Yes

Xanthine Oxidase Inhibitor

Oral: Prevention of attack of gouty arthritis and nephropathy; also used to treat secondary hyperuricemia which may occur during treatment of tumors or leukemia, and to prevent recurrent calcium oxalate calculi

Intravenous: Management of patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer chemotherapy which causes elevations of serum and urinary uric acid levels and who cannot tolerate oral therapy

C

Clinical effects on the fetus: There are few reports describing the use of allopurinol during pregnancy; no adverse fetal outcomes attributable to allopurinol have been reported in humans

Not to be used in pregnancy or lactation, or in patients with a previous severe allergy reaction to allopurinol or any component

Do not use to treat asymptomatic hyperuricemia. Discontinue at first signs of rash; reduce dosage in renal insufficiency, reinstate with caution in patients who have had a previous mild allergic reaction, use with caution in children; monitor liver function and complete blood counts before initiating therapy and periodically during therapy, use with caution in patients taking diuretics concurrently. Risk of skin rash may be increased in patients receiving amoxicillin or ampicillin. The risk of hypersensitivity may be increased in patients receiving thiazides, and possibly ACE inhibitors.

The most common adverse reaction to allopurinol is a skin rash (usually maculopapular; however, more severe reactions, including Stevens-Johnson syndrome, have also been reported). While some studies cite an incidence of these reactions as high as >10% of cases (often in association with ampicillin or amoxicillin), the product labeling cites a much lower incidence, reflected below. Allopurinol should be discontinued at the first appearance of a rash or other sign of hypersensitivity.

Dermatologic: Rash (1.5%)

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

Renal: Renal failure/impairment (1.2%)

<1%: Hypersensitivity syndrome, increased alkaline phosphatase or hepatic transaminases, granulomatous hepatitis, dyspepsia, pancreatitis, gynecomastia, agranulocytosis, aplastic anemia, acute tubular necrosis, interstitial nephritis, nephrolithiasis, vasculitis, TEN, exfoliative dermatitis, Stevens-Johnson syndrome, granuloma annulare, toxic pustuloderma, peripheral neuropathy, neuritis, paresthesia, bronchospasm, cataracts, macular retinitis, angioedema, epistaxis

At high dosages, it is a theoretical possibility that oxypurinol stones could be formed but no record of such occurrence in overdose exists

Alkalinization of the urine and forced diuresis can help prevent potential xanthine stone formation

Hepatic enzyme inhibitor

Increased toxicity:

Inhibits metabolism of azathioprine and mercaptopurine (reduce to 1/3 or 1/4 of usual dose)

Use with ampicillin or amoxicillin may increase the incidence of skin rash

Urinary acidification with large amounts of vitamin C may increase kidney stone formation

Thiazide diuretics enhance toxicity, monitor renal function; thiazide diuretics and captopril (possibly other ACE inhibitors) may increase risk of hypersensitivity

Vidarabine neurotoxicity may be enhanced

Cyclosporine levels may be increased

Hepatic iron uptake may be increased with iron supplements

Allopurinol prolongs half-life of oral anticoagulants; allopurinol increases serum half-life of theophylline; allopurinol may compete for excretion in renal tubule with chlorpropamide and increases chlorpropamide's serum half-life

Store intact vials of unreconstituted powder at 15°C to 30°C (59°F to 86°F). Allopurinol sodium for injection should be dissolved with 25 mL of sterile water for injection. Reconstitution should yield a clear, almost colorless solution with no more than a slight opalescence. The initial solution should be diluted to the desired concentration with 0.9% sodium chloride injection or 5% dextrose for injection. Sodium bicarbonate-containing solutions should not be used. A final concentration of no greater than 6 mg/mL is recommended. The solution should be stored at 20°C to 25°C (68°F to 77°F) and administration should begin within 10 hours after reconstitution. Do not refrigerate the reconstituted and/or diluted product.

Allopurinol inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. Allopurinol is metabolized to oxypurinol which is also an inhibitor of xanthine oxidase; allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines.

Decreases in serum uric acid occur in 1-2 days with nadir achieved in 1-2 weeks

Absorption:

Oral: ~80% of dose absorbed from GI tract; peak plasma concentrations are seen 30-120 minutes after administration

Rectal: Poor and erratic

Distribution: V_d~1.6 L/kg; V_ss: 0.84-0.87 L/kg; distributes into breast milk

Protein binding: <1%

Metabolism: ~75% metabolized to active metabolites, chiefly oxypurinol

Bioavailability: 49% to 53%

Half-life:

Normal renal function:

Parent drug: 1-3 hours

Oxypurinol: 18-30 hours

End-stage renal disease: Half-life is prolonged

Elimination: Both allopurinol and oxypurinol are dialyzable; 10% may be eliminated by enterohepatic excretion; excreted in urine, 76% as oxypurinol, 12% as unchanged allopurinol

Oral:

Children less than or equal to 10 years: 10 mg/kg/day in 2-3 divided doses or 200-300 mg/m²/day in 2-4 divided doses, maximum: 800 mg/24 hours

Alternative: <6 years: 150 mg/day in 3 divided doses; 6-10 years: 300 mg/day in 2-3 divided doses

Children >10 years and Adults: Daily doses >300 mg should be administered in divided doses

Myeloproliferative neoplastic disorders: 600-800 mg/day in 2-3 divided doses for prevention of acute uric acid nephropathy for 2-3 days starting 1-2 days before chemotherapy

