Each modified-release capsule contains ketoprofen 100 mg or 200 mg and omeprazole 20 mg Excipients: Each capsule contains propyl-p-hydroxybenzoate, methyl-p-hydroxybenzoate, and 80 mg or 105 mg sucrose

Modified-release capsule, hard (Modified-release capsule) The 100 mg/20 mg capsule, hard with opaque yellow cap and opaque white body, containing white to greyish-white spherical microgranules The 200 mg/20 mg capsule, hard with opaque white cap and body, containing white to greyish-white spherical microgranules

Symptomatic treatment of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis in patients with a previous history or who are at risk of developing NSAID associated gastric ulcers, duodenal ulcers and gastroduodenal erosions in whom continued treatment with ketoprofen is essential.

For oral use.

The capsule should be swallowed whole with food once daily, with a large glass of water.

Adults and adolescents over the age of 15 years:

The daily dose is 100 mg/20 mg to 200 mg/20 mg depending of the severity of symptoms.

The maximal daily dose is 200 mg/20 mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200 mg/20 mg daily, and higher doses are not recommended.

Ketoprofen/Omeprazole is not recommended for use in children below 15 years due to a lack of data on safety and efficacy.

In elderly patients, patients with renal impairment (creatinine clearance 30-50 ml/min), hepatic impairment or congestive heart failure, the starting dose is 100 mg/ 20mg. This may be increased incremently to a maximum dose of 200 mg/20 mg per day depending on the clinical response.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

hypersensitivity to ketoprofen or to omeprazole or to any of the excipients

• last trimester of pregnancy

• history of asthma induced by administration of ketoprofen or similar acting substances, such as other non-steroidal anti-inflammatory agents (NSAIDs) or acetylsalicylic acid

• severe hepatic failure

• severe renal failure

• severe heart failure

• active peptic ulcer

• gastrointestinal bleeding, cerebrovascular bleeding or other active bleeding

• Concomitant use with St. John's wort or atazanavir sulphate

• Combination therapy with clarithromycin should not be used in patients with hepatic impairment

Linked to Ketoprofen component

The use of Axorid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or 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 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.

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, in patients with a platelet function disorder and in the elderly. These patients should commence treatment on the lowest dose available.

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.

The association with omeprazole allows to decrease gastrointestinal toxicity. Nevertheless gastrointestinal haemorrhage or ulcers/perforations can occur at any time in the course of treatment. They are not necessarily preceded by premonitory signs and can occur in patients with no history of such manifestations. They have to be closely monitored.

When GI bleeding occurs in patients receiving Axorid, 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.

Patients with asthma associated with chronic rhinitis, chronic sinusitis and/or nasal polyposis are more likely to exhibit allergic reactions after taking acetylsalicylic acid and/or non-steroidal anti-inflammatory agents than the general population. Administration of this product may induce an attack of asthma.

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 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 the patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Urine output and renal function should be closely monitored in patients with renal or hepatic impairment, in patients on diuretic treatment, following major surgery which involved hypovolaemia, and particularly in the elderly.

In the elderly, as half-life of NSAIDs is longer, doses should be reduced.

During long-term treatment, monitoring of blood count and hepatic and renal function is recommended.

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 for these reactions early in the course of the therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Axorid should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Patients with a previous history of photosensitivity or phototoxicity reactions should be carefully monitored.

Ketoprofen, as any other NSAID, may mask symptoms of an underlying infectious disease.

Ketoprofen component in Axorid is a prolonged-release formulation, therefore this treatment is not suitable when a quick onset of efficacy at the beginning of the treatment is required.

Linked to Omeprazole component

Decreased gastric acidity increases gastric counts of bacteria normally present in the gastro-intestinal tract. Treatment with acid-reducing medicinal products leads to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter.

In patients with severe impaired hepatic function, liver enzyme values should be checked periodically during treatment with omeprazole.

During concomitant regimens with omeprazole and other medicinal products caution should be exercised when administering additional medicinal products as interactions might occur. This is particularly important with products with a narrow therapeutic index such as warfarin and phenytoin. Levels of these should be measured as a dose reduction may be needed. Levels of ciclosporin may be increased and therefore plasma levels should be monitored.

Although not known with oral omeprazole, blindness and deafness have been reported with the injectable form; therefore, in severely ill patients, monitoring of visual and auditory senses is recommended.

Reactions to excipients

This product contains sucrose and patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this product.

The omeprazole formulation contains parahydroxybenzoates and may cause allergic reactions (possibly delayed).

Linked to ketoprofen component

Certain substances or therapeutic classes have a potential to contribute to the occurrence of hyperkalaemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), heparins (of low molecular weight or non-fractionated), cyclosporin and tacrolimus, and trimethoprim.

