General Monograph, CPhA

Xanthine Oxidase Inhibiton

This monograph has been compiled by CPhA. It may contain information different from that approved by HPB, Health Canada, and the pharmaceutical manufacturers’ approval has not been requested.

Pharmacology: Allopurinol and its active metabolite, oxypurinol, inhibit xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Inhibition of this enzyme accounts for the major pharmacological effects of allopurinol. In addition, allopurinol increases reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis, via an action involving the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). The resultant increase in nucleotide concentration leads to feedback inhibition of de novo purine synthesis. Allopurinol thereby decreases uric acid concentrations in both serum and urine.

Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine. Plasma concentrations of these oxypurines are only slightly increased, and renal clearance is rapid and greater than that of uric acid. In the absence of allopurinol, normal urinary output of oxypurines is almost solely in the form of uric acid. After administration of allopurinol, it is composed of hypoxanthine, xanthine and uric acid. Since each has its independent solubility, the concentration of uric acid in plasma is reduced without exposing the urinary tract to an excessive load of uric acid, thus decreasing the risk of crystalluria. By lowering the uric acid concentration in plasma below its limits of solubility, allopurinol facilitates dissolution of tophi.

Indications: The treatment of gout, either primary, or secondary to hyperuricemia which occurs in polycythemia vera, myeloid metaplasia or other blood dyscrasias.

Allopurinol is also indicated in the treatment of primary or secondary uric acid nephropathy, with or without accompanying symptoms of gout.

Allopurinol may be useful in patients with gouty nephropathy, in those who form renal urate stones, and in those with unusually severe disease.

Allopurinol may be given prophylactically to prevent tissue urate deposition or renal calculi as well as acute urate nephropathy and resultant renal failure in patients with leukemias, lymphomas or other malignancies who are receiving radiation therapy or antineoplastic drugs that will result in elevated serum uric acid concentrations.

To prevent the occurrence and recurrence of uric acid stones and renal calcium lithiasis in patients with hyperuricemia and/or hyperuricosuria.

Allopurinol should not be given to patients who are hypersensitive to it or who have previously developed a severe reaction to this drug.

Warnings: Allopurinol should be discontinued at first appearance of skin rash or any sign of adverse reactions. The skin rash may be, in some instances, followed by more severe hypersensitivity reactions such as exfoliative, urticarial or purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme) and, very rarely, a generalized vasculitis which may lead to irreversible hepatotoxicity and death. Hypersensitivity reactions, frequently marked by fever and eosinophilia, usually begin 2 to 4 weeks after start of therapy and appear related to pre-existing renal dysfunction, elevated oxypurinol plasma levels and/or concurrent thiazide therapy.

Periodic liver function tests, renal function tests and complete blood cell counts should be performed in all patients on allopurinol. Alterations in liver function test results, including transient elevations of serum alkaline phosphatase, urinary urobilinogen, and serum AST and ALT, have occurred in some patients. Reversible hepatomegaly, hepatocellular damage (including necrosis), granulomatous changes, hepatitis and jaundice have also occurred.

Observe patients with impaired renal or hepatic functions carefully during the early stages of allopurinol administration and withdraw the drug if increased abnormalities in hepatic or renal function appear.

Precautions: Allopurinol is not effective for the treatment of acute gouty attacks since it has no anti-inflammatory action and may intensify and prolong inflammation during the acute phase.

Acute gouty attacks may be precipitated at the start of treatment with allopurinol in new patients, and these may continue even after serum uric acid concentrations begin to fall, usually for the first 6 to 12 months (see Dosage).

Because therapy with allopurinol is not without some serious risks, the drug is used for the management of gout when uricosurics cannot be used because of adverse effects, allergy, renal insufficiency or inadequate response, when there are visible tophi or radiographic evidence of uric acid deposits and stones, when urinary uric acid excretion is greater than 5.35 mmol/day, or when serum urate concentrations are greater than 510 to 540 µmol/L (8.5 to 9 mg/100 mL) and a family history of tophi and low urate excretion exists.

In conditions where the body’s miscible urate pool is greatly increased (e.g., malignant disease and its treatment; Lesch-Nyhan syndrome), the reduction of urate formation by allopurinol is accompanied by a relative rise in the xanthine and hypoxanthine fractions. In these circumstances, the absolute concentration of xanthine could rise to a level at which deposition in the urinary tract may occur. This risk may be minimized by adequate hydration to achieve maximum diuresis. Alkalinization, of considerable benefit in relation to urate stones, may be less so in relation to xanthine stones.

Drug Interactions : 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 may reduce gastrointestinal absorption of allopurinol. It is advisable that allopurinol be given at least 3 hours before an antacid.