Gout: Mild: 200-300 mg/day; Severe: 400-600 mg/day

Elderly: Initial: 100 mg/day, increase until desired uric acid level is obtained

Dosing adjustment in renal impairment: Must be adjusted due to accumulation of allopurinol and metabolites; removed by hemodialysis. Adult maintenance doses of allopurinol* (mg) based on creatinine clearance (mL/minute):

Cl_cr 140 mL/minute: 400 mg daily

Cl_cr 120 mL/minute: 350 mg daily

Cl_cr 100 mL/minute: 300 mg daily

Cl_cr 80 mL/minute: 250 mg daily

Cl_cr 60 mL/minute: 200 mg daily

Cl_cr 40 mL/minute: 150 mg daily

Cl_cr 20 mL/minute: 100 mg daily

Cl_cr 10 mL/minute: 100 mg every 2 days

Cl_cr 0 mL/minute: 100 mg every 3 days

*Doses based on a standard maintenance dose of 300 mg of allopurinol per day for a patient with a creatinine clearance of 100 mL/minute.

Hemodialysis: Administer dose posthemodialysis or administer 50% supplemental dose

I.V.: Intravenous daily dose can be given as a single infusion or in equally divided doses at 6-, 8-, or 12-hour intervals. A fluid intake sufficient to yield a daily urinary output of at least 2 L in adults and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

Children: Starting dose: 200 mg/m²/day

Adults: 200-400 mg/m²/day (max: 600 mg/day)

Dosing adjustment in renal impairment: I.V.:

Cl_cr 10-20 mL/minute: 200 mg/day

Cl_cr 3-10 mL/minute: 100 mg/day

Cl_cr <3 mL/minute: 100 mg/day at extended intervals

Should be administered after meals with plenty of fluid

The rate of infusion depends on the volume of the infusion. Whenever possible, therapy should be initiated at 24-48 hours before the start of chemotherapy known to cause tumor lysis (including adrenocorticosteroids). I.V. daily dose can be administered as a single infusion or in equally divided doses at 6-, 8-, or 12-hour intervals at the recommended final concentration of less than or equal to 6 mg/mL.

CBC, serum uric acid levels, I & O, hepatic and renal function, especially at start of therapy

Uric acid, serum: An increase occurs during childhood

Male: 3.4-7 mg/dL or slightly more

Female: 2.4-6 mg/dL or slightly more

Values >7 mg/dL are sometimes arbitrarily regarded as hyperuricemia, but there is no sharp line between normals on the one hand, and the serum uric acid of those with clinical gout. Normal ranges cannot be adjusted for purine ingestion, but high purine diet increases uric acid. Uric acid may be increased with body size, exercise, and stress.

May cause drowsiness

Rarely may cause bone marrow suppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Take as directed. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) to avoid possible adverse renal problems. While using this medication, do not use alcohol, other prescription or OTC medications, or vitamin substances without consulting prescriber. You may experience drowsiness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or heartburn (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); hair loss (reversible). Report skin rash or lesions; painful urination or blood in urine or stool; unresolved nausea or vomiting; numbness of extremities; pain or irritation of the eyes; swelling of lips, mouth, or tongue; unusual fatigue; easy bruising or bleeding; yellowing of skin or eyes; or any change in color of urine or stool. Pregnancy precautions: Inform prescriber if you are or intend to be pregnant.

Monitor CBC, serum uric acid levels, I & O, hepatic and renal function, especially at start of therapy

Injection: 500 mg

Tablet: 100 mg, 300 mg

Crush tablets to make a 5 mg/mL suspension in simple syrup; stable 14 days under refrigeration

Allen LV and Erickson MA 3d, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.

Appelbaum SJ, Mayersohn M, Dorr RT, et al, "Allopurinol Kinetics and Bioavailability. Intravenous, Oral and Rectal Administration," Cancer Chemother Pharmacol, 1982, 8(1):93-8.

Bennett WM, Aronoff GR, Golper TA, et al, Drug Prescribing in Renal Failure, Philadelphia, PA: American College of Physicians, 1987.

Day RO, Birkett DJ, Hicks, M, et al, "New Uses for Allopurinol," Drugs, 1994, 48(3):399-44.

Elasy T, Kaminsky D, Tracy M, et al, "Allopurinol Hypersensitivity Syndrome Revisited," West J Med, 1995, 162(4):360-1.

Emmerson BT, "The Management of Gout," N Engl J Med, 1996, 334(7):445-51.

Ferner RE, Simmonds HA, and Bateman DN, "Allopurinol Kinetics After Massive Overdose," Hum Toxicol, 1988, 7(3):293-4.

Hande KR and Garrow GC, "Acute Tumor Lysis Syndrome in Patients With High-Grade Non-Hodgkin's Lymphoma," Am J Med, 1993, 94(2):133-9.

Krakoff IH and Murphy ML, "Hyperuricemia in Neoplastic Disease in Children: Prevention With Allopurinol, A Xanthine Oxidase Inhibitor" Pediatrics, 1968, 41(1):52-6.

McInnes GT, Lawson DH, and Jick H, "Acute Adverse Reactions Attributed to Allopurinol in Hospitalized Patients," Ann Rheum Dis, 1981, 40(3):245-9.

Murrell GA and Rapeport WG, "Clinical Pharmacokinetics of Allopurinol," Clin Pharmacokinet, 1986, 11(5):343-53.

Parra E, Gota R, Gamen A, et al, "Granulomatous Interstitial Nephritis Secondary to Allopurinol Treatment," Clin Nephrol, 1995, 43(5):350.

Vinciullo C, "Allopurinol Hypersensitivity," Med J Aust, 1984, 141(7):449-50.