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Sulfinpyrazone

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: G-28315; Sulfinpirazona; Sulfinpirazonas; Sulfinpyratsoni; Sulfinpyrazon; Sulfinpyrazonum; Sulphinpyrazone; Sulphoxyphenylpyrazolidine; Szulfinpirazon
BAN: Sulfinpyrazone
INN: Sulfinpyrazone [rINN (en)]
INN: Sulfinpirazona [rINN (es)]
INN: Sulfinpyrazone [rINN (fr)]
INN: Sulfinpyrazonum [rINN (la)]
INN: Сульфинпиразон [rINN (ru)]
Chemical name: 1,2-Diphenyl-4-(2-phenylsulphinylethyl)pyrazolidine-3,5-dione
Molecular formula: C23H20N2O3S =404.5
CAS: 57-96-5
ATC code: M04AB02
Read code: y031Q; y07ex

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Sulfinpyrazone). A white or almost white powder. Very slightly soluble in water; sparingly soluble in alcohol; dissolves in dilute solutions of alkali hydroxides. Protect from light.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Sulfinpyrazone). A white to off-white powder. Practically insoluble in water and in petroleum spirit; soluble in alcohol and in acetone; sparingly soluble in dilute alkali.

Adverse Effects and Treatment

The most frequent adverse effects of sulfinpyrazone involve the gastrointestinal tract, and include nausea, vomiting, diarrhoea and abdominal pain. It may cause gastric bleeding or aggravate existing peptic ulcers. Skin rashes have been reported, and may be associated with a hypersensitivity reaction. Aplastic anaemia, agranulocytosis, leucopenia, and thrombocytopenia have been reported rarely as have raised liver enzyme values, jaundice, and hepatitis, renal impairment, salt and water retention, and acute renal failure.

When used in chronic gout, particularly during the first few months of treatment, sulfinpyrazone may precipitate acute attacks and there is a risk of uric acid renal calculi developing.

Symptoms of overdosage include hypotension, acute renal failure, arrhythmias, respiratory disorders, convulsions, and coma, as well as gastrointestinal effects. Treatment of overdose may involve activated charcoal if a substantial amount has been ingested within 1 hour of presentation, followed by symptomatic and supportive therapy.

Effects on the kidneys. Although renal failure has been reported occasionally in patients receiving sulfinpyrazone for gout many of the cases have occurred in those given the drug for myocardial infarction. Acute renal failure may also occur after overdose or in patients with intravascular volume depletion.

Precautions

Sulfinpyrazone should not be started during an acute attack of gout; however, treatment is usually continued when acute attacks occur in patients already receiving the drug, and the acute attack is treated separately. Sulfinpyrazone is not suitable for the control of hyperuricaemia associated with cancer or cancer chemotherapy.

Sulfinpyrazone should be given with care to patients with renal impairment or heart failure and is contra-indicated in those with severe renal or hepatic impairment. It is also contra-indicated in patients with blood dyscrasias or blood coagulation disorders, and in patients with uric acid renal calculi or peptic ulcer disease or a history of such disorders.

Sulfinpyrazone should not be given to patients hypersensitive to it or to other pyrazole derivatives such as phenylbutazone; nor should it be given to patients in whom hypersensitivity reactions (including bronchospastic reactions in asthmatics) have been provoked by aspirin or by other drugs with prostaglandin-synthetase inhibiting activity.

To reduce the risk of uric acid renal calculi an adequate fluid intake (2 to 3 litres daily) is required; alkalinising the urine with sodium bicarbonate or potassium citrate may also be considered. It is recommended that patients have periodic full blood counts to detect any haematological abnormalities.

Renal-function tests involving aminohippuric acid or phenolsulfonphthalein may be invalidated.

Porphyria. Sulfinpyrazone is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems.

