Allopurinol

Pronunciation

Class: Antigout Agents
VA Class: MS400
CAS Number: 315-30-0
Brands: Aloprim, Zyloprim

Introduction

Xanthine oxidase inhibitor; structural isomer of hypoxanthine.152 156

Uses for Allopurinol

Gout

Reduction of serum and urinary uric acid concentrations in primary and secondary gout.156 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.a

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.a

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

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Not recommended for management of asymptomatic hyperuricemia;156 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.a

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

Chemotherapy-induced Hyperuricemia

A component of therapy (with urinary alkalinization and IV hydration)160 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.152 153 156

Oral allopurinol may be slower and less effective in decreasing plasma uric acid concentrations than IV rasburicase.157 158 159 160 161

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.156

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

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.a

Allopurinol Dosage and Administration

General

  • Maintain fluid intake to yield daily urine output of ≥2 L.152 156 Maintain neutral or, preferably, alkaline urine.152 156

Gout

  • Transition period of several months may be required when allopurinol is added to regimen of colchicine, uricosuric agents, and/or anti-inflammatory agents.156 a During transition period, administer drugs concomitantly, adjusting allopurinol dosage to achieve normal serum urate concentrations and freedom from acute gouty attacks for several months.156 a Withdraw uricosuric agent gradually over several weeks.156 a

Chemotherapy-induced Hyperuricemia

  • For prevention of acute uric acid nephropathy in patients undergoing chemotherapy, begin allopurinol treatment 24–48 hours before initiating chemotherapy.152 a

Administration

Administer orally156 or by IV infusion.152

Oral Administration

Usually administered orally once daily, preferably after meals.156 If oral dose >300 mg, administer in divided doses.156

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.152 Should be diluted further before IV administration.152

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.152 Do not use diluent containing sodium bicarbonate.152

Rate of Administration

Administer daily dosage by continuous infusion or in equally divided intermittent IV infusions at 6-, 8-, or 12-hour intervals.152 Infusion rate depends on volume of infusate.152

Dosage

Available as allopurinol (oral) or allopurinol sodium (for IV use); dosage is expressed in terms of allopurinol.152 156

Pediatric Patients

Chemotherapy-induced Hyperuricemia
Oral

Children <6 years of age: Initially, 150 mg daily.156

Children 6–10 years of age: Initially, 300 mg daily.156

Adjust dosage after about 48 hours according to patient response.156

IV

Children ≤10 years of age: Initial dosage of 200 mg/m2 daily.152 a

Children >10 years of age: 200–400 mg/m2 daily.152 162

Adults

Gout
Oral

Initially, 100 mg daily.156 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.156 Usual dosage is 200–300 mg daily in patients with mild gout and 400–600 mg daily in those with moderately severe tophaceous gout.156

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.156

Chemotherapy-induced Hyperuricemia
Oral

600–800 mg daily for 2–3 days.156

IV

200–400 mg/m2 daily.152

Recurrent Calcium Oxalate Renal Calculi
Oral

Initially, 200–300 mg daily.156 Titrate dosage based on 24-hour urinary urate determinations.156

Prescribing Limits

Pediatric Patients

IV

Children >10 years of age: Maximum 600 mg daily.152

Adults

Oral

Maximum 800 mg daily.156

IV

Maximum 600 mg daily.152

Special Populations

Renal Impairment

Oral
Initial Oral Dosage in Patients with Renal Impairment

Clcr (mL/min)

Initial Dosage

10–20

200 mg daily156

<10

≤100 mg daily156

<3

Increase dosage interval (e.g., 300 mg twice weekly)156 a

Maintenance Oral Dosage in Patients with Renal Impairment150

Clcr (mL/min)

Maintenance Dosage

80

250 mg daily

60

200 mg daily

40

150 mg daily

20

100 mg daily

10

100 mg every 2 days

 0

100 mg every 3 days

IV
Maintenance IV Dosage in Patients with Renal Impairment152

Clcr (mL/min)

Maintenance Dosage

10–20

200 mg daily

3–10

100 mg daily

<3

100 mg at extended intervals

Cautions for Allopurinol

Contraindications

  • Known hypersensitivity to allopurinol or previous serious reaction.152 156

Warnings/Precautions

Warnings

Hepatic Effects

Hepatotoxic reactions and elevations of serum transaminase or alkaline phosphatase concentrations reported.152 156

Perform liver function tests (especially in patients with preexisting liver disease) before and periodically during therapy, particularly during initial months of therapy.152 156 a

If anorexia, weight loss, or pruritus develops, assess liver function.152 156

CNS Effects

Drowsiness may occur; performance of activities requiring mental alertness may be impaired.152

Sensitivity Reactions

Hypersensitivity Reactions

Severe hypersensitivity reactions (including fatalities) have been reported following appearance of rash.152 156 Discontinue at first appearance of rash or any sign that may indicate hypersensitivity reaction.152 156

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.152 156

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.156

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.156 a

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.152 156

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).152 156 a

Specific Populations

Pregnancy

Category C.152 156

Lactation

Allopurinol and oxypurinol distribute into milk; use with caution in nursing women.152 156

Pediatric Use

Rarely indicated in children except in those with hyperuricemia secondary to neoplastic disease, cancer chemotherapy, or genetic disorders of purine metabolism.156 a

Safety and efficacy profile for allopurinol sodium for injection in children is similar to that in adults.152

Geriatric Use

Select dosage carefully due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.152 154 Elimination may be prolonged due to age-related changes in renal function.154

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.152

Renal Impairment

Increased half-life.152 Reduce dosage.150 152 153 156 (See Renal Impairment under Dosage and Administration.)

