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Aloprim

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Aloprim

Warnings
Precautions

WARNINGS

ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances with oral allopurinol, a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity and, on rare occasions, death.

In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300 to 600 mg of ALOPRIM (allopurinol sodium) for Injection per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects (see PRECAUTIONS: DRUG INTERACTIONS).

A few cases of reversible clinical hepatotoxicity have been noted in patients taking oral allopurinol, and in some patients asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.

Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.

The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. Thus, in patients with decreased renal function, such combinations should be administered with caution.

PRECAUTIONS

General

A fluid intake sufficient to yield a daily urinary output of at least two liters in adults and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of xanthine calculi under the influence of allopurinol therapy and (2) help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

A few patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during allopurinol administration, although a decrease in BUN has also been observed. In patients with hyperuricemia due to malignancy, the vast majority of changes in renal function are attributable to the underlying malignancy rather than to therapy with allopurinol. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal function deteriorated after allopurinol was begun. Renal failure is rarely associated with hypersensitivity reactions to allopurinol.

Patients with decreased renal function do require lower doses of allopurinol. Patients should be carefully observed during the early stages of allopurinol administration so that the dosage can be appropriately adjusted for renal function.

In patients with severely impaired renal function or decreased urate clearance, the half-life of oxypurinol in the plasma is greatly prolonged. Patients should be treated with the lowest effective dose, in order to minimize possible side effects. The appropriate dose of ALOPRIM (allopurinol sodium) for Injection for patients with a creatinine clearance ≤ 10 mL/min is 100 mg per day. For patients with a creatinine clearance between 10 and 20 mL/min, a dose of 200 mg per day is recommended. With extreme renal impairment (creatinine clearance less than 3 mL/min), the interval between doses may also need to be extended.

Bone marrow suppression has been reported in patients receiving allopurinol; however, most of these patients were receiving concomitant medications with the known potential to cause such an effect. The suppression has occurred from as early as 6 weeks to as long as 6 years after the initiation of allopurinol therapy.

Laboratory Tests

The correct dosage and schedule for maintaining the serum uric acid within the normal range is best determined by using the serum uric acid as an index.

In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy (see WARNINGS).

Allopurinol and its primary active metabolite, oxypurinol, are eliminated by the kidneys; therefore, changes in renal function have a profound effect on dosage. In patients with decreased renal function, or who have concurrent illnesses which can affect renal function such as hypertension and diabetes mellitus, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient's allopurinol dosage reassessed.

The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are given allopurinol.

Carcinogenesis, Mutagenesis and Impairment of Fertility:

Carcinogenesis: Allopurinol was administered at doses up to 20 mg/kg/day to mice and rats for the majority of their life span. No evidence of carcinogenicity was seen in either mice or rats (at doses about 1/6 or 1/3 the recommended human dose on a mg/m2 basis, respectively).

Mutagenesis: Allopurinol administered intravenously to rats (50 mg/kg) was not incorporated into rapidly replicating intestinal DNA. No evidence of clastogenicity was observed in an in vivo micronucleus test in rats, or in lymphocytes taken from patients treated with allopurinol (mean duration of treatment 40 months), or in an in vitroassay with human lymphocytes.

Impairment of Fertility: Allopurinol oral doses of 20 mg/kg/day had no effect on male or female fertility in rats or rabbits (about 1/3 or 1/2 the human dose on a mg/m2 basis, respectively).

Pregnancy

Teratogenic Effects: Pregnancy Category C. 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. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Experience with allopurinol during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol. Two unpublished reports and one published paper describe women giving birth to normal offspring after receiving oral allopurinol during pregnancy. There have been no pregnancies reported in patients receiving ALOPRIM (allopurinol sodium) for Injection, but it is assumed that the same risks would apply.

Nursing Mothers

Allopurinol and oxypurinol have been found in the milk of a mother who was receiving allopurinol. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when allopurinol is administered to a nursing woman.

Pediatric Use

Clinical data are available on approximately 200 pediatric patients treated with ALOPRIM (allopurinol sodium) for Injection. The efficacy and safety profile observed in this patient population were similar to that observed in adults (see INDICATIONS and DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of ALOPRIM (allopurinol sodium) for Injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Last reviewed on RxList: 5/28/2009
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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