ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. In an uncontrolled, compassionate plea protocol, 125 of 1,378 patients reported total of 301 adverse reactions while receiving allopurinol sodium for injection. Most of the patients had advanced malignancies or serious underlying diseases and were taking multiple concomitant medications. Side effects directly attributable to allopurinol sodium for injection were reported in 19 patients. Fifteen of these adverse experiences were allergic in nature (rash, eosinophilia, local injection site reaction). One adverse experience of severe diarrhea and one incidence of nausea were also reported as being possibly attributable to allopurinol sodium for injection. Two patients had serious adverse experiences (decreased renal function and generalized seizure) reported as being possibly attributable to allopurinol sodium for injection.A listing of the adverse reactions regardless of causality reported from clinical trials follows: Incidence Greater Than 1%: Cutaneous/Dermatologc: rash (1.5%) Genitourinary: renal failure/insufficiency (1.2%) Gastrointestinal: nausea (1.3%), vomiting (1.2%) Incidence Less Than 1%: Body as 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 The most frequent adverse reaction to oral allopurinol is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol sodium for injection should be discontinued immediately if rash develops (see WARNINGS). For further details on hypersensitivity reactions to treatment with oral allopurinol, refer to the package insert for allopurinol tablets.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Allopurinol acts on purine catabolism without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. The degree of this decrease is dose dependent.Allopurinol is structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of 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 man. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism, however, because feedback inhibition is an integral part of purine biosynthesis. As result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to normal level of approximately 0.15 mg/dL. maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than mg/dL by high doses of allopurinol. These values are far below the saturation levels, at which point their precipitation would be expected to occur (above mg/dL).The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid. The increased xanthine and hypoxanthine in the urine have not been accompanied by problems of nephrolithiasis. There are isolated case reports of xanthine crystalluria in patients who were treated with oral allopurinol.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.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Children and Adults. The dosage of allopurinol sodium for injection to lower serum uric acid to normal or near-normal varies with the severity of the disease. The amount 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. In adults, in one clinical trial, doses over 600 mg day did not appear to be more effective. The recommended daily dose of allopurinol sodium for injection is as follows: Recommended Daily Dose Adult: 200 to 400 mg/m2/dayMaximum 600 mg/day Child: Starting Dose 200 mg/m2/day Hydration. fluid intake sufficient to yield daily urinary output of at least two liters in adults and the maintenance of neutral or, preferably, slightly alkaline urine are desirable.. Impaired Renal Function. The dose of allopurinol sodium for injection should be reduced in patients with impaired renal function to avoid accumulation of allopurinol and its metabolites: Creatinine Clearance Recommended Daily Dose 10 to 20 mL/min 200 mg/day to 10 mL/min 100 mg/day <3 mL/min 100 mg/day at extended intervals Administration. In both adults and children, the daily dose can be given as single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals at the recommended final concentration of not greater than mg/mL (see Preparation of Solution). The rate of infusion depends on the volume of infusate. Whenever possible, therapy with allopurinol sodium for injection should be initiated 24 to 48 hours before the start of chemotherapy known to cause tumor cell lysis (including adrenocorticosteroids).Allopurinol sodium for injection should not be mixed with or administered through the same intravenous port with agents which are incompatible in solution with allopurinol sodium for injection (see Preparation of Solution).. Preparation of Solution. Allopurinol sodium for injection must be reconstituted and diluted. The contents of each 50 mL vial should be dissolved with 25 mL of Sterile Water for Injection. Reconstitution yields clear, almost colorless solution with no more than slight opalescence. This concentrated solution has pH of 11.1 to 11.8. It should be diluted to the desired concentration with 0.9% Sodium Chloride Injection or 5% Dextrose for Injection. Sodium bicarbonate-containing solutions should not be used. final concentration of no greater than mg/mL is recommended. The solution should be stored at 20 to 25C (68 to 77F) and administration should begin within 10 hours after reconstitution. Do not refrigerate the reconstituted and/or diluted product.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use this product if particulate matter or discoloration is present.The following table lists drugs that are physically incompatible in solution with allopurinol sodium for injection. Drugs That are Physically Incompatible in Solution with Allopurinol Sodium for Injection Amikacin sulfate Hydroxyzine HCl Amphoterecin Idarubicin HCl Carmustine Imipenem-cilastatin sodium Cefotaxime sodium Mechlorethamine HCI Chlorpromazine HCI Meperidine HCl Cimetidine HCI Metoclopramide HCI Clindamycin phosphate Methylprednisolone sodium succinate Cytarabine Minocycline HCI Dacarbazine Nalbuphine HCI Daunorubicin HCI Netilmicin sulfate Diphenhydramine HCI Ondansetron HCl Doxorubicin HCI Prochlorperazine edisylate Doxycycline hyclate Promethazine HCl Droperidol Sodium bicarbonate Floxuridine Streptozocin Gentamicin sulfate Tobramycin sulfate Haloperidol lactate Vinorelbine tartrate.

