Platelet Inhibitory Agent – Uricosuric Agent – Prophylactic Agent for Reduction of Mortality Post-myocardial Infarction
Action And Clinical Pharmacology: Sulfinpyrazone inhibits thrombotic processes that are associated with platelet adhesion, aggregation and reduced platelet survival.
Sulfinpyrazone reduces serum urate levels, prevents formation of new tophi, and promotes resorption of existing tophi by increasing clearance of uric acid and water through the kidneys.
Sulfinpyrazone has been shown to reduce cardiac mortality during the second through the seventh month after myocardial infarction. Whether benefits can be expected after this period is unknown. The exact mechanism by which this is achieved is unclear.
Indications And Clinical Uses: Clinical states in which abnormal platelet behavior is a causative or associated factor, as demonstrated by: recurrent venous thrombosis, arteriovenous shunt thrombosis.
Chronic phases of gout, both the intercritical or silent stage and the gouty arthritis stage.
Prophylactic use post-myocardial infarction.
Contra-Indications: Initiation of sulfinpyrazone therapy during an acute attack of gout. Active peptic ulcer. Known or suspected hypersensitivity to sulfinpyrazone and other pyrazolone derivatives. A history of severe parenchymal lesions of the liver or kidneys (e.g., hepatitis, cirrhosis or acute interstitial nephritis). Patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by ASA or other prostaglandin-synthase inhibitors. Porphyria. A history of blood dyscrasis. Hemorrhagic diatheses (e.g., blood coagulation disorders).
Manufacturers’ Warnings In Clinical States: Especially in patients with elevated plasma uric acid levels and/or those with a history of nephrolithiasis or renal colic, and in patients receiving concomitant diuretic medication, particular care should be taken in initiating sulfinpyrazone therapy by ensuring adequate fluid intake, alkalinizing the urine if necessary, and using an incremental dosage regimen. Frequent determinations of BUN and serum creatinine should be done, especially during early drug treatment and in patients with significant renal impairment. When resuming treatment after interruption of the medication, the incremental dosage regimen should be adopted.
Avoid salicylate therapy, unless administered under careful supervision: Salicylates and citrates antagonize the uricosuric action of sulfinpyrazone and may therefore interfere with uric acid excretion and thus exacerbate gout.
Salicylates may cause unpredictable and, at times, serious prolongation of the bleeding time and in combination with sulfinpyrazone may cause bleeding episodes. If, during sulfinpyrazone therapy, ASA or other related substances which may affect hemostasis (e.g., NSAIDs) must be used, patients should be urged to report immediately any undue bleeding episode.
As salicylates compete with sulfinpyrazone not only for protein binding but also for renal tubular secretion, the plasma concentrations of both drugs may rise if co-administered.
Sulfinpyrazone should be administered with care to patients having a history of gastric disorder or healed peptic ulcer.
Should allergic skin reactions occur, discontinue sulfinpyrazone.
Pregnancy: The safe use of sulfinpyrazone in pregnancy has not been established. Sulfinpyrazone should not be used during pregnancy, especially in the first trimester, unless, in the opinion of the treating physician, the expected benefits outweigh the potential risks.
Lactation: It is not known whether sulfinpyrazone can be found in breast milk. The benefits of drug treatment for the mother and that of breast-feeding must be weighed against the risk for the child.
Precautions: As with all pyrazole compounds, patients receiving sulfinpyrazone should be kept under close medical supervision. Periodic blood counts are recommended.
As with any long-term treatment with uricosuric agents, renal function tests should be performed regularly, especially if the patient has pre-existing renal insufficiency.
Since sulfinpyrazone may lead to sodium and water retention, caution is indicated in patients with overt or latent heart failure.
At the start of treatment, attacks of gout may occur more frequently when urate is mobilized from affected joints. Patients should therefore be cautioned to maintain an adequate fluid intake (see Warnings). If an attack of gout occurs, sulfinpyrazone should be continued but supplemented by other treatments, e.g., colchicine or nonsteroidal antirheumatic drugs – but not salicylates (see Warnings). Prophylactic treatment with these agents may also be indicated when commencing treatment with sulfinpyrazone.
Initiation of treatment with Anturan during an acute attack of gout is contraindicated (see Contraindications).
Drug Interactions: Sulfinpyrazone should be used with caution in conjunction with oral anticoagulants (especially vitamin K antagonists such as nicoumalone and warfarin) since there may be an increased risk of hemorrhage. Sulfinpyrazone not only modifies platelet behavior and therefore interferes with the coagulation process, but also potentiates the action of anticoagulants by inhibiting their metabolism by microsomal liver enzymes. As a result, anticoagulant dosage must be adjusted according to the prothrombin time, which should be checked daily for a few days prior to initiating or withdrawing treatment. Regular estimates of bleeding time should be performed.
Displacement of sulfonamides from their plasma protein binding sites by pyrazoles may lead to a rise in their plasma concentrations and thus potentiate their action.
Sulfinpyrazone increases the half-lives and plasma concentrations of sulfonylureas (e.g., tolbutamide), both by displacement from serum albumin binding sites and by inhibiting metabolism by microsomal liver enzymes. Sulfinpyrazone may therefore potentiate the hypoglycemic effects of sulfonylureas. As with other pyrazole compounds (e.g., phenylbutazone), sulfinpyrazone may also potentiate the hypoglycemic effect of insulin.
