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For Leukemia, Lymphoma, Tumor, Dosage, Warning & Side Effects


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/m 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 vitro assay 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 ½ the human dose on
a mg/m basis, respectively).

Pregnancy

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/m 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.

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