Axorid 100 mg/20 mg modified-release capsules.

Axorid 200 mg/20 mg modified-release capsules.

Each modified-release capsule contains 100 mg or 200 mg ketoprofen and 20 mg omeprazole.

Excipients:

Each capsule contains propyl-p-hydroxybenzoate, methyl-p-hydroxybenzoate, and 80 mg or 105 mg sucrose.

For a full list of excipients, see section 6.1.

Modified-release capsule, hard.

(Modified-release capsule).

Capsule, hard with opaque yellow cap and opaque white body (100 mg/20 mg) or opaque white cap and body (200 mg/20 mg), 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 or duodenal ulcers.

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 (see section 4.4).

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 (see section 4.4).

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

• last trimester of pregnancy (see section 4.6)

• 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 (see section 4.5)

• Combination therapy with clarithromycin should not be used in patients with hepatic impairment (see section 4.5)

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 (see section 4.2).

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 (see also section 4.2 and 4.3).

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 (see section 4.3), 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 (see section 4.5).

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 Ketoprofen/Omeprazole Ethypharm, 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 (see section 4.8).

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 (see section 4.3).

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 (see section 4.2).

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 (see section 4.8). 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 (see section 4.5). 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 (see section 4.5).

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 (see section 4.4).

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin or heparin (see section 4.4).

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

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 (see section 4.3)

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.

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

Clopidogrel: : In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.

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.

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.

Pregnancy

Clinical experience of use in pregnancy is limited.

During the last trimester of pregnancy, all prostaglandin synthesis inhibitors might

• expose the fetus to:

• expose the mother and child, at the end of pregnancy, to possible prolongation of bleeding time

• inhibit uterine contractions and delay/prolong delivery

Consequently, Axorid should be administered only if necessary during the first two trimesters of pregnancy. With the exception of very restricted obstetrical uses that require specialised monitoring, Axorid is contraindicated in the last trimester of pregnancy.

Lactation

Since NSAIDs and omeprazole are excreted in breast milk, their use should be avoided during breast-feeding as a precautionary measure.

Fertility

The use of ketoprofen, as with any drug known to inhibit cyclooxygenase / prostaglandin synthesis, might impair 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.

Dizziness and drowsiness are common reactions associated with ketoprofen and omeprazole. Visual disturbances (see section 4.8) have also been reported. If patients are affected they should not drive, operate machinery or take part in activities where these symptoms could put themselves or others at risk.

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) (see section 4.4)

Linked to omeprazole component

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

Symptoms

Linked to ketoprofen component

In adults and adolescents, the main signs of overdose are headache, dizziness, drowsiness, nausea, vomiting, diarrhoea and abdominal pain. In serious intoxication, hypotension, respiratory depression and gastrointestinal haemorrhage have been observed.

Linked to omeprazole component

There have been rare reports of omeprazole overdoses up to 2,400 mg as a single oral dose. Symptoms including nausea, vomiting, dizziness, abdominal pain, diarrhoea, headache, apathy, depression and confusion have been reported. However, these were transient and without serious outcome and no specific treatment was needed.

Management of overdose due to ketoprofen

The patient should be transferred immediately to a specialised hospital unit where symptomatic treatment should be instituted. Owing to the slow release characteristics of the product, ketoprofen will continue to be absorbed 16 hours after ingestion.

Evacuation of gastric content or administration of activated charcoal may be performed in order to reduce the absorption of ketoprofen.

There is no specific antidote.

Pharmacotherapeutic group: Propionic acid derivates: ATC Code: M01AE53, associated to a proton pump inhibitor.

Ketoprofen is a non-steroidal anti-inflammatory agent of the propionic group, derived from arylcarboxylic acid.

It has the following properties:

• analgesic activity

• antipyretic activity

• anti-inflammatory activity

• inhibition of platelet functions

All these properties result from the reduction of prostaglandin synthesis by inhibition of the cyclo-oxygenase pathway.

Omeprazole, a substituted benzimidazole, is a gastric proton pump inhibitor, directly and dose-dependently inhibiting the enzyme H⁺,K⁺-ATPase, so blocking the final step of acid production from gastric parietal cells. It inhibits both basal and stimulated acid secretion, irrespective of the type of stimulus, increasing the pH-value and reducing the volume of the gastric acid secretion. It has low affinity for other membrane-bound receptors (such as the histamine H₂, muscarine M₁ or gastrinergic receptors).

Omeprazole is a pro-drug and, as a weak base, accumulates in the acid environment of the parietal cells and will only become effective after being protonised and rearranged. In an acid environment (pH of less than 4) the protonised omeprazole is converted to the active metabolite - omeprazole sulphonamide which covalently binds to the proton pump. The duration of the inhibition of acid secretion is therefore substantially longer than the period in which omeprazole-base is present in plasma. The degree of inhibition of acid secretion is directly correlated to the area under the plasma concentration-time curve (AUC) but not to the plasma concentration at any given time.

Axorid includes a prolonged-release form of ketoprofen and a gastroresistant release form of omeprazole, both suitable for a once-a-day therapeutic dosage regimen.

Pharmacokinetic profiles of ketoprofen and omeprazole components in Axorid are comparable to those of ketoprofen and omeprazole components administered separately.

Ketoprofen

Absorption

After oral administration, ketoprofen is almost completely absorbed from the intestinal tract but undergoes first-pass metabolism.

A maximum plasma concentration of about 4.5 µg/ml is attained about 6 hours after administration of a dose of 200 mg; levels are found at the 24th hour. The product does not accumulate after repeated administration in the course of treatment.

The degree of absorption is not influenced by concomitant food intake.

Distribution

Ketoprofen prolonged-release formulation procures continuous, regular impregnation with ketoprofen.

