensitivity, alopecia, and (rarely) bullous eruptions including Stevens-Johnson and toxic epidermal necrolysis.

Vision disorders include blurred vision (see section 4.4 Special warnings and special precautions for use).

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 a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

In the case of major gastro-intestinal adverse effects (peptic ulceration, haemorrhage or perforation) Oruvail should be withdrawn at once. Cases of overdosage have been reported with doses up to 2.5g of ketoprofen. In most instances the symptoms observed have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain, but adverse effects seen after overdosage with propionic acid derivatives such as hypotension, bronchospasm and gastrointestinal haemorrhage should be anticipated. There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present.

If renal failure is present, haemodialysis may be useful to remove circulating drug.

Ketoprofen is a non-steroidal anti-inflammatory arylcarboxylic acid derivative belonging to the propionic acid group of NSAIDs.

Ketoprofen has anti-inflammatory antipyretic properties and has central and peripheral analgesic activity.

However, its mode of action is not fully explained.

It inhibits prostaglandin synthetase and platelet aggregation.

General characteristics

Absorption:

Ketoprofen is rapidly and completely absorbed from the gastrointestinal tract. When administered with high caloric food, a slight decrease of bioavailability (13%) has been observed for sustained release formulations.

Distribution:

The drug is 99% bound to plasma protein.

The ketoprofen diffuses into synovial fluid and in intraarticular, capsular, synovial and tendon tissues. Ketoprofen crosses the brain blood barrier and the placenta barrier. For sustained release formulations, after the plateau (5^th to 12^th hour) ketoprofen levels decrease with an apparent half- life of 3 to 4 hours.

No accumulation of the drug has been found after repeated doses.

Biotransformation:

The biotransformation of ketoprofen is characterised by two main processes, hydroxylation and conjugation with glucuronic acid, the latter being the main pathway in man. Excretion of ketoprofen as unchanged drug is very low (less than 1%). Almost all administered ketoprofen is excreted as metabolites in the urine, of which 65 to 85% of administered dose is excreted as a glucuronide metabolite.

Excretion:

The drug is mainly excreted in the urine. Within five days following the oral administration, 75 to 90% of the dose are excreted in the urine. Fecal excretion is very low (1 to 8%).

Characteristics in patients:

Elderly patients:

Absorption of ketoprofen is not modified; there is an increased half-life (3 h) and decreased renal and plasma clearance.

Patients with renal insufficiency:

There is a decreased renal and plasma clearance and increased half-life correlated with severity of renal failure.

Patients with hepatic insufficiency:

There are no significant changes in the plasma clearance and elimination half-life. However, the unbound fraction is approximately doubled.

There is no other information available which could be of relevance to the prescriber in recognising the safety profile of Oruvail and which is not included in the relevant sections of this SPC.

Capsule contents

Sugar spheres (sucrose & maize starch)

Colloidal anhydrous silica

Shellac

Ethylcellulose

Talc

Capsule Shell

Erythrosine E127

Titanium Dioxide E171

Gelatin

Printing Ink

Erythrosine E127

Patent Blue V E131

Titanium Dioxide E171

Not applicable.

3 years.

Do not store above 25°C. Store in the original package in order to protect from light and moisture..

Outer cardboard carton containing blister pack made of 250 ug opaque white, unplasticated, uPVC film coated with 40 gsm PVdC and 20 ug hard temper aluminium foil, PVC-Acrylat heat seal lacquer.

Blister strip packs of 4,14, 28 or 56 capsules.

Not all pack sizes are marketed.

No special requirements.

sanofi-aventis Ireland Ltd.,

Citywest Business Campus,

Dublin 24.

PA 540/119/3

14^th August 1984/14^th August 2004

January 2010.