FDA

Allopurinol Sodium

Approved 26 Jan 2022InjectionInjectable

The FDA lists this product in 2 strengths and forms.

Indications

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 for injection is a xanthine oxidase inhibitor 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.

( 1 )

Contraindications

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

Warnings and precautions

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 )

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 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.

At a glance

Brand name: Allopurinol Sodium
Route: Injection
Dosage form: Injectable
Applicant: Gland
Status: Prescription
FDA approval: 26 Jan 2022
Application: ANDA212363-001

Indications

( 1 )

Warnings and precautions

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 )

5.1Skin Rash and Hypersensitivity Serious

Interactions

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

Capecitabine: Avoid the concomitant use of allopurinol ( 7.2 ).
Pegloticase: Discontinue and do not institute allopurinol therapy during treatment with pegloticase ( 7.2 ).
Mercaptopurine or Azathioprine: Reduce mercaptopurine or azathioprine dose as recommended in the respective prescribing information ( 7.2 ).
See full prescribing information for complete list of significant drug interactions (7 ).

7.1Drugs 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 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.

7.2 Other Drugs Known to Have Clinically Important Drug Interactions with Allopurinol Table 4: Interventions for Clinically Important Drug Interactions with Allopurinol Capecitabine Clinical Impact Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy. Intervention Avoid the use of allopurinol during treatment with capecitabine. Cyclosporine Clinical Impact Concomitant use of allopurinol increases cyclosporine concentrations which may increase the risk of adverse reactions.

Intervention Increase frequency of monitoring cyclosporine concentrations as reflected in the prescribing information when used concomitantly with allopurinol. Cytotoxic Agents Clinical Impact Concomitant use of allopurinol with cytotoxic agents increases bone marrow suppression among patients with neoplastic disease, except leukemia [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2) ] . Intervention Blood count monitoring and regular physician follow-up recommended.

Fluorouracil Clinical Impact Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil. Intervention Concomitant administration with fluorouracil should be avoided. Mercaptopurine or Azathioprine Clinical Impact 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 [see Warnings and Precautions (5.4) ] .

Intervention Reduce the dosage of mercaptopurine or azathioprine as recommended in the respective prescribing information. Pegloticase Clinical Impact Concomitant use of allopurinol and pegloticase may potentially blunt the rise of serum uric acid levels and increase the risk of pegloticase related anaphylaxis in patients whose uric acid level increase to above 6 mg/dL. Intervention Discontinue and do not institute allopurinol therapy during treatment with pegloticase.

Theophylline Clinical Impact Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline. Intervention Monitor and adjust theophylline doses as reflected in the prescribing information. Uricosuric Agents Clinical Impact 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.

Intervention Monitor uric acid levels due to the increased chance of hypouricemic effects. Warfarin Clinical Impact Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect. Intervention Patients on concomitant therapy should be monitored for excessive anticoagulation. The INR should be checked frequently and warfarin dosage adjusted accordingly when allopurinol is added to warfarin therapy.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

on findings in animals, allopurinol may cause fetal harm when administered to a 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 a clear pattern or increase in frequency of adverse developmental outcomes.

Among approximately 50 pregnancies described in published literature, 2 infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to a fetus. All pregnancies have a 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 a mg/m 2 basis).

However, there is a 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 a mg/m 2 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 a 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 2 (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.

Adverse reactions

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) ] Most common adverse reactions (incidence > 1%) are skin rash, nausea, vomiting, and renal failure/insufficiency. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 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

Allopurinol Sodium

Indications

Contraindications

Warnings and precautions

5.1Skin Rash and Hypersensitivity Serious

At a glance

Two medicines in one question?

Allopurinol Sodium

Indications

Contraindications

Warnings and precautions

5.1Skin Rash and Hypersensitivity Serious

At a glance

Two medicines in one question?

5.2Renal Function Impairment Treatment

5.3Hepatotoxicity Cases

5.4Myelosuppression

5.5Drowsiness

Interactions

7.1Drugs Known to Affect the Occurrence of Skin Rash and Hypersensitivity

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

Composition

Strengths and forms

Official product information