Rheumox capsules

1. Name Of The Medicinal Product

Rheumox Capsules

2. Qualitative And Quantitative Composition

Azapropazone Dihydrate 300mg

3. Pharmaceutical Form

Rheumox Capsules: Two-tone orange size 1 capsule, containing Azapropazone Dihydrate 300mg. This product also contains sunset yellow (E110) and erythrosine lake (E127).

4. Clinical Particulars

4.1 Therapeutic Indications

Rheumox is a non-steroidal anti-inflammatory analgesic agent indicated in the treatment of rheumatoid arthritis, ankylosing spondylitis and attacks of acute arthritis in patients for whom other therapy has been ineffective.

Rheumox should be used in suitable low-risk patients (see contraindications, precaution and warnings).

4.2 Posology And Method Of Administration

Route of Administration: Oral.

The lowest effective dose of Rheumox should be used for the shortest duration.

Dosage recommendations for Rheumox are lower for patients older than 60 years and for patients of any age who have reduced renal function. Rheumox is contraindicated in severe renal insufficiency. If any abnormality is suspected, renal function should be investigated before commencing treatment with Rheumox.

Rheumatoid arthritis and ankylosing spondylitis

Adults under 60 years with adequate renal function.

Rheumox 600 Tablets: One 600mg tablet night and morning.

Rheumox 300mg Capsules: One 300mg capsule four times daily or two 300mg capsules night and morning.

Adults over 60 years:

Rheumox 300mg capsules: One 300mg capsule twice daily.

Adults of any age with reduced renal function:

Please follow dosage instructions for adults over 60 years, given above.

Acute Gout

Adults under 60 years with adequate renal function: 1,800mg per day in divided doses until the acute symptoms subside, normally by the fourth day, after which 1200mg per day in divided doses is taken until symptoms have resolved. If symptoms persist then appropriate alternative therapy for chronic gout should be considered. In treating acute gout, it is good practice to ensure that the patient increases their fluid intake.

Adults over 60 years: Rheumox is not recommended in acute gout in patients with a creatinine clearance of less than 60ml per minute.

1,800mg in divided doses during the first 24 hours followed by 1,200mg per day in divided doses. A maximum maintenance dose of 600mg per day in divided doses should be achieved doses should be achieved as early as possible preferably by the fourth day. Treatment with Rheumox should only be continued until the acute symptoms resolve. If symptoms persist then appropriate alternative therapy for chronic gout should be considered. In treating acute gout, it is good practice to ensure that the patient increases their fluid intake.

Adults of any age with reduced renal function: Please follow dosage instructions for adults over 60 years, given above.

Children: Not recommended.

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

4.3 Contraindications

I: Use in patients with a history or evidence of peptic ulceration or ulcerative colitis.

II: Use in patients with severe renal insufficiency.

III: Rheumox should not be given to patients with a history or evidence of blood dyscrasia.

IV: Use in patients with a history or evidence of blood insufficiency.

V: Use in patients with severe hepatic insufficiency.

VI: Rheumox significantly potentiates the action of warfarin in many patients and must not be used with this or other oral anticoagulants.

VII: Rheumox increases the plasma concentration of phenytoin and should not be given to patients taking this drug.

VIII: Rheumox should not be given to patients taking methotrexate.

IX: Rheumox, as with other non-steroidal anti-inflammatory drugs (NSAIDs) should not be used in patients suffering from porphyria.

X: Rheumox should not be given to patients with Severe heart failure.

4.4 Special Warnings And Precautions For Use

I: Rheumox should only be considered for use in rheumatoid arthritis, ankylosing spondylitis and attacks of acute gouty arthritis in patients for whom other therapy has been ineffective.

II: Azapropazone should not be used in patients who are at a high risk of developing serious adverse events known to be associated with NSAID therapy, for example, patients who are suffering from gastrointestinal, severe renal or heart disease, or who are taking diuretics. This would include elderly patients and particularly those who are already have or are suspected to have any of these conditions. In addition, patients who are on long-term therapy or multiple therapies should be carefully evaluated before treatment with Rheumox is initiated.

III: Serious gastrointestinal adverse effects such as bleeding, ulceration and perforation can occur at any time with or without warning symptoms in patients treated with Rheumox. Although this applies to all patients treated with Rheumox. Although this applies to all patients, elderly or debilitated patients are less able to tolerate serious ulceration or bleeding events. If any sign of gastrointestinal bleeding occurs, Rheumox should be stopped immediately.

IV: Azapropazone is excreted unchanged mainly by the kidney and should therefore be used with caution in older patients and in adults with any reduced renal function. NSAIDs in general inhibit renal prostaglandin synthesis and in patients with reduced renal function this action may result in overt renal decompensation. In such cases, the reduced dosage recommendations for the treatment of adults over 60 years should be followed. If any abnormality is suspected, renal function should be fully investigated before commencing therapy with Rheumox. See also contraindications.

V: A large number of photosensitivity reactions have been reported in association with Rheumox. Patients taking azapropazone should be advised to avoid direct exposure to sunlight or to use sunblock preparations.

VI: Rheumox can cause fluid retention. It should therefore be used with caution in patients with fluid retention, hypertension or heart failure.

VII: If abnormal liver function tests occur, persist or worsen, or if clinical signs and symptoms indicate the development of liver disease, Rheumox should be discontinued.

