PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

ZYLOPRIM® (allopurinol)

100 mg 90 Tablets Bottle

NDC 70199-031-90

Rx Only

ZYLOPRIM® (allopurinol)
200 mg 90 Tablets Bottle

NDC 70199-032-90

Rx Only

ZYLOPRIM® (allopurinol)

300 mg 90 Tablets Bottle

NDC 70199-033-90

Rx Only

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animals, ZYLOPRIM 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 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
Human Data

Experience with ZYLOPRIM during human pregnancy has been limited partly because women of reproductive age rarely require treatment with ZYLOPRIM. A case report published in 2011 described the outcome of a full-term pregnancy in a 35-year-old woman who had recurrent kidney stones since age 18 who took allopurinol throughout the pregnancy. The child had multiple complex birth defects and died at 8 days of life. A second report in 2013 provided data on 31 prospectively ascertained pregnancies involving mothers exposed to allopurinol for varying durations during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the normal expected range; however, one child had severe malformations similar to those described in the cited earlier case report.

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 2.4 times the human dose on a mg/m2 basis). However, there is a published report in pregnant mice that single intraperitoneal doses of 50 mg/kg or 100 mg/kg (about 0.3 or 0.6 times 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.

8.2 Lactation

Risk Summary
Allopurinol and oxypurinol are present in human milk. Based on information from a single case report, allopurinol and its active metabolite, oxypurinol, were detected in the milk of a mother receiving 300 mg of allopurinol daily at 5 weeks postpartum. The estimated relative infant dose were 0.14 mg/kg and 0.2 mg/kg of allopurinol and between 7.2 mg/kg to 8 mg/kg of oxypurinol daily. There was no report of effects of allopurinol on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatments with ZYLOPRIM and for one week after the last dose.

8.4 Pediatric Use

Hyperuricemia Associated with Cancer Therapy
The safety and effectiveness of allopurinol for the management of pediatric patients with leukemia, lymphoma and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels have been established in approximately 200 pediatric patients. The efficacy and safety profile observed in this patient population were similar to that observed in adults.

Primary or Secondary Gout
The safety and effectiveness of ZYLOPRIM have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients.

Recurrent Calcium Oxalate Calculi
The safety and effectiveness of ZYLOPRIM have not been established for the management of pediatric patients with recurrent calcium oxalate calculi.

Inborn Errors of Metabolism
The safety and effectiveness of ZYLOPRIM have not been established in pediatric patients with rare inborn errors of purine metabolism.

8.6 Renal Impairment

ZYLOPRIM and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function have a profound effect on exposure. In patients with decreased renal function or who have concurrent illnesses which can affect renal function, perform periodic laboratory parameters of renal function and reassess the patient's dosage of ZYLOPRIM [see Dosage and Administration (2.6), Warnings and Precautions (5.3)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of tumorigenicity was observed in male or female mice or rats that received oral allopurinol for the majority of their life spans (greater than 88 weeks) at doses up to 20 mg/kg/day (0.1 and 0.2 times the MRHD on a mg/m2 basis in mice and rats, respectively).
Allopurinol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. Allopurinol administered intravenously to rats (50 mg/kg) was not incorporated into rapidly replicating intestinal DNA. No evidence of clastogenicity was observed in lymphocytes taken from patients treated with allopurinol (mean duration of treatment 40 months), or in an in vitro assay with human lymphocytes.
Allopurinol oral doses of 20 mg/kg/day had no effect on male or female fertility in rats or rabbits (approximately 0.2 or 0.5 times the MRHD on a mg/m2 basis, respectively).

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

ZYLOPRIM (allopurinol) is available in multiple tablet strengths with functional scoring and package sizes (bottles with child-resistant caps) as listed in Table 4.

TABLE 4: ZYLOPRIM Presentations

Tablet Strength	Tablet Description	Package Sizes (NDC)
100 mg	Flat-faced raised hexagon, beveled edge, white tablet, one side engraved “ZYLOPRIM 100” with a score bar, and plain on the other side	Bottles of: 90 tablets (NDC 70199-031-90) 100 tablets (NDC 70199-031-01) 500 tablets (NDC 70199-031-05) 1,000 tablets (NDC 70199-031-99)
200 mg	Biconvex, round, white scored tablets, imprinted ZYLOPRIM about the upper periphery, and 200 on the lower half, below the score, and plain on the other side	Bottles of: 90 tablets (NDC 70199-032-90) 100 tablets (NDC 70199-032-01) 500 tablets (NDC 70199-032-05) 1,000 tablets (NDC 70199-032-99)
300 mg	Flat-faced raised hexagon, beveled edge, peach tablet, one side engraved “ZYLOPRIM 300” with a score bar, and plain on the other side	Bottles of: 90 tablets (NDC 70199-033-90) 100 tablets (NDC 70199-033-01) 500 tablets (NDC 70199-033-05) 1,000 tablets (NDC 70199-033-99)

Storage and Handling
Store at 20°C to 25°C (USP Controlled Room Temperature) (68°F to 77°F) in a dry place. Dispense in a tight container as defined in the USP.