Allopurinol

ACE Inhibitors: Isolated case reports indicate that concurrent administration of ACE inhibitors and allopurinol may increase the risk of hypersensitivity reactions, e.g., Stevens-Johnson syndrome, especially in patients with chronic renal failure. Patients already established on this combination should be monitored, and if a reaction occurs, the drugs should be discontinued.

Alcohol: Uricosuric effect of allopurinol may be decreased by alcohol.

Amoxicillin or Ampicillin: Concurrent ampicillin or amoxicillin and allopurinol therapy has resulted in an increased incidence of drug-induced skin rash. It is not clear whether this is due to allopurinol therapy.

Antacids: Concurrent administration of aluminum hydroxide-containing antacids with allopurinol may reduce gastrointestinal absorption of allopurinol. It is advisable that allopurinol be given at least 3 hours before the antacid.

Anticoagulants, Oral: Occasionally patients on oral anticoagulants and allopurinol develop an enhanced anticoagulant effect. INR should be monitored, and the oral anticoagulant dosage should be adjusted as needed.

Azathioprine and Mercaptopurine (Thiopurines): Allopurinol increases the pharmacologic and toxic effects of thiopurines by inhibiting their metabolism. Concomitant administration of azathioprine or mercaptopurine with allopurinol requires that initial thiopurine doses be reduced to 25% or 33% of the recommended initial dose. Subsequent doses should be adjusted according to clinical response.

Chlorpropamide: Allopurinol can compete with chlorpropamide for renal tubular secretion. When renal function is poor, the recognized risk of chlorpropamide's prolonged hypoglycemic activity may be increased if allopurinol is given concomitantly.

Co-trimoxazole: A few cases of thrombocytopenia have been reported in patients using this combination.

Cyclophosphamide: Concurrent cyclophosphamide and allopurinol therapy may increase the incidence of bone marrow depression as compared with cyclophosphamide alone, but the mechanism for this interaction is not known.

Diuretics: Thiazides and ethacrynic acid, when given with allopurinol, may increase serum oxypurinol concentrations and may thereby increase the risk of serious allopurinol toxicity, including hypersensitivity reactions, particularly in patients with decreased renal function.

Theophylline: Doses exceeding 600 mg/day of allopurinol may decrease theophylline clearance when both drugs are used for longer than 2 weeks. Since increases in serum theophylline concentrations of 25% have been reported, some patients may require monitoring for signs of possible theophylline toxicity and dosage adjustments during concurrent allopurinol therapy.

Uricosurics: Concomitant administration of a uricosuric agent, e.g., probenecid, and allopurinol may alter the disposition of both drugs. The combination usually results in an additive lowering of the serum uric acid level.

Drowsiness may occur. Patients should be cautioned not to engage in activities where alertness is mandatory until their response to the drug is known.

Allopurinol and oxypurinol are distributed into breast milk. Limited data indicates that an exclusively breastfed infant would receive a near-therapeutic dose if allopurinol 300 mg daily were given to the lactating mother. Exclusively breastfed infants of mothers receiving allopurinol should be monitored for signs of allergic reaction such as rash. Also, perform periodic CBC and differential blood counts on infants whose mothers require treatment with allopurinol. Allopurinol is considered by the American Academy of Pediatrics to be compatible with breastfeeding.

Allopurinol should not be given to children except those with hyperuricemia secondary to malignancy or with Lesch-Nyhan syndrome, because safety and effectiveness have not been established in other conditions.

No adverse fetal outcomes attributable to allopurinol have been reported in humans. Assess risk versus benefit.

The following adverse effects have been reported occasionally: fever, general malaise, headache, vertigo, somnolence, taste perversion, hepatic necrosis, granulomatous hepatitis, abnormal liver function tests, rise in urea, hyperlipidemia, visual disorder, cataracts, macular changes, neuropathy, impotence, diabetes mellitus, furunculosis, hypertension, hematuria, edema, drowsiness, peripheral neuritis.

Diarrhea, intermittent abdominal pain, nausea and vomiting have been reported. Gastrointestinal symptoms may be decreased by taking allopurinol with meals.