DRUG INTERACTIONS SECTION.

Drug Interactions. The following drug interactions were observed in some patients undergoing treatment with oral allopurinol. Although the pattern of use for oral allopurinol includes longer term therapy, particularly for gout and renal calculi, the experience gained may be relevant.. Mercaptopurine/Azathioprine. Allopurinol inhibits the enzymatic oxidation of mercaptopurine and azathioprine to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Therefore, the concomitant administration of 300 to 600 mg of oral allopurinol per day will require reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects.. Dicumarol. It has been reported that allopurinol prolongs the half-life of the anticoagulant, dicumarol. Consequently, prothrombin time should be reassessed periodically in patients receiving both drugs. The clinical basis of this drug interaction has not been established.. Uricosuric Agents. Since the excretion of oxypurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxypurinol. As result, the concomitant administration of uricosuric agents decreases the inhibition of xanthine oxidase by oxypurinol and increases the urinary excretion of uric acid.. Thiazide Diuretics. Reports that the concomitant administration of allopurinol and thiazide diuretics contributed to increased allopurinol toxicity were reviewed; causal mechanism or cause-and-effect relationship was not found. Renal function should be monitored in patients on thiazide diuretics and allopurinol (see WARNINGS).. Ampicillin/Amoxicillin. An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of this reaction has not been established.. Cytotoxic Agents. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol. However, in well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.. Chlorpropamide. The half-life of chlorpropamide in the plasma may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency.. Cyclosporine. Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol sodium for injection. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.. Drug/Laboratory Test Interactions. Allopurinol is not known to alter the accuracy of laboratory tests.

GENERAL PRECAUTIONS SECTION.

General. fluid intake sufficient to yield daily urinary output of at least two liters in adults and the maintenance of 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 rise in BUN during allopurinol administration, although 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 allopurinol sodium for injection for patients with creatinine clearance <=10 mL/min is 100 mg per day. For patients with creatinine clearance between 10 and 20 mL/min, dose of 200 mg per day is recommended. With extreme renal impairment (creatinine clearance less than 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 weeks to as long as years after the initiation of allopurinol therapy.

PRECAUTIONS SECTION.

PRECAUTIONS. General. fluid intake sufficient to yield daily urinary output of at least two liters in adults and the maintenance of 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 rise in BUN during allopurinol administration, although 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 allopurinol sodium for injection for patients with creatinine clearance <=10 mL/min is 100 mg per day. For patients with creatinine clearance between 10 and 20 mL/min, dose of 200 mg per day is recommended. With extreme renal impairment (creatinine clearance less than 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 weeks to as long as 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 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 patients allopurinol dosage reassessed.The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are given allopurinol.. Drug Interactions. The following drug interactions were observed in some patients undergoing treatment with oral allopurinol. Although the pattern of use for oral allopurinol includes longer term therapy, particularly for gout and renal calculi, the experience gained may be relevant.. Mercaptopurine/Azathioprine. Allopurinol inhibits the enzymatic oxidation of mercaptopurine and azathioprine to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Therefore, the concomitant administration of 300 to 600 mg of oral allopurinol per day will require reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects.. Dicumarol. It has been reported that allopurinol prolongs the half-life of the anticoagulant, dicumarol. Consequently, prothrombin time should be reassessed periodically in patients receiving both drugs. The clinical basis of this drug interaction has not been established.. Uricosuric Agents. Since the excretion of oxypurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxypurinol. As result, the concomitant administration of uricosuric agents decreases the inhibition of xanthine oxidase by oxypurinol and increases the urinary excretion of uric acid.. Thiazide Diuretics. Reports that the concomitant administration of allopurinol and thiazide diuretics contributed to increased allopurinol toxicity were reviewed; causal mechanism or cause-and-effect relationship was not found. Renal function should be monitored in patients on thiazide diuretics and allopurinol (see WARNINGS).. Ampicillin/Amoxicillin. An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of this reaction has not been established.. Cytotoxic Agents. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol. However, in well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.. Chlorpropamide. The half-life of chlorpropamide in the plasma may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency.. Cyclosporine. Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol sodium for injection. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.. Drug/Laboratory Test Interactions. Allopurinol is not known to alter the accuracy of laboratory tests.. 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 mg/m2 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 1/2 the human dose on mg/m2 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 mg/m2 basis). However, there is 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 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 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 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 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 nursing woman.. Pediatric Use. Clinical data are available on approximately 200 pediatric patients treated with allopurinol sodium for injection. The efficacy and safety profile observed in this patient population were similar to that observed in adults (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).. Geriatric Use. Clinical studies of 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.

