Allopurinol (Page 3 of 5)

7.1 Drugs Known to Affect the Occurrence of Skin Rash and Hypersensitivity

Concomitant use of the following drugs may increase the risk of skin rash, which may be severe: bendamustine, thiazide diuretics, ampicillin and amoxicillin. Renal impairment may further increase risk with concomitant use of thiazide diuretics [see Warnings and Precautions (5.1) (5.2) and Clinical Pharmacology (12.2)].

Monitor renal function and reduce the dose of allopurinol in patients with concomitant thiazide diuretic use and impaired renal function [see Dosage and Administration (2.2)].

Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when use concomitantly with these drugs.

7.2 Other Drugs Known to Have Clinically Important Drug Interactions with Allopurinol

Table 4: Interventions for Clinically Important Drug Interactions with Allopurinol
Capecitabine
Clinical Impact Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy.
Intervention Avoid the use of allopurinol during treatment with capecitabine.
Cyclosporine
Clinical Impact Concomitant use of allopurinol increases cyclosporine concentrations which may increase the risk of adverse reactions.
Intervention Increase frequency of monitoring cyclosporine concentrations as reflectedin the prescribing information when used concomitantly with allopurinol.
Cytotoxic Agents
Clinical Impact Concomitant use of allopurinol with cytotoxic agents increases bone marrow suppression among patients with neoplastic disease, except leukemia [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)].
Intervention Blood count monitoring and regular physician follow-up recommended.
Fluorouracil
Clinical Impact Based on non-clinical data, allopurinol may decrease anti-tumor activitydue to suppression of phosphorylation of 5-fluorouracil.
Intervention Concomitant administration with fluorouracil should be avoided.
Mercaptopurine or Azathioprine
Clinical Impact Allopurinol inhibits xanthine oxidase mediated metabolism of mercaptopurine and azathioprine. Concomitant use of allopurinol increases the exposure of either mercaptopurine or azathioprine which may increase the risk of their adverse reactions including myelosuppression [see Warnings and Precautions (5.4)].
Intervention Reduce the dosage of mercaptopurine or azathioprine as recommended inthe respective prescribing information.
Pegloticase
Clinical Impact Concomitant use of allopurinol and pegloticase may potentially blunt the rise of serum uric acid levels and increase the risk of pegloticase related anaphylaxis in patients whose uric acid level increase to above 6 mg/dL.
Intervention Discontinue and do not institute allopurinol therapy during treatment withpegloticase.
Theophylline
Clinical Impact Concomitant use of allopurinol doses greater than or equal to 600 mg/daymay decrease the clearance of theophylline.
Intervention Monitor and adjust theophylline doses as reflected in the prescribinginformation.
Uricosuric Agents
Clinical Impact Uricosuric agents increase the excretion of the active allopurinol metabolite oxypurinol. Concomitant use with uricosuric agents decreases oxypurinol exposure which may reduce the inhibition of xanthine oxidase by oxypurinol and increases the urinary excretion of uric acid.
Intervention Monitor uric acid levels due to the increased chance of hypouricemiceffects.
Warfarin
Clinical Impact Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect.
Intervention Patients on concomitant therapy should be monitored for excessive anticoagulation. The INR should be checked frequently and warfarin dosage adjusted accordingly when allopurinol is added to warfarin therapy.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animals, allopurinol may cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been described in exposed animals (see Data). Allopurinol and its metabolite oxypurinol have been shown to cross the placenta following administration of maternal allopurinol.

Available limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in published literature, 2 infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to a fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

There was no evidence of fetotoxicity or teratogenicity in rats or rabbits treated during the period of organogenesis with oral allopurinol at doses up to 200 mg/kg/day and up to 100 mg/kg/day, respectively (about three times the human dose on a mg/m2 basis). However, there is a published report in pregnant mice that single intraperitoneal doses of 50 or 100 mg/kg (about 1/3 or 3/4 the human dose on a mg/m2 basis) of allopurinol on gestation days 10 or 13 produced significant increases in fetal deaths and teratogenic effects (cleft palate, harelip, and digital defects). It is uncertain whether these findings represented a fetal effect or an effect secondary to maternal toxicity. In another published study with no reported maternal toxicity, allopurinol administered orally at 15 or 45 mg/kg to pregnant rats during organogenesis caused embryonic resorptions, growth retardation, decreased fetal weight, and skeletal, liver, kidney, and brain abnormalities. In rats, maternal treatment with allopurinol in normoxic pregnancy has been shown to increase the cardiac protein levels of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) in the adult male offspring. The mechanism underlying this effect is not understood. However, this effect was not matched by an increase in left ventricular end diastolic pressure or sympathetic dominance in hearts of adult male offspring of normoxic pregnancy treated with allopurinol.

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