2.1 Recommended Dosage

Initiate therapy with ALOPRIM 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 ALOPRIM 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 ALOPRIM 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 ALOPRIM at a dose and frequency to maintain the serum uric acid within the normal range. Discontinue ALOPRIM 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 ALOPRIM in patients with impaired renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The recommended dosage reductions of ALOPRIM in adult patients with renal impairment are shown in Table 2.

Treatment with ALOPRIM 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 ALOPRIM [see Warnings and Precautions (5.2) and Use In Specific Populations (8.6)].

2.3 Preparation Instructions

Reconstitue and further dilute ALOPRIM prior to intravenous infusion.

Reconstitution

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Reconstitute each vial of ALOPRIM with 25 mL of Sterile Water for Injection, USP to obtain a concentration of 20 mg/mL of allopurinol.

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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

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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.

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Inspect the diluted solution for particulate matter or discoloration and discard if present.

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If not used immediately, the diluted ALOPRIM 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.

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If stored, the administration should be completed within 10 hours after reconstitution.

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Discard unused portion.

2.4 Administration Instructions

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

5.1 Skin 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 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 ALOPRIM 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 ALOPRIM is not recommended in HLA-B*58:01 positive patients unless the benefits clearly outweigh the risks.

Prior to starting ALOPRIM, 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 ALOPRIM may be increased in patients with decreased renal function receiving thiazide diuretics and ALOPRIM 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 ALOPRIM and seek medical attention if they develop a rash.

5.2 Renal Function Impairment

Treatment with ALOPRIM 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 ALOPRIM.

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 ALOPRIM [see Use In Specific Populations (8.6) and Dosage and Administration (2.1, 2.2)].

5.3 Hepatotoxicity

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 ALOPRIM in patients with elevated liver enzymes.

5.4 Myelosuppression

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 ALOPRIM 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 ALOPRIM. [see Drug Interactions (7)].

5.5 Drowsiness

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

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 ALOPRIM 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 ALOPRIM.

The most common adverse reaction was skin rash. Two patients experience serious adverse reactions (decreased renal function and generalized seizure) and one patient experienced severe diarrhea. Approximately 1.1% of patients experienced allergic adverse reactions (including rash, eosinophilia, local injection site reaction).

A listing of the adverse reactions reported from clinical trials follows:

Incidence Greater Than 1%:

Cutaneous/Dermatologic: rash (1.5%)

Genitourinary: renal failure/insufficiency (1.2%)

Gastrointestinal: nausea (1.3%), vomiting (1.2%)

Incidence Less Than 1%:

Body as a Whole: fever, pain, chills, alopecia, infection, sepsis, enlarged abdomen, mucositis/pharyngitis, blast crisis, cellulitis, hypervolemia

Cardiovascular: heart failure, cardiorespiratory arrest, hypertension, pulmonary embolus, hypotension, decreased venous pressure, flushing, headache, stroke, septic shock, cardiovascular disorder, ECG abnormality, hemorrhage, bradycardia, thrombophlebitis, ventricular fibrillation

Cutaneous/Dermatologic: urticaria, pruritus, local injection site reaction

Gastrointestinal: diarrhea, gastrointestinal bleeding, hyperbilirubinemia, splenomegaly, hepatomegaly, intestinal obstruction, jaundice, flatulence, constipation, liver failure, proctitis

Genitourinary: hematuria, increased creatinine, oliguria, kidney function abnormality, urinary tract infection

Hematologic: leukopenia, marrow aplasia, thrombocytopenia, eosinophilia, neutropenia, anemia, pancytopenia, ecchymosis, bone marrow suppression, disseminated intravascular coagulation

Metabolic: hypocalcemia, hyperphosphatemia, hypokalemia, hyperuricemia, electrolyte abnormality, hypercalcemia, hyperglycemia, hypernatremia, hyponatremia, metabolic acidosis, edema, glycosuria, hyperkalemia, lactic acidosis, water intoxication, hypomagnesemia

Neurologic: seizure, status epilepticus, myoclonus, twitching, agitation, mental status changes, cerebral infarction, coma, dystonia, paralysis, tremor

Pulmonary: respiratory failure/insufficiency, ARDS, increased respiration rate, apnea

Musculoskeletal: arthralgia

Other: hypotonia, diaphoresis, tumor lysis syndrome

7.1 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 ALOPRIM in patients with concomitant thiazide diuretic use and impaired renal function [see Dosage and Administration (2.2)].

Discontinue ALOPRIM 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 ALOPRIM

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of ALOPRIM 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 ALOPRIM did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients.

8.6 Renal Impairment

Allopurinol and its primary active metabolite, oxypurinol, are eliminated by the kidneys [see Clinical Pharmacology (12.3)]. Therefore, changes in renal function will likely increase allopurinal and oxypurinol 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 ALOPRIM 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.

12.1 Mechanism of Action

Allopurinol is a structural analogue of the natural purine base, hypoxanthine. Allopurinol and its oxypurinol metabolite inhibitor xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in humans. Allopurinol does not disrupt the biosynthesis of purines.

The action of oral allopurinol differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of allopurinol to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Following single 100 mg and 300 mg intravenous and oral administration of ALOPRIM, 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 1 compaired to oral administration at both dosages.

The Cmax and AUC0- inf for both allopurinol and oxypurinol following intravenous administration of ALOPRIM were dose proportional in the dose range of 100 to 300 mg.

12.5 Pharmacogenomics

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 1-2 % in indigenous peoples of the Americas and Hispanic populations, and <1% in people from European descent and Japanese.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).