Generic Name: allopurinol

Brand Names: Aloprim, Zyloprim, Lopurin

Uses

Gout

Reduction of serum and urinary uric acid concentrations in primary and secondary gout. In early uncomplicated gout, preferred over uricosurics in patients with urinary uric acid excretion >900 mg daily and in those with gouty nephropathy, urinary tract stones or obstruction, or azotemia.

Management of gout when uricosuric agents cannot be used because of adverse effects, allergy, or inadequate response; when there are visible tophi or radiographic evidence of uric acid deposits and stones; or when serum urate concentrations exceed 8.5–9 mg/dL and patient has family history of tophi and low urate excretion.

Management of primary or secondary gouty nephropathy with or without secondary oliguria.

Not recommended for management of asymptomatic hyperuricemia; however, some clinicians have suggested that therapy be initiated when serum urate concentrations exceed 9 mg/dL (by colorimetric method) because these concentrations often are associated with increased joint changes and renal complications.

Of no value in the treatment of acute gout attacks (due to lack of analgesic or anti-inflammatory activity).

Chemotherapy-induced Hyperuricemia

A component of therapy (with urinary alkalinization and IV hydration) in patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy expected to result in tumor lysis and subsequent elevations of serum and urinary uric acid concentrations.

Oral allopurinol may be slower and less effective in decreasing plasma uric acid concentrations than IV rasburicase.

Recurrent Renal Calculi

Management of recurrent calcium oxalate renal calculi in males and females whose urinary urate excretion exceeds 800 and 750 mg daily, respectively.

Prevention of uric acid renal calculi in patients with history of recurrent stone formation.

Other Uses

Has been used to reduce hyperuricemia secondary to glucose-6-phosphate dehydrogenase deficiency†, Lesch-Nyhan syndrome†, polycythemia vera†, or sarcoidosis† or secondary to administration of thiazides† or ethambutol†.

Dosage and Administration

General

• Maintain fluid intake to yield daily urine output of ≥2 L. Maintain neutral or, preferably, alkaline urine.

Gout

• Transition period of several months may be required when allopurinol is added to regimen of colchicine, uricosuric agents, and/or anti-inflammatory agents. During transition period, administer drugs concomitantly, adjusting allopurinol dosage to achieve normal serum urate concentrations and freedom from acute gouty attacks for several months. Withdraw uricosuric agent gradually over several weeks.

Chemotherapy-induced Hyperuricemia

• For prevention of acute uric acid nephropathy in patients undergoing chemotherapy, begin allopurinol treatment 24–48 hours before initiating chemotherapy.

Administration

Administer orally or by IV infusion.

Oral Administration

Usually administered orally once daily, preferably after meals. If oral dose >300 mg, administer in divided doses.

IV Infusion

For solution and drug compatibility information, see Stability under Compatibility.

Reconstitution

Reconstitute vial containing allopurinol sodium equivalent to 500 mg of allopurinol with 25 mL of sterile water for injection to provide a solution containing 20 mg/mL of allopurinol. Should be diluted further before IV administration.

Dilution

Dilute concentrate containing allopurinol 20 mg/mL with a compatible IV solution (see Solution Compatibility under Stability) to a final concentration of ≤6 mg/mL. Do not use diluent containing sodium bicarbonate.

Rate of Administration

Administer daily dosage by continuous infusion or in equally divided intermittent IV infusions at 6-, 8-, or 12-hour intervals. Infusion rate depends on volume of infusate.

Dosage

Available as allopurinol (oral) or allopurinol sodium (for IV use); dosage is expressed in terms of allopurinol.

Pediatric Patients

Chemotherapy-induced Hyperuricemia

Oral

Children <6 years of age: Initially, 150 mg daily.

Children 6–10 years of age: Initially, 300 mg daily.

Adjust dosage after about 48 hours according to patient response.

IV

Children ≤10 years of age: Initial dosage of 200 mg/m² daily.

Children >10 years of age: 200–400 mg/m² daily.

Adults

Gout

Oral

Initially, 100 mg daily. May increase dosage by 100 mg weekly until serum urate concentration falls to ≤6 mg/dL or until maximum recommended dosage of 800 mg daily is reached. Usual dosage is 200–300 mg daily in patients with mild gout and 400–600 mg daily in those with moderately severe tophaceous gout.

After serum urate concentrations are controlled, dosage reduction may be possible; average maintenance dosage is 300 mg daily, and minimum effective dosage is 100–200 mg daily.

Chemotherapy-induced Hyperuricemia

Oral

600–800 mg daily for 2–3 days.

IV

200–400 mg/m² daily.

Recurrent Calcium Oxalate Renal Calculi

Oral

Initially, 200–300 mg daily. Titrate dosage based on 24-hour urinary urate determinations.

Prescribing Limits

Pediatric Patients

IV

Children >10 years of age: Maximum 600 mg daily.

Adults

Oral

Maximum 800 mg daily.

IV

Maximum 600 mg daily.

Special Populations

Renal Impairment

Oral

IV

Cautions

Contraindications

• Known hypersensitivity to allopurinol or previous serious reaction.

Warnings/Precautions

Warnings

Hepatic Effects

Hepatotoxic reactions and elevations of serum transaminase or alkaline phosphatase concentrations reported.

Perform liver function tests (especially in patients with preexisting liver disease) before and periodically during therapy, particularly during initial months of therapy.

If anorexia, weight loss, or pruritus develops, assess liver function.

CNS Effects

Drowsiness may occur; performance of activities requiring mental alertness may be impaired.

