Allopurinol

ALLOPURINOL — allopurinol sodium injection, powder, lyophilized, for solution
Gland Pharma Limited

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage


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.Table 1: Recommended Daily Dose of Allopurinol for Injection

Adult Patients 200 mg/m2 /day to 400 mg/m2 /day intravenously Maximum 600 mg/day
Pediatric Patients Starting Dose 200 mg/m2 /day intravenously Maximum 400 mg/day

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.

2.2 Dosage Modifications in Patients with Renal Impairment

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.

Table 2: Recommended Daily Dose of Allopurinol for Injection in A dult 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, or100 mg every 24 hours

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)].

2.3 Preparation Instructions

Reconstitute and further dilute allopurinol for injection prior to intravenous infusion.
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.
Dilution
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP to obtain a final concentration of less than 6 mg/mL.
• Inspect the diluted solution for particulate matter or discoloration and discard if present.
• If not used immediately, the diluted allopurinol for injection solution can be stored at 20° to 25°C (68° to 77°F) for up to 10 hours after initial reconstitution. The storage includes time for infusion. Do not refrigerate the reconstituted and/or diluted product.
• If stored, the administration should be completed within 10 hours after reconstitution. • Discard unused portion.

2.4 Administration Instructions

Do not mix allopurinol 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.

Table 3: Drugs That Are Physically Incompatible in Solution with Allopurinol for Injection

Amikacin sulfate Hydroxyzine HCl
Amphotericin B Idarubicin HCl
Carmustine Imipenem-cilastatin sodium
Cefotaxime sodium Mechlorethamine HCl
Chlorpromazine HCl Meperidine HCl
Cimetidine HCl Metoclopramide HCl
Clindamycin phosphate Methylprednisolone sodium succinate
Cytarabine Minocycline HCl
Dacarbazine Nalbuphine HCl
Daunorubicin HCl Ondansetron HCl
Diphenhydramine HCl Prochlorperazine edisylate
Doxorubicin HCl Promethazine HCl
Doxycycline hyclate Sodium bicarbonate
Droperidol Streptozocin
Floxuridine Tobramycin sulfate
Gentamicin sulfate Vinorelbine tartrate
Haloperidol lactate

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

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 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.

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