Displacement of phenytoin by sulfinpyrazone from its plasma protein binding sites as well as inhibition of microsomal liver enzymes delays the metabolism of phenytoin, thus prolonging its half-life and raising its plasma concentration.
Sulfinpyrazone may raise the plasma concentration of penicillin by competing for serum albumin binding sites and renal tubular secretion.
Sulfinpyrazone lowers the plasma concentration of theophylline by inducing hepatic enzymes.
Sulfinpyrazone should not be administered with salicylates or related substances that interfere with hemostatis (see Warnings).
Adverse Reactions: The most frequently reported adverse reactions to sulfinpyrazone have been gastric complaints or disturbances, such as nausea, vomiting and diarrhea. Sulfinpyrazone may aggravate or reactivate peptic ulcer. There have been isolated cases of gastrointestinal bleeding and ulcers.
Impairment of renal function with accompanying changes in electrolytes has been reported. As well, occasional overt acute renal failure has been reported. A clear causal relationship could not be established. These events occurred with high initial doses of sulfinpyrazone; renal function returned to normal upon withdrawal of the drug.
Sodium and water retention have been reported.
Allergic skin rashes e.g., drug rash, urticaria, have been reported in rare instances. In cases of urticaria, the drug should be withdrawn (see Warnings).
Blood dyscrasias (anemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia) have rarely been associated with the administration of sulfinpyrazone.
Isolated cases of hepatic dysfunction (elevated transaminases and alkaline phosphatase), jaundice, and hepatitis have been reported (see Contraindications).
Symptoms And Treatment Of Overdose: Symptoms: (based on overdosage with pyrazolidine analogues): nausea, vomiting, pain in the upper abdomen, diarrhea, ataxia, gastrointestinal hemorrhage, hypotension, cardiac arrhythmias, hyperventilation, respiratory disorders, impairment of consciousness, coma, convulsions, oliguria or anuria, acute renal failure, renal colic and jaundice.
Treatment: There is no specific antidote for sulfinpyrazone. Induce emesis and/or gastric lavage; give activated charcoal; administer saline cathartic if deemed appropriate; administer i.v. glucose infusion; give symptomatic supportive treatment (see below). Dialysis is indicated in severe poisoning. Note that forced diuresis is of no value.
Symptomatic Management: Keep a close watch on the patient’s vital functions (level of consciousness, cardiovascular, respiratory, hepatic and renal functions). If necessary provide supportive measures.
Respiration: Analeptic therapy if respiration is affected. Endotracheal intubation and artificial respiration to combat respiratory failure.
Metabolic Acidosis: Sodium bicarbonate.
Acute renal colic due to high uric acid excretion and intraluminal urate crystallization in distal tubules and collecting ducts: Increase the solubility of uric acid by alkalinizing the urine (to pH 7 or above), by giving sodium bicarbonate and/or a carbonic anhydrase inhibitor such as acetazolamide. Administer fluid and a potent diuretic (e.g., furosemide or mannitol) to increase urine volume.
Prolonged renal failure: hemodialysis.
Gastrointestinal hemorrhage: Appropriate measures for early diagnosis and treatment if necessary.
Dosage And Administration: Since sulfinpyrazone has a potent uricosuric effect, treatment should be initiated with an incremental dosage regimen, as follows: 1st and 2nd day: 100 mg twice daily or 200 mg once daily; 3rd and 4th day: 200 mg twice daily; 5th and 6th day: 200 mg 3 times daily; from 7th day onwards: 200 mg 4 times daily.
Recurrent Venous Thrombosis and Arteriovenous Shunt Thrombosis: Maintenance daily dose is 600 to 800 mg in 3 to 4 divided doses and should be titrated to meet the patient’s needs.
Gout: Daily maintenance dose is 200 to 400 mg. The dosage may be increased up to 800 mg if necessary, or reduced to 200 mg when the urate blood level has been satisfactorily controlled. Minimum effective dose should be maintained without interruption even during acute attacks. The change from other uricosuric agents to sulfinpyrazone does not have to follow an incremental dosing regimen.
Reduction of Cardiac Mortality During the 2nd Through the 7th Month, after Myocardial Infarction: Daily maintenance dose is 200 mg q.i.d. Treatment following myocardial infarction should not be started until at least 2 weeks after the acute event.
Whenever possible, distribute the total dose over the 24-hour period. Sulfinpyrazone should be taken with meals or milk. The maximum recommended dosage is 800 mg daily.
Availability And Storage: Each white, round, biconvex, sugar-coated tablet, branded in blue with GEIGY on one side and ANTURAN on the other side, contains: sulfinpyrazone 200 mg. Nonmedicinal ingredients: carnauba wax, cellulose compounds, cerulean blue, gelatin, lactose, magnesium stearate, polyethylene glycol, silicon dioxide, starches (corn and synthetic), sugar, talc and titanium dioxide. Energy: 3.1 kJ (0.73 kcal). Sodium:
ANTURAN® Novartis Pharmaceuticals Sulfinpyrazone Platelet Inhibitory Agent – Uricosuric Agent – Prophylactic Agent for Reduction of Mortality Post-myocardial Infarction