WARNINGS SECTION.

WARNINGS. DISCONTINUE ALLOPURINOL SODIUM FOR INJECTION AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE HYPERSENSITIVITY REACTION. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking allopurinol. These reactions occur in approximately in 10,000 (0.05%) patients taking allopurinol. Other serious hypersensitivity reactions that have been reported include exfoliative, urticarial and purpuric lesions; generalized vasculitis; and irreversible hepatotoxicity.The HLA-B58:01 allele is genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B58:01 allele are at higher risk of allopurinol hypersensitivity syndrome (AHS), but hypersensitivity reactions have been reported in patients who do not carry this allele. The frequency of this allele is higher in individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry. Prior to starting Allopurinol Sodium for Injection, consider testing for the HLA-B58:01 allele in genetically at-risk populations. The use of Allopurinol Sodium for Injection is not recommended in HLA-B58:01 positive patients unless the benefits clearly outweigh the risks.The occurrence of hypersensitivity reactions may be increased in patients with renal impairment, especially in patients who are receiving thiazide diuretics. Reduce the dose of Allopurinol Sodium for Injection in patients with impaired renal function (see DOSAGE AND ADMINISTRATION-Impaired Renal Function).In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300 to 600 mg of allopurinol sodium for injection per day will require reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects (see PRECAUTIONS -Drug Interactions). few cases of reversible clinical hepatotoxicity have been noted in patients taking oral allopurinol, and in some patients asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Skin Rash and Hypersensitivity Inform patients that Allopurinol Sodium for Injection may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS). Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop the Allopurinol Sodium for Injection immediately if they develop any type of rash and seek medical attention [see Warnings and Precautions (5.1)]. Renal Function ImpairmentAdvise patients to stay well hydrated (e.g., liters of liquid per day) while taking Allopurinol Sodium for Injection [see Warnings and Precautions (5.2)].HepatotoxicityAdvise patients of the risk of hepatoxicity and to report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia to their healthcare provider [see Warnings and Precautions (5.3)].MyelosuppressionAdvise patients of the risk of myelosuppression and to report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider [see Warnings and Precautions (5.4)].Drowsiness Inform patients that drowsiness has been reported in patients taking Allopurinol Sodium for Injection and to be cautious when engaging in activities where alertness is mandatory [see Warnings and Precautions (5.5) ].PregnancyAdvise pregnant women of the potential risk to fetus. Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Allopurinol Sodium for Injection [see Use in Specific Populations (8.1)]. LactationAdvise women not to breastfeed during treatment with Allopurinol Sodium for Injection for one week after the last dose. [see Use in Specific Populations (8.2)]. For Product Inquiry call 1-877-845-0689.Manufactured byHIKMA FARMACEUTICA (PORTUGAL), S.A.Estrada do Rio da Mo, 8, 8A 8B Fervenca 2705-906 Terrugem SNT, PORTUGAL Distributed byHikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922Revised March 2022 PIN408-WES/4.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Allopurinol reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation in dose dependent manner. The pharmacological action of allopurinol is generally believed to be mediated by its oxypurinol metabolite.. Effect on Hypoxanthine and Xanthine. Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism because feedback inhibition is an integral part of purine biosynthesis. As result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to normal level of approximately 0.15 mg/dL. maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than mg/dL by high doses of allopurinol. These values are far below the saturation levels, at which point their precipitation would be expected to occur (above mg/dL). The increased xanthine and hypoxanthine in the urine in patients who were treated with oral allopurinol have not been accompanied by problems of nephrolithiasis; however, there are isolated case reports of xanthine crystalluria.. Drug Interaction Studies. Fluorouracil. Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil.. Pegloticase. Concomitant use of Allopurinol Sodium for Injection and pegloticase may potentially blunt the rise of serum uric acid levels required for monitoring the safe use of pegloticase.. Cytotoxic Agents. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol.. Thiazide Diuretics. Reports that the concomitant administration of allopurinol and thiazide diuretics contributed to increased allopurinol toxicity were reviewed; however, causal mechanism or cause-and-effect relationship was not found.