Aloprim

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.

Table 1:

Recommended Daily Dose of ALOPRIM Adult Patients 200 mg/m 2 /day to 400 mg/m 2 /day intravenously Maximum 600 mg/day Pediatric Patients Starting Dose 200 mg/m 2 /day intravenously Maximum 400 mg/day The dosage of 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.

3) ] . The recommended dosage reductions of ALOPRIM in adult patients with renal impairment are shown in Table 2.

Table 2:

Recommended Daily Dose of ALOPRIM in Adult Patients with Renal Impairment Creatinine Clearance Recommended Daily Dose 10 to 20 mL/min 200 mg/day Less than 10 mL/min 100 mg/day On dialysis 50 mg every 12 hours, or 100 mg every 24 hours Treatment with ALOPRIM has not been studied in pediatric patients with severe renal impairment or on dialysis.

6) ] . 3 Preparation Instructions Reconstitue and further dilute ALOPRIM prior to intravenous infusion. Reconstitution • Reconstitute each vial of ALOPRIM 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.

9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP to obtain a final concentration of less than 6 mg/mL. • Inspect the diluted solution for particulate matter or discoloration and discard if present. • If not used immediately, the diluted ALOPRIM solution can be stored at 20° to 25°C (68° to 77°F) for up to 10 hours after initial reconstitution.

5) ] Most common adverse reactions (incidence > 1%) are skin rash, nausea, vomiting, and renal failure/insufficiency. gov/medwatch. 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. 1% of patients experienced allergic adverse reactions (including rash, eosinophilia, local injection site reaction).

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

5 WARNINGS AND PRECAUTIONS • Skin Rash and Hypersensitivity: Discontinue ALOPRIM 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.

1 ) • Renal Function Impairment: Patients with decreased renal function require lower doses of allopurinol. 2 ) • Hepatotoxicity: If signs and symptoms of hepatotoxicity develop, liver function evaluation should be performed. 3 ) • Myelosuppression: Bone marrow suppression has been reported with allopurinol.

4 ) • Drowsiness: Drowsiness has been reported in patients taking ALOPRIM. 1) ] . 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. 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. 1) ] . Patients should stop ALOPRIM and seek medical attention if they develop a rash.

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