Sensitivity Reactions

Hypersensitivity Reactions

Severe hypersensitivity reactions (including fatalities) have been reported following appearance of rash. Discontinue at first appearance of rash or any sign that may indicate hypersensitivity reaction.

Hypersensitivity reactions may occur more frequently in patients with renal impairment receiving allopurinol and thiazide diuretics; use these drugs with caution and careful monitoring in this population.

General Precautions

Acute Gout

Allopurinol is of no value in the treatment of acute gout attacks; will prolong and exacerbate inflammation during the acute phase.

May increase frequency of acute attacks during the first 6–12 months of therapy; therefore, administer prophylactic doses of colchicine concurrently during the first 3–6 months of therapy.

Hydration

Maintain sufficient fluid intake and a neutral or slightly alkaline urine to avoid possible formation of xanthine calculi and to prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Adequate Laboratory Monitoring

Perform liver and renal function tests and complete blood cell counts before and periodically during therapy (particularly during initial months of therapy).

Specific Populations

Pregnancy

Category C.

Lactation

Allopurinol and oxypurinol distribute into milk; use with caution in nursing women.

Pediatric Use

Rarely indicated in children except in those with hyperuricemia secondary to neoplastic disease, cancer chemotherapy, or genetic disorders of purine metabolism.

Safety and efficacy profile for allopurinol sodium for injection in children is similar to that in adults.

Geriatric Use

Select dosage carefully due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Elimination may be prolonged due to age-related changes in renal function.

Numbers of geriatric patients in clinical studies of IV allopurinol sodium insufficient to determine whether they respond differently than younger adults; other clinical experience identified no difference in response.

Renal Impairment

Increased half-life. Reduce dosage. (See Renal Impairment under Dosage and Administration.)

Monitor closely; if deterioration in renal function occurs and persists, reduce dosage or discontinue drug.

Possible increased risk of rash.

Concomitant therapy with a thiazide diuretic in patients with renal impairment may increase risk of allopurinol-induced hypersensitivity reactions; use with caution in such patients and observe closely. (See Specific Drugs under Interactions.)

Common Adverse Effects

Oral therapy: pruritic maculopapular rash.

IV therapy: rash, renal failure/impairment, nausea, vomiting.

Interactions

Does not inhibit hepatic microsomal enzymes.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

About 80–90% absorbed following oral administration; peak plasma concentrations of allopurinol and oxypurinol are reached in 1.5 and 4.5 hours, respectively.

Following IV infusion over 30 minutes, peak plasma concentrations of allopurinol and oxypurinol are reached in about 30 minutes and 4 hours, respectively.

Onset

In patients with gout, serum urate concentrations begin to decrease slowly within 24–48 hours; minimum concentrations may not be reached for about 1–3 weeks. Because of continued mobilization of urate deposits, substantial reduction of uric acid may be delayed 6–12 months or may not occur in some patients.

Duration

After discontinuance of therapy, serum urate concentrations return to pretreatment levels within 1–2 weeks.

Special Populations

In geriatric patients (71–93 years of age), peak plasma concentrations and AUC of oxypurinol following oral allopurinol dose are 50–60% higher than in younger adults (24–35 years of age); apparently related to changes in renal function in older population.

Distribution

Extent

Uniformly distributed in total tissue water, except in the brain where concentrations are approximately 50% of those in other tissues. Allopurinol and oxypurinol are distributed into milk.

Plasma Protein Binding

Allopurinol and oxypurinol are not bound to plasma proteins.

Elimination

Metabolism

Rapidly metabolized by xanthine oxidase; metabolized principally to an active metabolite, oxypurinol.

Elimination Route

Excreted in urine as oxypurinol (about 70%) and in feces as unchanged drug (about 20%) within 48–72 hours.

Allopurinol and oxypurinol are dialyzable.

Half-life

1–3 and 18–30 hours for allopurinol and oxypurinol, respectively.

Special Populations

In patients with severe renal impairment or decreased urate clearance, plasma half-life of oxypurinol is greatly prolonged.

Patients genetically deficient in xanthine oxidase are unable to convert allopurinol to oxypurinol.

Stability

Storage

Oral

Tablets

15–25°C in dry place; protect from light.

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Store diluted allopurinol sodium solutions containing ≤6 mg/mL of allopurinol at 20–25°C; use within 10 hours of reconstitution. Do not refrigerate reconstituted and/or diluted solutions.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Drug Compatibility

Actions

• Allopurinol and its active metabolite, oxypurinol, inhibit xanthine oxidase. Inhibition of xanthine oxidase blocks conversion of oxypurines (hypoxanthine, xanthine) to uric acid, resulting in decreases in serum and urine uric acid concentrations and increases in serum and urine concentrations of hypoxanthine and xanthine.
• Decreases de novo purine biosynthesis by indirectly increasing oxypurine and allopurinol ribonucleotide concentrations and decreasing phosphoribosylpyrophosphate concentrations. Also decreases serum uric acid concentrations by increasing incorporation of hypoxanthine and xanthine into DNA and RNA.
• Has no analgesic, anti-inflammatory, or uricosuric activity.

Advice to Patients

• Importance of discontinuing drug and consulting clinician at first sign of rash, painful urination, blood in urine, irritation of eyes, or swelling of lips or mouth.
• Importance of maintaining fluid intake sufficient to yield daily urine output of ≥2 L.
• Administering drug after meals may minimize gastric irritation.
• Importance of continuing allopurinol therapy as prescribed for gout; optimal benefit may be delayed for 2–6 weeks.
• Potential for drug to cause drowsiness and impair mental alertness; use caution when operating machinery or performing hazardous tasks until effects on individual are known.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions May 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.