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following single 100 mg and 300 mg intravenous and oral administration of Allopurinol Sodium for Injection, the relative intravenous Cmax was approximately 3-fold and 3.8-fold and AUC0-inf was approximately 1.9-fold higher for allopurinol at both dosages, respectively. The relative intravenous oxypurinol Cmax and AUC0-inf was approximately compared to oral administration at both dosages.The Cmax and AUC0- inf for both allopurinol and oxypurinol following intravenous administration of Allopurinol Sodium for Injection were dose proportional in the dose range of 100 to 300 mg. Distribution. The steady-state allopurinol volume of distribution (mean +- S.D.) is approximately 0.87 +- 0.13 L/Kg following intravenous adminstration.. Elimination. The half-life (mean +- S.D.) of allopurinol and oxypurinol are approximately 1.21 +- 0.33 and 23.5 +- 4.5 hours following intravenous administration, respectively. The net renal clearance of oxypurinol about 30 mL/min.. Metabolism. Allopurinol is weak CYP1A2 inhibitor. Allopurinol is rapidly eliminated from the systemic circulation primarily via oxidative metabolism to oxypurinol. The oxypurinol (alloxanthine) metabolite is also xanthine oxidase inhibitor and is present in systemic circulation in much higher concentrations and for much longer period than allopurinol. In general, the ratio of the area under the plasma concentration vs time curve (AUC0-inf) between oxypurinol and allopurinol was in the magnitude of 30 to 40.. Excretion. Approximately 12% of an allopurinol intravenous dose was excreted unchanged, 76% excreted as oxypurinol, and the remaining dose excreted as riboside conjugates in the urine. Oxypurinol was primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption.. Drug Interaction Studies. Capecitabine. Concomitant use with allopurinol may decrease concentration of capecitabines active metabolites, which may decrease capecitabine efficacy.. Cyclosporine. Concomitant use of allopurinol increases cyclosporine concentrations which may increase the risk of adverse reactions.. Mercaptopurine or Azathioprine. 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.. Theophylline. Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline.. Uricosuric Agents. 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.. Warfarin. Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary. Based on findings in animals, Allopurinol Sodium for Injection may cause fetal harm when administered to 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 clear pattern or increase in frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in published literature, infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to fetus.All pregnancies have 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 mg/m2 basis). However, there is 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 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 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 (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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm (8.1).Lactation: Advise not to breastfeed (8.2).. 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 Sodium for Injection may cause fetal harm when administered to 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 clear pattern or increase in frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in published literature, infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to fetus.All pregnancies have 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 mg/m2 basis). However, there is 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 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 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 (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 single case report, allopurinol and its active metabolite, oxypurinol, were detected in the milk of 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 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 breastfed child, advise women not to breastfeed during treatments with Allopurinol Sodium for Injection and for one week after the last dose. 8.4 Pediatric Use. The safety and effectiveness of Allopurinol Sodium for Injection 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 Sodium for Injection did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients.. 8.6Renal 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 exposure. In patients with decreased renal function, or who have concurrent illnesses that can affect renal function such as hypertension and diabetes mellitus, perform periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed.In patients with severely impaired renal function or decreased urate clearance, the half-life of oxypurinol in the plasma is greatly prolonged. Reduce the dose of Allopurinol Sodium for Injection in patients with creatinine clearance <= 20 mL/min [see Dosage and Administration (2.2)]. Patients should be treated with the lowest effective dose, in order to minimize possible side effects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Skin Rash and Hypersensitivity: Discontinue Allopurinol Sodium for Injection at the first appearance of skin rash or other signs which may indicate hypersensitivity reaction. Allopurinol has been associated with serious and sometimes fatal dermatologic reactions. (5.1)Renal Function Impairment: Patients with decreased renal function require lower doses of allopurinol. (5.2)Hepatotoxicity: If signs and symptoms of hepatotoxicity develop, liver function evaluation should be performed. (5.3)Myelosuppression: Bone marrow suppression has been reported with allopurinol. (5.4) Drowsiness: Drowsiness has been reported in patients taking Allopurinol Sodium for Injection. (5.5). Skin Rash and Hypersensitivity: Discontinue Allopurinol Sodium for Injection at the first appearance of skin rash or other signs which may indicate hypersensitivity reaction. Allopurinol has been associated with serious and sometimes fatal dermatologic reactions. (5.1). Renal Function Impairment: Patients with decreased renal function require lower doses of allopurinol. (5.2). Hepatotoxicity: If signs and symptoms of hepatotoxicity develop, liver function evaluation should be performed. (5.3). Myelosuppression: Bone marrow suppression has been reported with allopurinol. (5.4) Drowsiness: Drowsiness has been reported in patients taking Allopurinol Sodium for Injection. (5.5). 