There have been occasional reports of reduction in the number of circulating formed elements of the blood, including bone marrow suppression, granulocytopenia and thrombocytopenia, usually in association with renal and/or hepatic disorders or in whom concomitant drugs have been administered which have a potential for causing these reactions.

Skin rash, usually maculopapular, is the most commonly reported adverse effect. Incidence of skin rash may be increased in the presence of renal disorders. In some instances, rashes have been followed by severe hypersensitivity reactions. Allopurinol should be discontinued immediately if such reactions occur (see Warnings). Exfoliative, urticarial or purpuric lesions, Stevens-Johnson syndrome (erythema multiforme), bullae and toxic epidermal necrolysis have also been reported. A few cases of alopecia with or without accompanying dermatitis have been reported. After recovery from mild reactions allopurinol may, if desired, be reintroduced at a low dose (e.g., 50 mg/day) and gradually increased. If the rash recurs, allopurinol should be discontinued permanently. The drug should not be reinstituted in patients who have had a severe reaction.

Skin reactions associated with exfoliation, fever, chills, nausea and vomiting, lymphadenopathy, arthralgia and/or eosinophilia have occurred. These reactions may occur at any time during therapy and necessitate the immediate and permanent withdrawal of allopurinol. A generalized hypersensitivity vasculitis has rarely led to irreversible hepatotoxicity and death. Corticosteroids may be beneficial in managing such reactions.

When generalized hypersensitivity reactions have occurred, renal and/or hepatic dysfunction have usually been present.

Children ≤ 10 years of age: 10 mg/kg/day in two to three divided doses. Maximum 800 mg/24 hours.

Alternatively in children < 6 years of age: 150 mg/day in three divided doses; 6 to 10 years of age: 300 mg/day in two to three divided doses.

For gout in children > 10 years of age and adults: 200 to 600 mg/day.

Response should be evaluated after approximately 48 hours by monitoring serum uric acid and/or urinary uric acid concentrations and adjusting the dose if necessary.

Because allopurinol concentrations are difficult to determine and because serum concentrations may not adequately reflect the amount of drug bound to xanthine oxidase in the tissues, serum urate concentrations should be used to monitor therapy. The upper limit of normal is about 430 µmol/L for men and postmenopausal women and 345 µmol/L for premenopausal women. By selecting the appropriate dose of allopurinol and using uricosuric agents in certain patients, it is possible to reduce the serum uric acid concentration to normal and, if desired, to hold it as low as 120 to 180 µmol/L. Combined therapy of allopurinol and a uricosuric agent will often allow a dosage reduction of both agents.

In patients who are being treated with uricosuric agents, colchicine and/or NSAIDs, it is wise to continue this therapy while adjusting the allopurinol dosage until a normal serum uric acid concentration and freedom from acute attacks have been maintained for several months. If desired, the patient may then be maintained on allopurinol therapy exclusively. When a uricosuric agent is being withdrawn, dosage of the uricosuric agent should be tapered over several weeks.

Prevention of Uric Acid Nephropathy During Treatment of Neoplastic Disease: Allopurinol 600 to 800 mg daily for 2 or 3 days starting 1 or 2 days prior to chemotherapy or radiation therapy. When allopurinol is used with mercaptopurine or azathioprine, the dosage of the latter drugs must be reduced (see Precautions, Drug Interactions). Continue treatment at a dosage adjusted to the serum uric acid concentration until there is no longer a risk of hyperuricemia and hyperuricosuria.

Allopurinol treatment can be maintained during cancer treatment, for prophylaxis of hyperuricemia that may be secondary to cancer or cancer chemotherapy. In prolonged treatment, 300 to 400 mg of allopurinol daily is usually sufficient to control the serum uric acid concentration.

Prophylaxis of Renal Calcium Lithiasis: 200 to 300 mg daily. Therapy should be continued indefinitely. Some patients have received maintenance doses of 200 to 300 mg daily for more than 7 years. In some patients, the maintenance dose may be reduced to 100 to 200 mg daily.

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