Angiotensin Converting Enzyme Inhibitors: Isolated case reports indicate that concurrent administration of captopril and allopurinol may predispose to hypersensitivity reactions, e.g., Stevens-Johnson syndrome. Patients on the combination should be monitored, and if a reaction occurs, the drugs should be discontinued.

Azathioprine and Mercaptopurine: Allopurinol increases the pharmacologic and toxic effects of thiopurines by increasing their half-lives. Concomitant administration of azathioprine or mercaptopurine and 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: In the presence of allopurinol, there may be competition 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.

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

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.

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.

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.

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

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

Children: 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.

Pregnancy: Allopurinol is not recommended for use during pregnancy or in women of childbearing potential unless the potential benefits outweigh the possible risks.

Lactation: Allopurinol and oxypurinol are distributed into milk. Use with caution in nursing women.

Adverse Effects: Dermatologic: 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. Withdraw allopurinol 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, withdraw allopurinol permanently. The drug should not be reinstituted in patients who have had a severe reaction.

Generalized Hypersensitivity: 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.

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

Hematologic: 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.

Miscellaneous: 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.

Symptoms: Nausea and vomiting.

Treatment: No treatment is normally required provided allopurinol is withdrawn and adequate hydration is maintained to facilitate the drug’s excretion.

Dosage: Dosage of allopurinol varies with the severity of the disease and should be adjusted according to the response and tolerance of the patient.

Adults: Dosage range of 100 to 800 mg daily divided into 1 to 3 doses. Single dose should not exceed 300 mg. Allopurinol is better tolerated when taken with meals.

In all patients receiving allopurinol, a high fluid intake (e.g., 2.5 to 3 L) and the maintenance of a neutral or, preferably, slightly alkaline urine are recommended.

Gout: Some investigators have reported an increase in acute attacks of gout during the early stages of allopurinol administration. Accordingly, allopurinol should be initiated at a dose of 100 to 200 mg daily and inreased by 100 mg daily at weekly intervals, until a serum uric acid concentration of about 360 µmol/L (6 mg/dL) or less is attained, or until the maximum recommended dosage of 800 mg/day (in patients with normal renal function) is reached. In addition, concurrent administration of colchicine (0.6 mg twice daily) or a nonsteroidal anti-inflammatory drug is recommended as prophylaxis during the first 3 to 6 months of allopurinol therapy. Serum urate concentrations are often reduced more slowly with allopurinol and minimum concentrations may not be reached for 1 to 3 weeks.

After serum urate concentrations are controlled, it may be possible to reduce dosage; the minimum effective dose is 100 to 200 mg/day. The average maintenance dosage is 200 to 300 mg/day for patients with mild gout, 400 to 600 mg/day for patients with moderately severe tophaceous gout, and 700 to 800 mg/day in severe conditions.

Dosage in Renal Impairment: Since allopurinol and its metabolites are excreted by the kidney, drug accumulation can occur in renal failure and the initial dose of allopurinol should consequently be reduced. With a creatinine clearance of 0.33 to 0.17 mL/s, a daily dosage of 200 mg of allopurinol is suitable. When the creatinine clearance is less than 0.17 mL/s, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 0.05 mL/s), the interval between doses may also need to be lengthened. Some clinicians recommend the following maintenance dosages of allopurinol based on the patient’s creatinine clearance. Refer to the Clin-Info Section for estimation of creatinine clearance.

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 the selection of the appropriate dose, together with the use of 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 uricosurics will often result in a dosage reduction of both agents.

In patients who are being treated with uricosuric agents, colchicine and/or anti-inflammatory agents, 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 transferred to allopurinol therapy exclusively. When a uricosuric agent is being withdrawn, dosage of the uricosuric agent should be gradually reduced over several weeks.

Prevention of Uric Acid Nephropathy during Aggressive Therapy of Neoplastic Disease: Treatment with 600 to 800 mg daily for 2 or 3 days prior to chemotherapy or irradiation is advisable. When allopurinol is used with mercaptopurine or azathioprine, dosage of the latter drugs must be reduced (see Precautions). Continue treatment at a dosage adjusted to the serum uric acid concentration until there is no longer a threat of hyperuricemia and hyperuricosuria. Allopurinol treatment can be maintained during cancer therapy for prophylaxis of hyperuricemia which may arise during the natural crises of the disease. In prolonged treatment, 300 to 400 mg of allopurinol daily is usually enough 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.

Children: For the treatment of secondary hyperuricemia associated with malignancies (6 to 10 years of age): 300 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.

ALLOPURINOLGeneral Monograph, CPhAXanthine Oxidase Inhibitor This monograph has been compiled by CPhA.

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