These Highlights Do Not Include All The Information Needed To Use Allopurinol For Injection Safely And Effectively. See Full Prescribing Information For Allopurinol For Injection.

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.

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.

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-4H-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 C₅H₃N₄NaO. The structural formula is:

The pKa of allopurinol sodium is 9.31.

Drowsiness has been reported in patients taking allopurinol [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 or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants.

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.

Clinical studies of allopurinol did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients.

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 in patients with elevated liver enzymes.

A compassionate use trial of allopurinol conducted in the United States from 1977 through 1989 included 718 evaluable patients with malignancies requiring treatment with cytotoxic chemotherapy who were unable to ingest or retain oral medication. Of these patients, 411 had established hyperuricemia and 307 had normal serum urate levels at the time that treatment was initiated. Normal serum uric acid levels were achieved in 68% of the former (reduction of serum uric acid was documented in 93%), and were maintained throughout chemotherapy in 97% of the latter. Because of the study design, it was not possible to assess the impact of the treatment with allopurinol on the clinical outcome of the patient groups.

Allopurinol for injection is contraindicated in patients with a history of severe reaction to any formulation of allopurinol.

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)]

Clinically important interactions with the drugs listed below were observed in patients undergoing treatment with an oral allopurinol formulation.

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 6 weeks to as late as 6 years after the initiation of allopurinol therapy. Discontinue use of allopurinol 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 [see Drug Interactions (7)].

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 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.

Allopurinol reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation in a dose dependent manner. The pharmacological action of allopurinol is generally believed to be mediated by its oxypurinol metabolite.

Following single 100 mg and 300 mg intravenous and oral administration of allopurinol, the relative intravenous C_max was approximately 3-fold and 3.8-fold and AUC_0-inf was approximately 1.9-fold higher for allopurinol at both dosages, respectively. The relative intravenous oxypurinol C_max and AUC_0-inf was approximately 1 compared to oral administration at both dosages.

The C_max and AUC_0-inf for both allopurinol and oxypurinol following intravenous administration of allopurinol were dose proportional in the dose range of 100 to 300 mg.

The HLA-B*58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol [see Warnings and Precautions (5.1)]. The frequency of the HLA-B*58:01 allele ranges from 8 to 10% in Han Chinese populations, about 8% in Thai populations, and about 6% in Korean populations based upon published literature and available databases. The frequency of the HLA-B*58:01 allele is about 4% in Blacks, about 1 to 2 % in indigenous peoples of the Americas and Hispanic populations, and <1% in people from European descent and Japanese.

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.

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.

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 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.

• Skin Rash and Hypersensitivity: Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a 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. (5.5)

• Recommended Dosage (2.2)

• Recommended Dosage in Adult Patients with Renal Impairment (2.2, 5.2, 8.6)

Reconstitute and further dilute allopurinol for injection prior to intravenous infusion.

For Injection: 500 mg of allopurinol as a sterile, white lyophilized powder or cake in a single-dose vial for reconstitution.

Treatment with allopurinol 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.

Monitor serum creatinine at least daily during the early stages of allopurinol administration. Maintain fluid intake sufficient to yield a urinary output of at least 2 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 [see Use in Specific Populations (8.6) and Dosage and Administration (2.1, 2.2)].

• Pregnancy: May cause fetal harm (8.1).
• Lactation: Advise not to breastfeed (8.2).

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

Do not mix allopurinol for injection with or administer it through the same intravenous port as agents which are incompatible in solution with allopurinol for injection. The following table lists drugs that are known to be physically incompatible in solution with allopurinol for injection.

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 5 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 at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction.

The HLA-B*58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B*58:01 allele are at a 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 is not recommended in HLA-B*58:01 positive patients unless the benefits clearly outweigh the risks.

Prior to starting allopurinol, consider testing for the HLA-B*58:01 allele in genetically at-risk populations. Screening is generally not recommended in patients from populations in which the prevalence of HLA-B*58:01 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-B*58:01 status.

Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazide diuretics and allopurinol 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 and seek medical attention if they develop a rash.

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.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Discard unused portion.

NDC 65219-380-30

Allopurinol for Injection

500 mg/vial

For Intravenous Infusion

Single-Dose Vial

Rx only

Sterile

NDC 65219-380-30

Allopurinol for Injection

500 mg/vial

For Intravenous Infusion

Discard Unused Portion

Single-Dose Vial

Sterile

Rx only

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 a mg/m² basis, respectively).