Ketoprofen is 99 % bound to plasma proteins.

Ketoprofen diffuses into synovial fluid, where levels higher than the serum concentrations are found more than 4 hours after oral administration.

It crosses the placental barrier.

Metabolism

Two processes are involved in the biotransformation of ketoprofen: one very minor (hydroxylation), and the other largely predominant (conjugation with glucuronic acid).

Less than 1 % of the dose of ketoprofen administered is recovered in unchanged form in the urine, whereas the glucuronide metabolite accounts for about 65 to 75 %.

Excretion

The drug is excreted as metabolites essentially by the urinary route. The rate of excretion is rapid, since 50 % of the dose administered is eliminated in the first 6 hours, regardless of the route of administration. The prolonged-release form does not alter the renal excretion processes.

The half-life for the terminal elimination phase is about 7 hours.

In the 5 days after oral administration, 75 to 90 % of the dose is excreted by the kidneys and 1 to 8 % in the faeces.

Populations at risk

The elimination of ketoprofen is decreased in the elderly and the half-life is prolonged.

The half-life in patients with renal insufficiency increases with the severity of the impairment (see section 4.2).

Omeprazole

Absorption and Distribution

Omeprazole is acid labile and is formulated as gastroresistant granules. Absorption takes place in the small intestine with peak plasma concentrations of omeprazole occurring within 1 to 3 hours after oral administration. Absolute bioavailability is about 30-40 % at doses of 20-40 mg. The distribution volume of omeprazole in the body is relatively small (0.3 l/kg of body weight) and corresponds to that of the extracellular fluid and approximately 95% is protein bound.

After intravenous administration of 40 mg omeprazole for 5 days, the absolute measured bioavailability increased by about 50 %; this can be explained by decreased hepatic clearance due to saturation of the CYP2C19 enzyme.

Concomitant administration with food

Concomitant administration of food delays omeprazole absorption with lower peak concentrations but without affecting bioavailability.

Metabolism

Omeprazole is entirely metabolised, mainly in the liver by CYP 2C19. A small percentage of the patients lack a functional CYP2C19 enzyme and have reduced elimination rate of omeprazole. The sulphone, sulphide and hydroxy-omeprazole metabolites are found in plasma but have no significant effect on acid secretion.

About 20% of administered dose is excreted in faeces and the remaining 80% is excreted in urine as metabolites (mainly hydroxy-omeprazole and the corresponding carboxylic acid).

Elimination

The plasma half-life is about 40 minutes, and the total plasma clearance is 0.3 to 0.6 l/min. In a small percentage of the patients (CYP 2 C19 poor metabolisers) a reduced elimination rate of omeprazole has been observed. In these cases, the terminal elimination half-life can be approximately 3 times as long as the normal value, and the area under the plasma concentration-time curve (AUC) can increase by up to 10 fold.

Pharmacokinetics in the elderly

The bioavailability of omeprazole is slightly elevated in the elderly and the elimination rate slightly diminished, but individual values are nearly equal to that of young healthy subjects and there is no indication that elderly patients on therapeutic doses of omeprazole are at increased risk of increased adverse effects

Pharmacokinetics in renal impairment

In patients with renal impairment, the kinetics of omeprazole was very similar to that in healthy subjects. But, as renal elimination is the most important excretory pathway for metabolised omeprazole, the elimination rate is reduced corresponding to the degree of renal function reduction.

Pharmacokinetics in hepatic impairment

In patients with chronic hepatic disease the clearance of omeprazole is reduced, and the plasma half-life can increase up to approximately 3 hours. The bioavailability can then be greater than 90%. 20 mg of omeprazole once daily for 4 weeks was tolerated well, and no accumulation of omeprazole or its metabolites was observed.

No preclinical data on the combination of active substances are available.

Ketoprofen

In several in vitro and in vivo mutagenicity tests ketoprofen had no significant positive effects. Long-term experiments in rats and mice showed no evidence of a carcinogenic potential of ketoprofen.

Experiments in various animal species showed no evidence of a teratogenic effect of ketoprofen.

From 6 mg/kg/day, ketoprofen resulted in an impairment of implantation and fertility in female rats.

Omeprazole

Preclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity, toxicity to reproduction or genotoxicity. Gastric enterochromaffin-like-cell hyperplasia and carcinoids have been observed in life-long studies in rats treated with omeprazole or subjected to partial fundectomy. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition.

Capsule contents:

Sucrose

Maize starch

Hypromellose

Dimethicone emulsion (containing propyl-p-hydroxybenzoate (E216), methyl-p-hydroxybenzoate (E218), sorbic acid, sodium benzoate, polysorbate 20, octylphenoxy polyethoxy ethanol and propylene glycol)

Polysorbate 80

Mannitol

Diacetylated monoglycerides

Talc

Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30%

Polyacrylate dispersion 30%

Ammonio methacrylate copolymer type A

Ammonio methacrylate copolymer type B

Triethyl citrate

Stearoyl macrogolglycerides

Colloidal anhydrous silica

Capsule shell:

Yellow iron oxide (E 172)

Titanium dioxide (E 171)

Gelatin

Not applicable.

18 months.

Do not store above 25°C.

Store in the original container in order to protect from moisture.

Polyethylene bottles with a tamper evident polypropylene screw cap containing silica gel desiccant, packed in cardboard boxes. Pack sizes: 10, 28 or 30 capsules.

Not all pack sizes may be marketed.

No special requirements.

Meda Pharmaceuticals Ltd.

Skyway House,

Parsonage Road,

Takeley,

Bishop's Stortford,

CM22 6PU,

United Kingdom

23/2/2009

16/12/2011