5.1Skin Rash and Hypersensitivity. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking allopurinol [see Adverse Reactions (6.1)]. These reactions occur in approximately in 10,000 (0.05%) patients taking allopurinol. Other serious hypersensitivity reactions that have been reported include exfoliative, urticarial and purpuric lesions; generalized vasculitis; and irreversible hepatotoxicity. Discontinue Allopurinol Sodium for Injection at the first appearance of skin rash or other signs which may indicate hypersensitivity reaction.The HLA-B58:01 allele is genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B58:01 allele are at higher risk of allopurinol hypersensitivity syndrome (AHS), but hypersensitivity reactions have been reported in patients who do not carry this allele. The frequency of this allele is higher in individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry [see Clinical Pharmacology (12.5)]. The use of Allopurinol Sodium for Injection is not recommended in HLA-B58:01 positive patients unless the benefits clearly outweigh the risks.Prior to starting Allopurinol Sodium for Injection, consider testing for the HLA-B58:01 allele in genetically at-risk populations. Screening is generally not recommended in patients from populations in which the prevalence of HLA-B58:01 is low, or in current allopurinol users, as the risk of SJS/TEN/DRESS is largely confined to the first few months of therapy, regardless of HLA-B58:01 status.Hypersensitivity reactions to Allopurinol Sodium for Injection may be increased in patients with decreased renal function receiving thiazide diuretics and Allopurinol Sodium for Injection concurrently. In addition, concomitant use of the following drugs may increase the risk of skin rash, which may be severe: bendamustine, thiazide diuretics, ampicillin and amoxicillin [see Drug Interactions (7.1)]. Patients should stop Allopurinol Sodium for Injection and seek medical attention if they develop rash.. 5.2Renal Function Impairment. Treatment with Allopurinol Sodium for Injection may result in renal impairment due to formation of xanthine calculi or due to precipitation of urates in patients receiving concomitant uricosuric agents. Patients with pre-existing renal disease, including renal impairment or history of kidney stones, may be at increased risk for worsening renal impairment due to xanthine calculi or precipitation of urates while receiving treatment with Allopurinol Sodium for Injection. Monitor serum creatinine at least daily during the early stages of allopurinol administration. Maintain fluid intake sufficient to yield urinary output of at least liters per day in adults. In patients with severely impaired renal function or increase in uric acid concentration associated with decreased urate clearance, reduce the dosage of Allopurinol Sodium for Injection [see Use In Specific Populations (8.6) and Dosage and Administration (2.1, 2.2)]. 5.3Hepatotoxicity. Cases of reversible clinical hepatotoxicity have been noted in patients taking oral allopurinol. In some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluate liver enzymes. In patients with pre-existing liver disease, monitor liver enzymes periodically during the early stages of therapy. Discontinue Allopurinol Sodium for Injection in patients with elevated liver enzymes. 5.4Myelosuppression. Myelosuppression, manifested by anemia, leukopenia or thrombocytopenia, has been reported in patients receiving allopurinol [see Adverse Reactions (6.1)]. The cytopenias have occurred from as early as weeks to as late as years after the initiation of allopurinol therapy. Discontinue use of Allopurinol Sodium for Injection in patients with unexplained cytopenias. Concomitant use with allopurinol with cytotoxic drugs associated with myelosuppression may increase the risk of myelosuppression. Monitor blood counts more frequently [see Drug Interactions (7)].Concomitant use with allopurinol increases the exposure of either mercaptopurine or azathioprine which may increase the risk of myelosuppression. Reduce the dosage of mercaptopurine or azathioprine as recommended in the respective prescribing information when used concomitantly with Allopurinol Sodium for Injection. [see Drug Interactions (7)].. 5.5Drowsiness. Drowsiness has been reported in patients taking Allopurinol Sodium for Injection [see Adverse Reactions (6.1)]. Advise patients to avoid operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness when starting Allopurinol Sodium for Injection or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of Allopurinol Sodium for Injection may be additive to those of alcohol and other CNS depressants.