Allopurinol

1 INDICATIONS AND USAGE Allopurinol for injection is indicated for the management of adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels and who cannot tolerate oral therapy. Allopurinol for injection is a xanthine oxidase inhibitor indicated for the management of adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels and who cannot tolerate oral therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION • Recommended Dosage ( 2.2 ) Adult Patients 200 mg/m 2 /day to 400 mg/m 2 /day Maximum 600 mg/day Pediatric Patients Starting Dose 200 mg/m 2 /day Maximum 400 mg/day • Recommended Dosage in Adult Patients with Renal Impairment ( 2.2 , 5.2, 8.6 ) Creatinine Clearance Recommended Daily Dose 10 to 20 mL/min 200 mg/day Less than 10 mL/min 100 mg/day On dialysis 50 mg every 12 hours, or 100 mg every 24 hours 2.1 Recommended Dosage Initiate therapy with allopurinol for injection 24 to 48 hours before the start of chemotherapy known to cause tumor cell lysis. Additionally, administer fluids sufficient to yield a daily urinary output of at least two liters in adults with a neutral or, preferably, slightly alkaline urine. The recommended daily dose of allopurinol for injection is shown in Table 1. Administer the daily dose as single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals at a rate appropriate for the volume of infusate. Table 1: Recommended Daily Dose of Allopurinol for Injection Adult Patients 200 mg/m 2 /day to 400 mg/m 2 /day intravenously Maximum 600 mg/day Pediatric Patients Starting Dose 200 mg/m 2 /day intravenously Maximum 400 mg/day The dosage of allopurinol for injection to lower serum uric acid to normal or near-normal varies with the severity of the disease. Monitor serum uric acid levels at least daily and administer allopurinol for injection at a dose and frequency to maintain the serum uric acid within the normal range. Discontinue allopurinol for injection when the patient is able to take oral therapy or when the risk of tumor lysis has abated. 2.2 Dosage Modifications in Patients with Renal Impairment Reduce the dose of allopurinol for injection in patients with impaired renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. The recommended dosage reductions of allopurinol for injection in adult patients with renal impairment are shown in Table 2. Table 2: Recommended Daily Dose of Allopurinol for Injection in A dult Patients with Renal Impairment Creatinine Clearance Recommended Daily Dose 10 to 20 mL/min 200 mg/day Less than 10 mL/min 100 mg/day On dialysis 50 mg every 12 hours, or 100 mg every 24 hours Treatment with allopurinol for injection has not been studied in pediatric patients with severe renal impairment or on dialysis. For pediatric patients with severe renal impairment or on dialysis, consider the risks and potential benefits before initiating treatment with allopurinol for injection [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ]. 2.3 Preparation Instructions Reconstitute and further dilute allopurinol for injection prior to intravenous infusion. Reconstitution • Reconstitute each vial of allopurinol for injection with 25 mL of Sterile Water for Injection, USP to obtain a concentration of 20 mg/mL of allopurinol. • Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear as a clear, almost colorless solution with no more than a slight opalescence. Do not use if the reconstituted solution contains particulate matter or discoloration is present. Dilution • Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP to obtain a final concentration of less than 6 mg/mL. • Inspect the diluted solution for particulate matter or discoloration and discard if present. • If not used immediately, the diluted allopurinol for injection solution can be stored at 20° to 25°C (68° to 77°F) for up to 10 hours after initial reconstitution. The storage includes time for infusion. Do not refrigerate the reconstituted and/or diluted product. • If stored, the administration should be completed within 10 hours after reconstitution. • Discard unused portion. 2.4 Administration Instructions Do not mix allopurinol for injection with or administer it through the same intravenous port as agents which are incompatible in solutio …

3 DOSAGE FORMS AND STRENGTHS For Injection: 500 mg of allopurinol as a sterile, white lyophilized powder or cake in a single-dose vial for reconstitution. For injection: 500 mg as a white lyophilized powder or cake in a single-dose vial for reconstitution ( 3 )

