Orudis 50

In terms of the active ingredient

Ketoprofen 50mg

Capsules

Recommended in the management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and periarticular disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low back pain (strain, lumbago, sciatica, fibrositis), painful musculoskeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery.

Orudis reduces joint pain and inflammation and facilitates increase in mobility and functional independence.

It does not cure the underlying disease.

Oral dosage 50 - 100mg twice daily, morning and evening, depending on patient's weight and on the severity of symptoms.

The maximum daily dose is 200mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200mg daily, and higher doses are not recommended (see also section 4.4).

Best results are obtained by titrating dosage to suit each patient: start with a low dosage in mild chronic disease and a high dosage in acute or severe disease. Some patients derive greater benefit by treatment with capsules only, some with a combined capsule/suppository regimen and others with a higher dosage at night time than at early morning. Where patients require a maximum oral dosage initially, an attempt should be made to reduce this dosage for maintenance since lower dosage might be better tolerated for purposes of long-term treatment.

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.

Paediatric dosage: Not established.

To limit occurrence of gastrointestinal disturbance, capsules should always be taken with food (milk, meals).

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

Ketoprofen is contraindicated in patients who have a history of hypersensitivity reactions such as asthmatic attacks, rhinitis, angioedema, urticaria or other allergic-type reactions to ketoprofen, any other ingredients in this medicine, ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8 – Undesirable effects).

Ketoprofen is also contraindicated in the following cases:

− Severe heart failure

− active peptic ulcer or any history of gastrointestinal haemorrhage, ulceration or perforation

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

− severe hepatic insufficiency

− severe renal insufficiency

− third trimester of pregnancy

Disease in children (safety/dosage during long-term treatment has not been established).

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

The use of Orudis with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5.

Elderly:

The elderly have an increased risk of adverse reactions to NSAIDs, especially gastro-intestinal bleeding and perforation which may be fatal (see Section 4.2 – Posology and method of administration).

Cardiovascular, Renal and Hepatic impairment:

At the start of treatment, renal function must be carefully monitored in patients with heart impairment, heart failure, liver dysfunction, 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. (see also Section 4.3 – Contra-indications).

NSAIDs have also been reported to cause nephrotoxicity in various forms and this can lead to interstitial nephritis, nephrotic syndrome and renal failure.

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

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 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).

Respiratory disorders:

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

Gastro-intestinal 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.

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).

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAlD 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 aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

NSAIDs should only be given with care to patients with a history of gastro-intestinal disease (e.g. ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8 – Undesirable effects). 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 corticosteroids, or anti-coagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see Section 4.5).

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

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 Section 4.8 - Undesirable effects).

Female fertility:

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

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

Infectious disease:

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.

Visual disturbances:

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

Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e.ticlopidine, clopidogrel):

Increased risk of bleeding. If coadministration is unavoidable, patient should be closely monitored. (see section 4.4 – Special warnings and precautions for use)

Lithium: Ketoprofen can increase lithium blood levels to possibly toxic levels due to decreased elimination of lithium. If administered together, plasma concentrations of lithium should be monitored in order to adjust the lithium dose.

Other analgesics/NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates:

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects, particularly gastrointestinal ulceration and bleeding. (see Section 4.4 – Special warnings and precaurtions for use).

Methotrexate: Serious interactions have been recorded after the use of high dose methotrexate with NSAIDs, including ketoprofen, due to decreased elimination of 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. 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.

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

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

Antihpertensives: Reduced antihypertensive effect.

Diuretics: Risk of reduced diuretic effect. 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 initiating coadministration therapy and renal function monitored when the treatment is started (see section 4.4 – Special warnings and precautions for use).

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

Cyclosporin: Increased risk of nephrotoxicity.

Corticosteroids: Increased risk of GI ulceration or bleeding. (see Section 4.4 Special warnings and precautions for use).

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.

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

Thrombolytics: Increased risk of bleeding.

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

Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (section 4.4 – Special warnings and precautions for use).

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.

Zidovudine: increased risk of haematological toxicity when NSAlDs 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

No embryopathic effects have been demonstrated in animals. 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 discernable pattern.

It is recommended to avoid ketoprofen during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of premature closure of the ductus arteriosus), use in the last trimester of pregnancy is contra-indicated (see Section 4.3 - Contra-indications). The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.

Lactation

See Section 4.4 – Special warnings and 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.

