Ketoprofen Other names: 2-(3-Benzoylphenyl)propionic acid

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects, particularly gastrointestinal ulceration and bleeding.

Increased risk of bleeding.

• Heparin
• Vitamin K antagonists (such as warfarin)
• Platelet aggregation inhibitors (such as ticlopidine, clopidogrel)
• Thrombin inhibitors (such as dabigatran)
• Direct factor Xa inhibitors (such as apixaban, rivaroxaban, edoxaban)

If coadministration is unavoidable, patient should be closely monitored.

Increased risk of gastrointestinal ulceration or bleeding.

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 cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure.

Increased risk of gastrointestinal bleeding.

Increased risk of bleeding.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. A pharmacokinetic interaction between ketoprofen and digoxin has not been demonstrated. However, caution is advised, in particular in patients with renal impairment, since NSAIDs may reduce renal function and decrease renal clearance of cardiac glycosides.

Beta blockers, angiotensin converting enzyme inhibitors, diuretics.

Risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).

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.

i.e. potassium salts, potassium-sparing diuretics, ACE inhibitors and angiotensin II antagonists, NSAIDs, heparins (low molecular-weight or unfractioned), cyclosporine, tacrolimus and trimethoprim.

The risk of hyperkalaemia can be enhanced when the drugs mentioned above are administered concomitantly.

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.

Increased risk of nephrotoxicity, particularly in elderly subjects.

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 NSAIDs therapy.

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 15 mg/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 15 mg/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.

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

In patients concomitantly receiving nicorandil and NSAIDs, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage.

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

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

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus, particularly in elderly subjects.

Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.

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.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population. Administration of ketoprofen can cause asthma attacks or bronchospasm, particularly in subjects allergic to aspirin or NSAIDs.

In patients with systemic lupus erythematosis (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.

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.

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 long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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 from 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 post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

During the first and second trimester of pregnancy, ketoprofen should not be given unless clearly necessary. If ketoprofen 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 foetus 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 the pregnancy, to:
• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• Inhibition of uterine contractions resulting in delayed or prolonged labour.

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

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

Trace amounts of ketoprofen are excreted in breast milk; therefore ketoprofen gel should not be used during breast feeding.

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

Oral administration

The following CIOMS frequency rating is used, when applicable: 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 adverse reactions have been reported with ketoprofen in adults:

Blood and lymphatic system disorders

Rare: haemorrhagic anaemia, anaemia due to bleeding

Not known: agranulocytosis, thrombocytopenia, bone marrow failure, haemolytic anaemia, leucopenia, neutropenia

Immune system disorders

Rare: anaphylactic reactions (including shock)

Psychiatric disorders

Not known: depression, hallucinations, confusion, mood altered

Nervous system disorders

Uncommon: headache, dizziness, somnolence

Rare: paraesthesia

Not known: convulsions, dysgeusia, vertigo, malaise, 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.

Eye disorders

Rare: visual disturbances such as blurred vision

Not known: optic neuritis

Ear and labyrinth disorders

Rare: tinnitus

Cardiac disorders

Not known: exacerbation of heart failure, oedema

Vascular disorders

Not known: hypertension, vasodilatation, vasculitis (including leucocytoclastic vasculitis)

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Respiratory, thoracic and mediastinal disorders

Rare: asthma, asthmatic attack

Not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis, non-specific allergic reactions, dyspnoea

Gastrointestinal disorders

Common: dyspepsia, nausea, abdominal pain, vomiting

Uncommon: constipation, diarrhoea, flatulence, gastritis

Rare: stomatitis, peptic ulcer

Very rare: pancreatitis (very rare reports of pancreatitis have been noted with NSAIDs)

Not known: exacerbation of colitis and Crohn’s disease, gastrointestinal haemorrhage and perforation, gastralgia, melaena, haematemesis

Gastrointestinal bleeding may sometimes be fatal, particularly in the elderly.

Hepatobiliary disorders

Rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis disorders

Not known: abnormal liver function, jaundice

Skin and subcutaneous disorders

Uncommon: rash, pruritis

Not known: photosensitivity reactions, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome, toxic epidermal necrolysis acute generalised exanthematous pustulosis, exfoliative and bullous dermatoses (including epidermal necrolysis, erythema multiforme), purpura

Renal and urinary disorders

Not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome, renal function tests abnormal

General disorders and administration site conditions

Uncommon: oedema, fatigue

Not known: headache, taste perversion

Metabolism and nutritional disorders

Not known: hyponatraemia, hyperkalaemia

Investigations

Rare: weight increased

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).

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

Topical application

The following CIOMS frequency rating is used: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000); very rare (<1/10 000), not known (cannot be estimated from the available data).

Immune System disorders

Not known: anaphylactic shock, angioedema, hypersensitivity reactions

Skin and subcutaneous tissue disorders

Uncommon: Local skin reactions such as erythema, eczema, pruritis and burning sensations.

Rare: Dermatological: photosensitisation and urticaria. Cases of more severe reactions such as bullous or phlyctenular eczema which may spread or become generalised have occurred rarely.

Renal and urinary disorders

Very rare: Cases of aggravation of previous renal insufficiency