4 CONTRAINDICATIONS Allopurinol for injection is contraindicated in patients with a history of severe reaction to any formulation of allopurinol. Known hypersensitivity to allopurinol. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Skin Rash and Hypersensitivity [see Warnings and Precautions ( 5.1 )] Renal Function Impairment [see Warnings and Precautions ( 5.2 )] Hepatotoxicity [see Warnings and Precautions ( 5.3 )] Myelosuppression [see Warnings and Precautions ( 5.4 )] Drowsiness [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence > 1%) are skin rash, nausea, vomiting, and renal failure/insufficiency. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of allopurinol was evaluated in an uncontrolled compassionate use study of 1,378 patients with advanced malignancies requiring treatment with cytotoxic chemotherapy and in patients with other serious conditions. Adverse reactions were reported in 9% (125/1378) of the patients treated with allopurinol. The most common adverse reaction was skin rash. Two patients experience serious adverse reactions (decreased renal function and generalized seizure) and one patient experienced severe diarrhea. Approximately 1.1% of patients experienced allergic adverse reactions (including rash, eosinophilia, local injection site reaction). A listing of the adverse reactions reported from clinical trials follows: Incidence Greater Than 1%: Cutaneous/Dermatologic: rash (1.5%) Genitourinary: renal failure/insufficiency (1.2%) Gastrointestinal: nausea (1.3%), vomiting (1.2%) Incidence Less Than 1%: Body as a Whole: fever, pain, chills, alopecia, infection, sepsis, enlarged abdomen, mucositis/pharyngitis, blast crisis, cellulitis, hypervolemia Cardiovascular: heart failure, cardiorespiratory arrest, hypertension, pulmonary embolus, hypotension, decreased venous pressure, flushing, headache, stroke, septic shock, cardiovascular disorder, ECG abnormality, hemorrhage, bradycardia, thrombophlebitis, ventricular fibrillation Cutaneous/Dermatologic: urticaria, pruritus, local injection site reaction Gastrointestinal: diarrhea, gastrointestinal bleeding, hyperbilirubinemia, splenomegaly, hepatomegaly, intestinal obstruction, jaundice, flatulence, constipation, liver failure, proctitis Genitourinary: hematuria, increased creatinine, oliguria, kidney function abnormality, urinary tract infection Hematologic: leukopenia, marrow aplasia, thrombocytopenia, eosinophilia, neutropenia, anemia, pancytopenia, ecchymosis, bone marrow suppression, disseminated intravascular coagulation Metabolic: hypocalcemia, hyperphosphatemia, hypokalemia, hyperuricemia, electrolyte abnormality, hypercalcemia, hyperglycemia, hypernatremia, hyponatremia, metabolic acidosis, edema, glycosuria, hyperkalemia, lactic acidosis, water intoxication, hypomagnesemia Neurologic: seizure, status epilepticus, myoclonus, twitching, agitation, mental status changes, cerebral infarction, coma, dystonia, paralysis, tremor Pulmonary: respiratory failure/insufficiency, ARDS, increased respiration rate, apnea Musculoskeletal: arthralgia Other: hypotonia, diaphoresis, tumor lysis syndrome

7 DRUG INTERACTIONS Clinically important interactions with the drugs listed below were observed in patients undergoing treatment with an oral allopurinol formulation. Capecitabine: Avoid the concomitant use of allopurinol ( 7.2 ). Pegloticase: Discontinue and do not institute allopurinol therapy during treatment with pegloticase ( 7.2 ). Mercaptopurine or Azathioprine: Reduce mercaptopurine or azathioprine dose as recommended in the respective prescribing information ( 7.2 ). See full prescribing information for complete list of significant drug interactions ( 7 ). 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 reflected in 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 activity due 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 in the 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 with pegloticase. Theophylline Clinical Impact Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline. Intervention Monitor and adjust theophylline doses as reflected in the prescribing information. 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. Interv …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm ( 8.1 ). • Lactation: Advise not to breastfeed ( 8.2 ). 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/m 2 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/m 2 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. 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 at five weeks postpartum at an estimated relative infant dose of 0.14 and 0.2 mg/kg of allopurinol and between 7.2 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 allopurinol and for one week after the last dose. 8.4 Pediatric Use The safety and effectiveness of allopurinol 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. 8.5 Geriatric Use Clinical studies of allopurinol did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients. 8.6 Renal Impairment Allopurinol and its primary active metabolite, oxypurinol, are eliminated by the kidneys [see Clinical Pharmacology (12.3) ]. Therefore, changes in renal function will likely increase allopurinal and oxypurinol exposur …

12.1 Mechanism of Action Allopurinol is a structural analogue of the natural purine base, hypoxanthine. Allopurinol and its oxypurinol metabolite inhibitor xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in humans. Allopurinol does not disrupt the biosynthesis of purines. The action of oral allopurinol differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of allopurinol to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.

11 DESCRIPTION Allopurinol for Injection, a xanthine oxidase inhibitor, is a sterile, white, lyophilized powder or cake, in a single-dose vial for reconstitution. Each vial contains 500 mg of allopurinol equivalent to 580.7 mg of allopurinol sodium and 153 mg of sodium hydroxide as a solubilizer. Sodium hydroxide is also used as a pH adjuster. Allopurinol for Injection contains no preservatives. Allopurinol is a xanthine oxidase inhibitor. The chemical name for allopurinol sodium is 1,5-dihydro-4 H -pyrazolo[3,4- d ]pyrimidin-4-one monosodium salt. It is a white amorphous mass with a molecular weight of 158.09 and molecular formula C 5 H 3 N 4 NaO. The structural formula is: The pKa of allopurinol sodium is 9.31. allopurinol-spl-structure

10 OVERDOSAGE In the management of overdosage, there is no specific antidote for allopurinol. Both allopurinol and oxypurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING Allopurinol for Injection is supplied in 30 mL flint glass single-dose vials. Each vial contains 500 mg of allopurinol as a sterile, white, lyophilized powder or cake for reconstitution. Product Code Unit of Sale Strength 380130 NDC 65219-380-30 Individually packaged 500 mg/vial Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Discard unused portion.