VIII: Inhibition of renal lithium clearance by Rheumox has not been reported but the possibility of this occurring should be borne in mind.

IX: Rheumox may be precipitate bronchospasm in patients with bronchial asthma or allergic disease.

X: The concomitant administration of corticosteroids with Rheumox may increase the risk of gastrointestinal bleeding and ulceration.

XI: Patients on long-term treatment with Rheumox should be carefully monitored and regularly reviewed. Haematological effects associated with chronic NSAID therapy should be borne in mind.

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

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 Azapropazone.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

I: Consult the section 'Contraindication' with phenytoin, warfarin and methotrexate.

II: Since azapropazone is highly protein bound, it may possibly displace other protein bound drugs. It may therefore interfere with the blood sugar lowering effect of oral hypoglycaemic agents. Concurrent use of the drugs is not recommended.

III: Concomitant use with azapropazone of lithium or digoxin may cause an increase in serum levels of these compounds. Concomitant use of cimetidine may cause an increase in azapropazone and decrease in cimetidine plasma levels respectively.

4.6 Pregnancy And Lactation

Animal reproduction studies did not result in foetal abnormalities but safety in human pregnancy cannot be assumed and its use should be avoided in pregnancy whenever possible.

Azapropazone is excreted in small quantities in breast milk and should not therefore be used in breast feeding women.

4.7 Effects On Ability To Drive And Use Machines

None stated (presumed to be safer or unlikely) to produce any effect).

4.8 Undesirable Effects

See also contraindications, precautions and warnings.

I: Serious gastrointestinal events including bleeding, gastric and duodenal ulceration, perforation and haemorrhage have been reported.

Epidemiological studies show that these reactions occur more frequently than for other NSAIDs. In addition diarrhoea, dyspepsia, nauseam, vomiting, melaena, and stomatitis have also been reported.

II: Blood disorders including thrombocytopenia, pancytopenia, neutropenia and leucopenia have been reported. Anaemia and haemolytic anaemia have also been reported and some patients may develop a positive direct Coombs test with haemolytic anaemia. Rheumox should be discontinued in the presence of haemolytic anaemia or a positive direct Coombs test.

III: NSAIDs have been reported to cause nephrotoxicity in various forms and their use can lead to interstitial nephritis, nephrotic syndrome and renal failure. Renal impairment and renal failure have been reported in association with Rheumox.

IV: Oedema and angioneurotic oedema.

V: Occasional central nervous system effects including dizziness, headache, and fatigue.

VI: Skin rashes including a high frequency of photosensitivity reactions.

VII: Allergic alveolitis, pulmonary fibrosis and fibrosing alveolitis has been reported rarely and if this occurs Rheumox should be continued. Many NSAIDs may propitiate bronchospasm in patients with bronchial asthma or allergic disease, and this has been reported in association with Rheumox.

VIII: Hepatic side effects including jaundice and hepatitis have been reported rarely.

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

4.9 Overdose

If overdosage should occur, two specific courses of action are suggested on theoretical grounds. Since Rheumox is poorly soluble in gastric juice, stomach lavage should recover any gastric residue of the drug, provided of course that it is done early enough. Since Rheumox is predominantly excreted by the kidney, forced alkaline diuresis is theoretically indicated.

In addition to the above mentioned treatment, patients should be managed with symptomatic and supportive care.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Azapropazone is a non-steroidal anti-inflammatory agent with anti-inflammatory analgesic and antipyretic actively established by standard animal pharmacology tests and confirmed via clinical studies and use in man. In addition, this active ingredient is hyperuricaemic, reducing serum urate by enhancing urate excretion.

5.2 Pharmacokinetic Properties

Rheumox 600 and Rheumox Capsules are immediate release preparations containing the active ingredient azapropazone dihydrate. Human pharmacokinetic studies with azapropazone have demonstrated rapid absorption following oral dosing with the attainment of maximum plasma levels at approximately 4 hours post dosing.

Azapropazone is reported to be highly bound to the plasma protein following absorption and in animal studies its distributions throughout body tissues is related to plasma concentration.

Only low concentrations are reported in the brain and fatty tissues thus confirming the low lipophilic activity of azapropazone.

Metabolic studies have demonstrated that azapropazone is not extensively metabolised and is excreted primarily as unchanged azapropazone by the kidney.

5.3 Preclinical Safety Data

The oral LD50 of azapropazone in rats was 4200mg/kg. This value is equivalent to 150 times the maximum recommended human dose.

When administered to animals at the maximum tolerated daily doses, azapropazone did not exhibit a carcinogenic effect.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Lauryl sulphate, silica, gelatin, erythrosine E127, sunset yellow E110 and titanium dioxide E171.

6.2 Incompatibilities

None started.

6.3 Shelf Life

Blister packs 36 months

Amber glass bottle 60 months

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

Screw cap amber glass bottle (pack sizes: 12, 28, 56, 100, 112, 500)

PVC/aluminium foil blisters (pack sizes: 4, 14, 28, 56, 112)

6.6 Special Precautions For Disposal And Other Handling

None stated.

Administrative Data

7. Marketing Authorisation Holder

Goldshield Pharmaceuticals Ltd.

NLA Tower

Croydon

Surrey

CR0 OXT

UK.

8. Marketing Authorisation Number(S)

PL 12762/0021

9. Date Of First Authorisation/Renewal Of The Authorisation

01st February 1998

10. Date Of Revision Of The Text

12/04/2007