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.

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 a mg/m² basis, respectively).

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.

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)].

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.

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.

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.

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-4H-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 C₅H₃N₄NaO. The structural formula is:

The pKa of allopurinol sodium is 9.31.

Drowsiness has been reported in patients taking allopurinol [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 or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants.

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.

Clinical studies of allopurinol did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients.

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 in patients with elevated liver enzymes.

A compassionate use trial of allopurinol conducted in the United States from 1977 through 1989 included 718 evaluable patients with malignancies requiring treatment with cytotoxic chemotherapy who were unable to ingest or retain oral medication. Of these patients, 411 had established hyperuricemia and 307 had normal serum urate levels at the time that treatment was initiated. Normal serum uric acid levels were achieved in 68% of the former (reduction of serum uric acid was documented in 93%), and were maintained throughout chemotherapy in 97% of the latter. Because of the study design, it was not possible to assess the impact of the treatment with allopurinol on the clinical outcome of the patient groups.

Allopurinol for injection is contraindicated in patients with a history of severe reaction to any formulation of allopurinol.

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)]

Clinically important interactions with the drugs listed below were observed in patients undergoing treatment with an oral allopurinol formulation.

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 6 weeks to as late as 6 years after the initiation of allopurinol therapy. Discontinue use of allopurinol 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 [see Drug Interactions (7)].

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 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.

Allopurinol reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation in a dose dependent manner. The pharmacological action of allopurinol is generally believed to be mediated by its oxypurinol metabolite.

Following single 100 mg and 300 mg intravenous and oral administration of allopurinol, the relative intravenous C_max was approximately 3-fold and 3.8-fold and AUC_0-inf was approximately 1.9-fold higher for allopurinol at both dosages, respectively. The relative intravenous oxypurinol C_max and AUC_0-inf was approximately 1 compared to oral administration at both dosages.

The C_max and AUC_0-inf for both allopurinol and oxypurinol following intravenous administration of allopurinol were dose proportional in the dose range of 100 to 300 mg.

The HLA-B*58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol [see Warnings and Precautions (5.1)]. The frequency of the HLA-B*58:01 allele ranges from 8 to 10% in Han Chinese populations, about 8% in Thai populations, and about 6% in Korean populations based upon published literature and available databases. The frequency of the HLA-B*58:01 allele is about 4% in Blacks, about 1 to 2 % in indigenous peoples of the Americas and Hispanic populations, and <1% in people from European descent and Japanese.

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.

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.

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 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.

• Skin Rash and Hypersensitivity: Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a 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. (5.5)

• Recommended Dosage (2.2)

• Recommended Dosage in Adult Patients with Renal Impairment (2.2, 5.2, 8.6)

Reconstitute and further dilute allopurinol for injection prior to intravenous infusion.

For Injection: 500 mg of allopurinol as a sterile, white lyophilized powder or cake in a single-dose vial for reconstitution.

Treatment with allopurinol 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.

Monitor serum creatinine at least daily during the early stages of allopurinol administration. Maintain fluid intake sufficient to yield a urinary output of at least 2 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 [see Use in Specific Populations (8.6) and Dosage and Administration (2.1, 2.2)].

• Pregnancy: May cause fetal harm (8.1).
• Lactation: Advise not to breastfeed (8.2).

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

Do not mix allopurinol for injection with or administer it through the same intravenous port as agents which are incompatible in solution with allopurinol for injection. The following table lists drugs that are known to be physically incompatible in solution with allopurinol for injection.

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 5 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 at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction.

The HLA-B*58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B*58:01 allele are at a 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 is not recommended in HLA-B*58:01 positive patients unless the benefits clearly outweigh the risks.

Prior to starting allopurinol, consider testing for the HLA-B*58:01 allele in genetically at-risk populations. Screening is generally not recommended in patients from populations in which the prevalence of HLA-B*58:01 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-B*58:01 status.

Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazide diuretics and allopurinol 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 and seek medical attention if they develop a rash.

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.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Discard unused portion.

NDC 65219-380-30

Allopurinol for Injection

500 mg/vial

For Intravenous Infusion

Single-Dose Vial

Rx only

Sterile

NDC 65219-380-30

Allopurinol for Injection

500 mg/vial

For Intravenous Infusion

Discard Unused Portion

Single-Dose Vial

Sterile

Rx only

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 a mg/m² basis, respectively).

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.

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 a mg/m² basis, respectively).

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.

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)].

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.