Blood and the lymphatic system disorder:

−thrombocytopenia, anemia due to bleeding, neutropenia, agranulocytosis, bone marrow aplasia and haemolytic anaemia

Immune system disorders:

−dermatological reactions: rash, pruritus, urticaria, angioedema

−respiratory reactions: aggravated asthma, asthmatic attack, dyspnoea, bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs)

−anaphylactic reactions (including shock)

- non-specific allergic reactions

Psychiatric disorders:

−somnolence, mood disorders

Nervous system disorders:

− Depression, confusion, hallucinations, vertigo,dizziness, paraesthesia, convulsions

- malaise, fatigue and drowsiness

- reports of aseptic meningitis (especially in patients with existing auto-immune disorders such as systemic lupus erythematosis, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4).

Eye disorders:

−visual disturbances such as blurred vision (see section 6)

- optic neuritis

Ear and labyrinth disorders:

−tinnitus

Cardiac disorders:

−oedema, hypertension, vasodilatation, cardiac failure

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 section 4.4).

Gastrointestinal disorders:

− gastralgia, dyspepsia, abdominal pain, nausea, vomiting, diarrhoea, constipation, flatulence

− gastritis, stomatitis, exacerbation of colitis and Crohn's disease

− peptic ulcer, gastrointestinal bleeding and perforation

- melaena, haematemesis

- pancreatitis; very rare reports of pancreatitis have been noted with NSAIDs

Gastro-intestinal bleeding may sometimes be fatal, particularly in the elderly (see Section 4.4 Special warnings and precautions for use).

Hepato-biliary disorders:

− elevation of transaminase levels, abnormal liver function, jaundice and rare cases of hepatitis

Skin and subcutaneous tissue disorders:

-Photosensitivity reactions, alopecia, purpura, exfoliative and bullous dermatoses ( including epidermal necrolysis, erythema multiforme, Stevens Johnson Syndrome and Toxic Epidermal Necrolysis).

Renal and urinary disorders:

−abnormal renal function tests, acute renal failure, interstitial nephritis, nephriticsyndrome

General disorders and administration site conditions:

−headache, oedema, weight gain, taste perversion

In all cases of major adverse effects Orudis should be withdrawn at once.

Symptoms

Like other propionic acid derivatives, ketoprofen is of low toxicity in overdosage; symptoms after acute ketoprofen intoxication are largely limited to drowsiness, abdominal pain and vomiting. Headache, nausea, rarely diarrhoea, disorientation, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions may also occur. Adverse effects seen after overdosage with propionic acid derivatives such as hypotension, bronchospasm and gastro-intestinal haemorrhage should be anticipated.

In cases of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures:

Treatment is supportive and symptomatic.

Within one hour of ingestion, consideration should be given to administering activated charcoal. Alternatively, in adults, gastric lavage should be considered if the patient presents within 1 hour of ingesting a potentially toxic amount.

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.

The benefit of gastric decontamination is uncertain.

Other measures may be indicated by the patient's clinical condition.

Ketoprofen overall has the properties of a potent non-steroidal anti-inflammatory agent. It has the following pharmacological effects.

Anti-inflammatory

It inhibits the development of carageenan-induced abscesses in rats at 1mg/kg and UV-radiation induced erythema in guinea pigs at 6mg/kg. It is also a potent inhibitor of PGE₂ and PGF_{2 ∞} synthesis in guinea pigs and human chopped lung preparations.

Analgesic

Ketoprofen effectively reduced visceral pain in mice caused by phenyl benzoquinone or by bradykinin following P.O. administration at about 6mg/kg.

Antipyretic

Ketoprofen (2 and 6mg/kg) inhibited hyperthermia caused by s.c. injection of brewer's yeast in rats and, at 1mg/kg, hyperthermia caused by i.v. administration of antigonococcal vaccine to rabbits.

Ketoprofen at 10mg/kg i.v. did not affect the cardiovascular, respiratory, central nervous system or autonomic nervous systems.

Ketoprofen is completely absorbed from Orudis capsules and maximum plasma concentrations occur after ½ - 1 hour. It declines thereafter with a elimination half-life of about 2 - 3 hours. There is no accumulation on continued daily dosing.

No additional data of relevance to the prescriber

Lactose, magnesium stearate

Capsule shells (Elanco & Scherer)

Opaque purple cap: Brilliant Blue FCF (E133), Erythrosine (E127), Titanium Dioxide (E171), Gelatin. Opaque green base: Brilliant Blue FCF (E133), Yellow iron Oxide (E172), Titanium Dioxide (E171), Gelatin

Capsule shells (Capsulgel)

Opaque purple cap: Patent Blue V (E131), Erythrosine (E127), Titanium Dioxide (E171), Gelatin. Opaque green base: Yellow iron Oxide (E172), Patent Blue V (E131), Titanium Dioxide (E171), Gelatin

None stated

60 months

Store in a dry place below 25^oC. Protect from light.

Cardboard carton containing blister packs of 112 capsules

None stated.

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

PL 04425/0576

13/09/2006

8 July 2009

POM