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Allopurinol


Pronunciation

 (al oh PURE i nole)


U.S. Brand Names

 Aloprim™; Zyloprim®


Synonyms

 Allopurinol Sodium


Generic Available

 Yes


Canadian Brand Names

 Apo-Allopurinol®; Zyloprim®


Use

Oral: Prevention of attack of gouty arthritis and nephropathy; treatment of secondary hyperuricemia which may occur during treatment of tumors or leukemia; prevention of recurrent calcium oxalate calculi

I.V.: Treatment of elevated serum and urinary uric acid levels when oral therapy is not tolerated in patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer chemotherapy


Pregnancy Risk Factor

 C


Pregnancy Implications

 There are few reports describing the use of allopurinol during pregnancy; no adverse fetal outcomes attributable to allopurinol have been reported in humans; use only if potential benefit outweighs the potential risk to the fetus.


Lactation

 Enters breast milk/use caution (AAP rates "compatible")


Contraindications

 Hypersensitivity to allopurinol or any component of the formulation


Warnings/Precautions

 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. Use caution with mercaptopurine or azathioprine; dosage adjustment required.


Adverse Reactions

 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.

>1%:

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, toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, granuloma annulare, toxic pustuloderma, peripheral neuropathy, neuritis, paresthesia, bronchospasm, cataracts, macular retinitis, angioedema, epistaxis


Overdosage/Toxicology

 If significant amounts of allopurinol have been absorbed, it is theoretically possible that oxypurinol stones could form, but no record of such occurrence exists. Alkalinization of urine and forced diuresis can help prevent potential xanthine stone formation.


Drug Interactions

Ampicillin, amoxicillin: Incidence of rash may be increased.

Anticoagulants: Allopurinol may prolong the half-life of anticoagulants, effect seen with dicumarol; monitor.

ACE inhibitors: Captopril may increase risk of hypersensitivity.

Azathioprine: Metabolism inhibited by allopurinol; reduce azathioprine dose by 1 /3 or 1 /4.

Chlorpropamide: Half-life of chlorpropamide may be increased.

Cyclosporine: Allopurinol may increase cyclosporine serum levels.

Mercaptopurine: Metabolism inhibited by allopurinol; reduce mercaptopurine dose by 1 /3 or 1 /4.

Thiazide diuretics: Toxicity and risk of hypersensitivity may be increased.

Theophylline: Half-life of theophylline may be increased.

Vidarabine: Neurotoxicity may be enhanced.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may decrease effectiveness).

Iron supplements: Hepatic iron uptake may be increased.

Vitamin C: Large amounts of vitamin C may acidify urine and increase kidney stone formation.


Stability

Powder for injection: Store at controlled room temperature of 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. It may then be added to NS or D5W. A final concentration of no greater than 6 mg/mL is recommended. Following reconstitution, intravenous solutions should be stored at 20°C to 25°C (68°F to 77°F). Do not refrigerate reconstituted and/or diluted product. Must be administered within 10 hours of solution preparation.

Tablet: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F).


Compatibility

 Stable in D5W, NS, sterile water for injection

Y-site administration: Compatible: Acyclovir, aminophylline, aztreonam, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, cefazolin, cefoperazone, cefotetan, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cisplatin, co-trimoxazole, cyclophosphamide, dactinomycin, dexamethasone sodium phosphate, doxorubicin liposome, enalaprilat, etoposide, famotidine, fluconazole, fludarabine, fluorouracil, furosemide, ganciclovir, heparin, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, ifosfamide, lorazepam, mannitol, mesna, methotrexate, metronidazole, mitoxantrone, morphine, piperacillin, plicamycin, potassium chloride, ranitidine, thiotepa, ticarcillin, ticarcillin/clavulanate, vancomycin, vinblastine, vincristine, zidovudine. Incompatible: Amikacin, amphotericin B, carmustine, cefotaxime, chlorpromazine, cimetidine, clindamycin, cytarabine, dacarbazine, daunorubicin, diphenhydramine, doxorubicin, doxycycline, droperidol, floxuridine, gentamicin, haloperidol, hydroxyzine, idarubicin, imipenem/cilastatin, mechlorethamine, meperidine, methylprednisolone sodium succinate, metoclopramide, minocycline, nalbuphine, netilmicin, ondansetron, prochlorperazine edisylate, promethazine, sodium bicarbonate, streptozocin, tobramycin, vinorelbine


Mechanism of Action

 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.


Pharmacodynamics/Kinetics

Onset of action: Peak effect: 1-2 weeks

Absorption: Oral: ~80%; Rectal: Poor and erratic

Distribution: Vd: ~1.6 L/kg; Vss: 0.84-0.87 L/kg; enters breast milk

Protein binding: <1%

Metabolism: ~75% to active metabolites, chiefly oxypurinol

Bioavailability: 49% to 53%

Half-life elimination:

Normal renal function: Parent drug: 1-3 hours; Oxypurinol: 18-30 hours

End-stage renal disease: Prolonged

Time to peak, plasma: Oral: 30-120 minutes

Excretion: Urine (76% as oxypurinol, 12% as unchanged drug)

Allopurinol and oxypurinol are dialyzable


Dosage

Oral: Doses >300 mg should be given in divided doses.

Children 10 years: Secondary hyperuricemia associated with chemotherapy: 10 mg/kg/day in 2-3 divided doses or 200-300 mg/m 2 /day in 2-4 divided doses, maximum: 800 mg/24 hours

Alternative (manufacturer labeling): <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:

Secondary hyperuricemia associated with chemotherapy: 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; to reduce the possibility of acute gouty attacks, initiate dose at 100 mg/day and increase weekly to recommended dosage.