The occurrence of hyperkalaemia may depend upon the existence of a combination of factors.

This risk is increased by combined administration of the above-named substances.

Concomitant administration of ketoprofen with the following products calls for strict monitoring. If the combination can not be avoided, close clinical observation and monitoring of laboratory values are required.

Concomitant use not recommended

Other NSAIDs (including salicylates at high doses): increased risk of gastrointestinal ulcer and haemorrhage (due to additive synergic effects).

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin or heparin.

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

Lithium: elevation of the blood lithium levels, which may attain toxic levels (via reduced renal excretion of lithium).

If necessary, blood lithium levels should be closely monitored and the dosage of lithium adjusted during the combined treatment and after withdrawal of the NSAID.

Methotrexate (at doses above 15 mg/week):

Increased haematotoxicity of methotrexate (due to a reduction of renal clearance of methotrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding sites by NSAIDs).

Methotrexate should not be administered less than 12 hours before the start or after the end of a ketoprofen treatment.

Combinations to be administered with precaution

Diuretics, angiotensin converting enzyme inhibitors: acute renal failure in dehydrated patients (reduced glomerular filtration due to decreased renal prostaglandin synthesis).

Additionally, the antihypertensive effect is reduced.

The patient should be hydrated and renal function monitored at the start of treatment.

Methotrexate at low doses (less than 15 mg/week): increased haematotoxicity of methotrexate (due to a reduction of renal clearance of methotrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding sites).

Weekly monitoring of blood count is recommended during the first weeks of combined treatment.

Closer observation is necessary in the event of any (even mild) impairment of renal function and in elderly subjects.

Pentoxifylline: increased risk of haemorrhage.

Clinical observation should be increased and bleeding time monitored more frequently.

Zidovudine: risk of increased toxic effects on red blood cells (effect on the reticulocytes), with onset of severe anaemia eight days after the start of the NSAID treatment.

Full blood count and reticulocytes count are recommended eight to 15 days after the start of the NSAID treatment.

Beta-blockers (by extrapolation from reported interaction with indomethacin): reduced antihypertensive effect (inhibition of vasodilator prostaglandins by NSAIDs).

Ciclosporin, tacrolimus: risk of additive nephrotoxic effects, particularly in elderly subjects.

Intrauterine contraceptive device: there is a controversial possibility of decreased efficacy of the intrauterine contraceptive device.

Thrombolytics: increased risk of haemorrhage.

Linked to omeprazole component

Contraindications of concomitant use

St. John's wort: potential clinically significant decrease in omeprazole plasma concentrations.

Atazanavir: reduction in atazanavir exposure levels.

Clarithromycin: increase of plasma concentrations of omeprazole and clarithromycin in patients with hepatic impairment.

Combinations to be administered with precaution

Medicinal products metabolized by cytochrome P450: omeprazole is metabolised in the liver through cytochrome P450 isoforms (mainly CYP 2C19, S-mephenytoin hydroxylase) and inhibits enzymes of the CYP2C subfamily (CYP 2C19 and CYP 2C9) and can delay the elimination of other active substances metabolised by these enzymes. This has been observed for phenytoin and warfarin and benzodiazepines such as diazepam, triazolam and flurazepam. Periodic monitoring of patients receiving warfarin or phenytoin is recommended and a reduction of warfarin or phenytoin dose may be necessary. Other active substances that could be affected are hexabarbital, citalopram, imipramine, and clomipramine. Omeprazole may inhibit the hepatic metabolism of disulfiram with some possibly related cases of muscular rigidity reported.

Ciclosporin: the plasma levels of ciclosporin should be monitored in the patients treated with omeprazole, as an increase in ciclosporin levels is possible.

Digoxin: simultaneous treatment with omeprazole and digoxin in healthy subjects led to a 10 % increase in the bioavailability of digoxin as a result of increased gastric pH.

Ketoconazole, itraconazole: due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during omeprazole treatment.

Vitamin B12: omeprazole may reduce the oral absorption of vitamin B12. This should be taken into account in patients with low basal levels who undergo a long-term treatment with omeprazole.

There is no evidence of an interaction of omeprazole with caffeine, propranolol, theophylline, metoprolol, lidocaine, quinidine, phenacetin, estradiol, amoxicillin, budesonide, diclofenac, metronidazole, naproxen, piroxicam, or antacids. The absorption of omeprazole is not affected by alcohol.

Linked to ketoprofen component

The most commonly-observed adverse events are gastrointestinal in nature.

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 small increased risk of arterial thrombotic events (for example myocardial infarction or stroke)

Linked to omeprazole component

Some of the common reactions such as sleepiness, insomnia, vertigo and headache, GI symptoms, improve during continued therapy.

Meda Pharmaceuticals

POM – Prescription Only Medicine

05 March 2010