Interactions

Doses of sulfinpyrazone may need to be increased if it is given with other drugs, such as diuretics or pyrazinamide, that increase uric acid concentrations. Sulfinpyrazone and salicylates including aspirin are mutually antagonistic and should not be used together. There may also be an increased risk of bleeding when sulfinpyrazone is used with other drugs such as aspirin that inhibit platelet function.

Sulfinpyrazone’s renal tubular secretion is inhibited by probenecid although with little clinical effect. Since sulfinpyrazone, like probenecid, inhibits the tubular secretion of weak organic acids, interactions can be expected with penicillins although the effect is not considered to be clinically useful.

Sulfinpyrazone can potentiate the action of some drugs. The most significant interaction of this type involves warfarin, acenocoumarol, and possibly other coumarin anticoagulants. Patients receiving sulfinpyrazone and such an anticoagulant should have their prothrombin times monitored and the anticoagulant dosage reduced as appropriate. Similarly, sulfinpyrazone may potentiate the effects of phenytoin (see Antigout Drugs), and possibly some sulfona-mides and sulfonylureas.

In contrast, sulfinpyrazone may increase the metabolism of theophylline and diminish its activity.

Pharmacokinetics

Sulfinpyrazone is readily absorbed from the gastrointestinal tract. It is about 98% bound to plasma proteins and has a plasma half-life of about 2 to 4 hours. Sulfinpyrazone is partly metabolised in the liver and some of the metabolites are active. On long-term therapy, sulfinpyrazone induces its own metabolism. Unchanged drug and metabolites are mainly excreted in the urine.

Uses and Administration

Sulfinpyrazone is a uricosuric drug used to treat hyperuricaemia associated with chronic gout. It also has some antiplatelet activity.

Sulfinpyrazone is used in chronic gout to inhibit the renal tubular reabsorption of uric acid so increasing the urinary excretion of uric acid, lowering plasma-urate concentrations, and eventually reducing urate deposits in the tissues. It is therefore of value in hyperuricaemia caused by decreased uric acid excretion rather than increased urate production and is not used for hyperuricaemia associated with cancer or cancer therapy. Sulfinpyrazone has little analgesic or anti-inflammatory action and is of no value in acute gout. Initially, it may increase plasma concentrations of urate and uric acid by dissolving deposits. This can trigger or exacerbate acute attacks, hence sulfinpyrazone should not be given until an acute attack has completely subsided, and an NSAID or colchicine may be given during the first few months.

The initial oral dose of sulfinpyrazone in the UK is 100 to 200 mg daily (the USA allows up to 200 mg twice daily), taken with meals or milk. This may be gradually increased over 1 to 3 weeks until a daily dosage of 600 mg is reached; up to 800 mg daily may be given if necessary. After the plasma-urate concentration has been controlled, the daily maintenance dose may be reduced to as low as 200 mg. An adequate fluid intake is required to prevent formation of uric acid renal calculi.

Antiplatelet therapy. Sulfinpyrazone inhibits platelet function, thereby inhibiting thrombosis. A meta-analysis of studies, conducted by the Antiplatelet Trialists’ Collaboration, has shown that it reduces the risk of myocardial infarction, stroke, or vascular death in patients at high risk of occlusive vascular disease and also reduces the risk of occlusion in patients undergoing arterial reperfusion and revascularisation procedures. However, aspirin is the most widely used antiplatelet therapy, as discussed under Cardiovascular Risk Reduction.

Preparations

British Pharmacopoeia 2008: Sulfinpyrazone Tablets

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Sulfinpyrazone Capsules; Sulfinpyrazone Tablets.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Anturan¤; Austria: Anturan¤; Canada: Anturan¤; Novo-Pyrazone¤; France: Anturan¤; Germany: Anturano¤; Ireland: Anturan¤; Israel: Anturan¤; Italy: Enturen; Netherlands: Enturen¤; New Zealand: Anturan¤; SPZ¤; Portugal: Sulfinona; South Africa: Anturan¤; Spain: Falizal¤; Switzerland: Anturan¤; United Kingdom: Anturan; United States: Anturane

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