ALLOPURINOL SODIUM

Allopurinol Sodium 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 162.5 mg of sodium hydroxide as a solubilizer. Sodium hydroxide is also used as a pH adjuster. Allopurinol Sodium 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 Structural Formula

Allopurinol Sodium 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 Sodium 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 )

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 Sodium 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 Sodium 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 Sodium 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 Sodium 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 Sodium for Injection at a dose and frequency to maintain the serum uric acid within the normal range. Discontinue Allopurinol Sodium 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 Sodium 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 Sodium for Injection in adult patients with renal impairment are shown in Table 2. Table 2: Recommended Daily Dose of Allopurinol Sodium for Injection in Adult 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 Sodium 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 Sodium for Injection [see Warnings and Precautions (5.2) and Use In Specific Populations (8.6) ] . 2.3 Preparation Instructions Reconstitute and further dilute Allopurinol Sodium for Injection prior to intravenous infusion. Reconstitution Reconstitute each vial of Allopurinol Sodium 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 Sodium 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 Sodium for Injection with or administer it through the same intravenous port as agents which are incompatible in solution with Allopurinol Sodium for Injection. The following table lists drugs that are known to be physically incompatible in solution with Allopurinol Sodium for Injection. Table 3: Drugs That Are Physically Incompatible in Solution with Allopurinol Sodium for Injection Amikacin sulfate Hydroxyzine HCl Amphotericin B Idarubicin HCl Carmustine Imipenem-cilastatin sodium Cefotaxime sodium Mechlorethamine HCl Chlorpromazine HCl Meperidine HCl Cimetidine HCl Metoclopramide HCl Clindamycin phosphate Methylprednisolone sodium succinate Cytarabine Minocycline HCl Dacarbazine Nalbuphine HCl Daunorubicin HCl Ondansetron HCl Diphenhydramine HCl Prochlorperazine edisylate Doxorubicin HCl Promethazine HCl Doxycycline hyclate Sodium bicarbonate Droperidol Streptozocin Floxuridine Tobramycin sulfate Gentamicin sulfate Vinorelbine tartrate Haloperidol lactate

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

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) ] Hepatoxicity [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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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 Sodium for Injection 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 Sodium for Injection. 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

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 Sodium for Injection in patients with concomitant thiazide diuretic use and impaired renal function [see Dosage and Administration (2.2) ]. Discontinue Allopurinol Sodium for Injection 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 Sodium for Injection Table 4: Interventions for Clinically Important Drug Interactions with Allopurinol Sodium for Injection 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 Sodium for Injection 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 Sodium for Injection. 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 Sodium for Injection 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 Sodium for Injection 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. Intervention Monitor uric acid levels due to the increased chance of hypouricemic effects. Warfarin Clinical Impact Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect. Intervention Patients on concomitant therapy should be monitored for excessive anticoagulation. The INR should be checked frequently and warfarin dosage adjusted accordingly when allopurinol is added to warfarin therapy.