ZYLOPRIM (Page 3 of 4)

Pregnancy

Teratogenic Effects: Pregnancy Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this 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 clearly needed.

Experience with ZYLOPRIM during human pregnancy has been limited partly because women of reproductive age rarely require treatment with ZYLOPRIM. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving ZYLOPRIM during pregnancy.

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

Pediatric Use: ZYLOPRIM is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of ZYLOPRIM (allopurinol) began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of gout (average 6% in early studies). An analysis of current usage suggests that the incidence of acute gouty attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

The most frequent adverse reaction to ZYLOPRIM is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with ZYLOPRIM should be discontinued immediately if a rash develops (see WARNINGS). Some patients with the most severe reaction also had fever, chills, arthralgias, cholestatic jaundice, eosinophilia and mild leukocytosis or leukopenia. Among 55 patients with gout treated with ZYLOPRIM for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a pruritic maculopapular skin eruption, sometimes scaly or exfoliative. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin rash may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving ampicillin or amoxicillin concurrently with ZYLOPRIM has been reported to be increased (see PRECAUTIONS).

Most Common Reactions* Probably Causally Related:

Gastrointestinal: Diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase.
Metabolic and Nutritional: Acute attacks of gout.
Skin and Appendages: Rash, maculopapular rash.
*Early clinical studies and incidence rates from early clinical experience with ZYLOPRIM suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of gout following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage (see ADVERSE REACTIONS introduction, INDICATIONS AND USAGE, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Incidence Less Than 1% Probably Causally Related:

Body As a Whole: Ecchymosis, fever, headache.
Cardiovascular: Necrotizing angiitis, vasculitis.
Gastrointestinal: Hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, dyspepsia.
Hemic and Lymphatic: Thrombocytopenia, eosinophilia, leukocytosis, leukopenia.
Musculoskeletal: Myopathy, arthralgias.
Nervous: Peripheral neuropathy, neuritis, paresthesia, somnolence.
Respiratory: Epistaxis.
Skin and Appendages: Erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), hypersensitivity vasculitis, purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis, lichen planus.
Special Senses: Taste loss/perversion.
Urogenital: Renal failure, uremia (see PRECAUTIONS).

Incidence Less Than 1% Causal Relationship Unknown:

Body As a Whole: Malaise.
Cardiovascular: Pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation.
Endocrine: Infertility (male), hypercalcemia, gynecomastia (male).
Gastrointestinal: Hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia.
Hemic and Lymphatic: Aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesion of bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis.
Musculoskeletal: Myalgia.
Nervous: Optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido, depression, amnesia, tinnitus, asthenia, insomnia.
Respiratory: Bronchospasm, asthma, pharyngitis, rhinitis.
Skin and Appendages: Furunculosis, facial edema, sweating, skin edema.
Special Senses: Cataracts, macular retinitis, iritis, conjunctivitis, amblyopia.
Urogenital: Nephritis, impotence, primary hematuria, albuminuria.

OVERDOSAGE

Massive overdosing or acute poisoning by ZYLOPRIM has not been reported.

In mice, the 50% lethal dose (LD50 ) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose).

In the management of overdosage there is no specific antidote for ZYLOPRIM. There has been no clinical experience in the management of a patient who has taken massive amounts of ZYLOPRIM.

Both ZYLOPRIM and oxipurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of ZYLOPRIM is unknown.

DOSAGE AND ADMINISTRATION

The dosage of ZYLOPRIM to accomplish full control of gout and to lower serum uric acid to normal or near-normal levels varies with the severity of the disease. The average is 200 to 300 mg/day for patients with mild gout and 400 to 600 mg/day for those with moderately severe tophaceous gout. The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300-mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily. To reduce the possibility of flare-up of acute gouty attacks, it is recommended that the patient start with a low dose of ZYLOPRIM (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximal recommended dosage.

Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about 7 mg/dL for men and postmenopausal women and 6 mg/dL for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using uricosuric agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as 2 to 3 mg/dL and keep it there indefinitely.

While adjusting the dosage of ZYLOPRIM in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

In transferring a patient from a uricosuric agent to ZYLOPRIM, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of ZYLOPRIM gradually increased to the required dose needed to maintain a normal serum uric acid level.

It should also be noted that ZYLOPRIM is generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

Since ZYLOPRIM and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of ZYLOPRIM should consequently be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of ZYLOPRIM is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to be lengthened.

The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

For the prevention of uric acid nephropathy during the vigorous therapy of neoplastic disease, treatment with 600 to 800 mg daily for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with gout govern the regulation of dosage for maintenance purposes in secondary hyperuricemia.

The dose of ZYLOPRIM recommended for management of recurrent calcium oxalate stones in hyperuricosuric patients is 200 to 300 mg/day in divided doses or as the single equivalent. This dose may be adjusted up or down depending upon the resultant control of the hyperuricosuria based upon subsequent 24 hour urinary urate determinations. Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.

Children, 6 to 10 years of age, with secondary hyperuricemia associated with malignancies may be given 300 mg ZYLOPRIM daily while those under 6 years are generally given 150 mg daily. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.

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