Monitor closely; if deterioration in renal function occurs and persists, reduce dosage or discontinue drug.152 156

Possible increased risk of rash.a

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.152 (See Specific Drugs under Interactions.)

Common Adverse Effects

Oral therapy: pruritic maculopapular rash.156

IV therapy: rash, renal failure/impairment, nausea, vomiting.152

Interactions for Allopurinol

Does not inhibit hepatic microsomal enzymes.a

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential for increased serum urate concentrations156 a

May need to increase allopurinol dosage156 a

Ampicillin and Amoxicillin

Increased incidence of rash in patients with hyperuricemia152 156 a

Clinical importance not determined; avoid concomitant use, if possiblea

Anticoagulants (e.g., dicumarol, warfarin)

Inhibition of dicumarol metabolism;a 152 156 not shown to substantially potentiate anticoagulant effect of warfarina

In patients receiving dicumarol and allopurinol, monitor PT and observe patient for increased anticoagulant effects152 156 a

Azathioprine

Inhibition of azathioprine metabolism; possible increase in toxic effects (including bone marrow depression)152 156

Decrease azathioprine dosage initially by 66–75%; base subsequent dosage adjustments on patient response and toxic effects152 156

Chlorpropamide

Potential for adverse hepatorenal reactions;a competition with chlorpropamide for renal tubular secretion152 156

Observe for signs of excessive hypoglycemia, especially in patients with renal impairment152 156

Co-trimoxazole

Rare cases of thrombocytopeniaa

Cyclophosphamide

Potential for bone marrow depression; mechanism not known152 156 a

Cyclosporine

Increased blood concentrations of cyclosporine152 156

Monitor blood concentration and consider dosage adjustments of cyclosporine152 156

Diazoxide

Potential for increased serum urate concentrations156 a

May need to increase allopurinol dosage156 a

Diuretics (e.g., thiazides, ethacrynic acid)

Potential for increased serum urate concentrations; potential for increased serum oxypurinol concentrations and increased risk of allopurinol toxicity, including hypersensitivity reactions, particularly in patients with renal impairment152 156 a

Monitor renal function; adjust dosage of allopurinol if necessary152 156 a

Mercaptopurine

Inhibition of mercaptopurine metabolism; possible increase in toxic effects (including bone marrow depression)152 156

Decrease mercaptopurine dosage initially by 66–75%; base subsequent dosage adjustments on patient response and toxic effects152 156

Pyrazinamide

Potential for increased serum urate concentrations156 a

May need to increase allopurinol dosage156 a

Uricosurics

Increased uric acid excretion; possible reduction in inhibition of xanthine oxidase by oxypurinol; possible renal precipitation of oxypurines152 156 a

May use smaller doses of each druga

Allopurinol Pharmacokinetics

Absorption

Bioavailability

About 80–90% absorbed following oral administration;156 a peak plasma concentrations of allopurinol and oxypurinol are reached in 1.5 and 4.5 hours, respectively.156

Following IV infusion over 30 minutes, peak plasma concentrations of allopurinol and oxypurinol are reached in about 30 minutes and 4 hours, respectively.152

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.156 a 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.156 a

Duration

After discontinuance of therapy, serum urate concentrations return to pretreatment levels within 1–2 weeks.a 156

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.154

Distribution

Extent

Uniformly distributed in total tissue water, except in the brain where concentrations are approximately 50% of those in other tissues.a Allopurinol and oxypurinol are distributed into milk.152 156

Plasma Protein Binding

Allopurinol and oxypurinol are not bound to plasma proteins.a

Elimination

Metabolism

Rapidly metabolized by xanthine oxidase; metabolized principally to an active metabolite, oxypurinol.152 156

Elimination Route

Excreted in urine as oxypurinol (about 70%) and in feces as unchanged drug (about 20%) within 48–72 hours.152 156 a

Allopurinol and oxypurinol are dialyzable.156

Half-life

1–3 and 18–30 hours for allopurinol and oxypurinol, respectively.152 156 a

Special Populations

In patients with severe renal impairment or decreased urate clearance, plasma half-life of oxypurinol is greatly prolonged.152 156

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

Stability

Storage

Oral

Tablets

15–25°C in dry place; protect from light.156

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).152

Store diluted allopurinol sodium solutions containing ≤6 mg/mL of allopurinol at 20–25°C; use within 10 hours of reconstitution.152 Do not refrigerate reconstituted and/or diluted solutions.152

Compatibility

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

Parenteral

Solution Compatibility152

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Y-Site Compatibilityb

Compatible

Acyclovir sodium

Aminophylline

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Cefazolin sodium

Cefotetan disodium

Ceftazidime

Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Cisplatin

Co-trimoxazole

Cyclophosphamide

Dactinomycin

Dexamethasone sodium phosphate

Doxorubicin HCl liposome injection

Enalaprilat

Etoposide

Famotidine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Ganciclovir sodium

Granisetron HCl

Heparin sodium

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Ifosfamide

Lorazepam

Mannitol

Mesna

Methotrexate sodium

Metronidazole

Mitoxantrone HCl

Morphine sulfate

Plicamycin

Potassium chloride

Ranitidine HCl

Teniposide

Thiotepa

Ticarcillin disodium

Ticarcillin disodium–clavulanate potassium

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Zidovudine

Incompatible

Amikacin sulfate

Amphotericin B

Carmustine

Cefotaxime sodium

Chlorpromazine HCl

Cimetidine HCl

Clindamycin phosphate

Cytarabine

Dacarbazine

Daunorubicin HCl

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Floxuridine

Gentamicin sulfate

Haloperidol lactate

Hydroxyzine HCl

Idarubicin HCl

Imipenem–cilastatin sodium

Mechlorethamine HCl

Meperidine HCl

Methylprednisolone sodium succinate

Metoclopramide HCl

Minocycline HCl

Nalbuphine HCl

Ondansetron HCl

Prochlorperazine edisylate

Promethazine HCl

Sodium bicarbonate

Streptozocin

Tobramycin sulfate

Vinorelbine tartrate

Actions

  • Allopurinol and its active metabolite, oxypurinol, inhibit xanthine oxidase.152 156 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.152 156

  • Decreases de novo purine biosynthesis by indirectly increasing oxypurine and allopurinol ribonucleotide concentrations and decreasing phosphoribosylpyrophosphate concentrations.a Also decreases serum uric acid concentrations by increasing incorporation of hypoxanthine and xanthine into DNA and RNA.152 a

  • Has no analgesic, anti-inflammatory, or uricosuric activity.153

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.152 156

  • Importance of maintaining fluid intake sufficient to yield daily urine output of ≥2 L.152 156

  • Administering drug after meals may minimize gastric irritation.156

  • Importance of continuing allopurinol therapy as prescribed for gout; optimal benefit may be delayed for 2–6 weeks.156

  • 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.152 156

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.152 156

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.152 156

  • Importance of informing patients of other important precautionary information.152 156 (See Cautions.)

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Allopurinol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg*

Zyloprim (with povidone; scored)

Prometheus

300 mg*

Zyloprim (with povidone; scored)

Prometheus

Allopurinol Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infustion only

500 mg (of allopurinol)

Aloprim

Nabi

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Allopurinol 100MG Tablets (WATSON LABS): 100/$13.99 or 300/$33.96

Allopurinol 300MG Tablets (WATSON LABS): 100/$23.99 or 300/$55.98

Zyloprim 100MG Tablets (PROMETHEUS): 30/$69.98 or 90/$139.94

Zyloprim 300MG Tablets (PROMETHEUS): 30/$103.99 or 90/$279.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 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.

References

150. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984; 76:47-56. [IDIS 180407] [PubMed 6691361]

151. Ettinger B, Tang A, Citron JT et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med. 1986; 315:1386-9. [IDIS 223014] [PubMed 3534570]

152. Nabi. Aloprim (allopurinol sodium) for injection prescribing information. Boca Raton, FL; 2003 Feb.

153. Smalley RV, Guaspari A, Haase-Statz S et al. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol. 2000; 18:1758-63. [IDIS 447152] [PubMed 10764437]

154. Turnheim K, Krivanek P, Oberbauer R. Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects. Br J Clin Pharmacol. 1999; 48:501-9. [IDIS 437123] [PubMed 10583019]

155. Newton DW. Introduction: physicochemical determinants of incompatibility and instability of drugs for injection and infusion. In: Trissel LA. Handbook of injectable drugs. 3rd ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc., Inc.; 1983:xi-xxi.

156. Prometheus. Zyloprim (allopurinol) tablets prescribing information. San Diego, CA; 2003 Oct.

157. Sanofi-Synthelabo Inc. Elitek (rasburicase) injection for intravenous use prescribing information. New York, NY; 2002 Jul 22.

158. Goldman SC, Holcenberg JS, Finklestein JZ et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001; 97:2998-3003. [IDIS 463743] [PubMed 11342423]

159. Easton J, Noble S, Jarvis B. Rasburicase. Pediatr Drugs. 2001; 3:433-9

160. Anon. Rasburicase (Elitek) for hyperuricemia. Med Letter Drug Ther. 2002; 44:96-7.

161. Lohr LK. Rasburicase, a new, recombinate form of urate oxidase, treats hyperuricemia in tumor lysis syndrome. Hem/Onc Today. October 2002. From the Hem/Onc Today website. Accessed 2003 Jan 23.

162. Nabi, Boca Raton, FL: Personal communication.

a. AHFS Drug Information 2003. McEvoy GK, ed. Allopurinol. American Society of Health-System Pharmacists; 2003: page 3546-50.

b. Trissel LA. Handbook on injectable drugs. 13th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2005:23-29.

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