Recurrent calcium oxalate stones: 200-300 mg/day in single or divided doses

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

I.V.: Hyperuricemia secondary to chemotherapy: 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 10 years: Starting dose: 200 mg/m 2 /day

Children >10 years and Adults: 200-400 mg/m 2 /day (max: 600 mg/day)

Dosing adjustment in renal impairment: Must be adjusted due to accumulation of allopurinol and metabolites:

Oral: Removed by hemodialysis; adult maintenance doses of allopurinol (mg) based on creatinine clearance (mL/minute): See table.


Creatinine Clearance<br/>(mL/min)

Adult Maintenance Doses of Allopurinol1

Creatinine Clearance
(mL/min) 		Maintenance Dose of Allopurinol
(mg)
140 400 daily
120 350 daily
100 300 daily
80 250 daily
60 200 daily
40 150 daily
20 100 daily
10 100 every 2 days
0 100 every 3 days
1 This table is based on a standard maintenance dose of 300 mg of allopurinol per day for a patient with a creatinine clearance of 100 mL/min.

Hemodialysis: Administer dose posthemodialysis or administer 50% supplemental dose

I.V.:

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

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

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


Administration

Oral: Should administer oral forms after meals with plenty of fluid.

I.V.: 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 interval.


Monitoring Parameters

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


Reference Range

 Uric acid, serum: An increase occurs during childhood

Adults:

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.


Dietary Considerations

 Should administer oral forms after meals with plenty of fluid. Fluid intake should be administered to yield neutral or slightly alkaline urine and an output of ~2 L (in adults).


Patient Education

 Take as directed. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. While using this medication, do not use alcohol, other prescriptions, OTC medications, or vitamins 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); or 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 precaution: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.


Nursing Implications

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


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause drowsiness


Mental Health: Effects on Psychiatric Treatment

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


Oncology: Emetic Potential

 Very low (<10%)


Oncology: Vesicant

 No


Dosage Forms

Injection, powder for reconstitution, as sodium (Aloprim™): 500 mg

Tablet (Zyloprim®): 100 mg, 300 mg


Extemporaneously Prepared

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

Nahata MC and Hipple TF, Pediatric Drug Formulations , 1st ed, Harvey Whitney Books Co, 1990.


References

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.

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

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.


International Brand Names

 Abopur® (DK); Adenock® (JP); Algut® (ID); Alinol® (TH); Allo 1A Pharma® (DE); Allo AbZ® (DE); Allo-basan® (CH, DE); Allobeta® (DE); Allo-Efeka® (DE); Allogut® (TR); Allohexal® (AU); Allonol® (FI); Allopin® (TH); Allopron-100® (RO); Allopur® (CH, NO); Allo-Puren® (DE); Allopurinol 1A Farma® (DK); Allopurinol 1A Pharma® (DE); Allopurinol 300 Craveri® (AR); Allopurinol 300 Lacefa® (AR); Allopurinol AL® (DE); Allopurinol Alpharma ApS® (SG); Allopurinol-BC® (AU); Allopurinol Beacons® (SG); Allopurinol® (BR, DE, GB, LU, PL, RO, RU); Allopurinol Craveri® (AR); Allopurinol Dak® (DK); Allopurinol DHA® (SG); Allopurinol EG® (BE); Allopurinol Fabra® (AR); Allopurinol Genericon® (AT); Allopurinol Gen Med® (AR); Allopurinol Helvepharm® (CH); Allopurinol Heumann® (DE); Allopurinol Hexal® (AR, DE); Allopurinol-Inca® (AR); Allopurinol Lindo® (DE); Allopurinol Nordic® (SE); Allopurinol Nycomed® (RU, SE); Allopurinolo Molteni® (IT); Allopurinol Phoenix® (AR); Allopurinol-ratiopharm® (DE, LU); Allopurinol SAD® (DK); Allopurinol Sandoz® (DE); Allopurinol Siegfried® (DE); Allopurinol Stada® (DE); Alloratio® (PL); Alloril® (IL); Allorin® (AU, HK, NZ); Allostad® (AT); Allotyrol® (AT); allo von ct® (DE); Allozym® (JP); Allpargin® (LU); Allupol® (PL); Allurit® (IT); Alopron® (CY); Alopurinol® (CL, HR, SI, YU); Alopurinol Faes® (ES); Alopurinol L.CH.® (CL); Alopurinol Mundogen® (ES); Alopurinol Normon® (CR, ES, GT, HN, PA, SV); Alopurinol Ratiopharm® (ES); Alopurinol Richet® (AR); Alosfar® (PT); Alositol® (JP); Alpuric® (BE, LU); Alurin® (GT); Anoprolin® (JP); Anzief® (JP); Apnol® (TH); Apo-Allopurinol® (CA, CZ, NZ, PL, SG); Apurin® (AT, DK, FI, NL); Apurin® [inj.] (NL); Apurol® (TH); Arturic® (FI, NO); Atisuril® (MX); Benoxuric® (ID); Bleminol® (DE); Burmadon® (RO); Caplenal® (CZ, GB, HK, IE); Capurate® (AU); Cellidrin® (CH, DE); Clint® (CY); Cosuric® (GB); Docallopu® (BE); Dropinol® (CL); dura AL® (DE); Erloric® (SG); Esloric® (BD); Foligan® (DE); Gewapurol® (AT); Gichtex® (AT, RO); Gotir® (AR); Hexanurat® (DK); Huma-Purol® (HU); Isoric® (ID); Jenapurinol® (DE); Kemorinol® (ID); Ketanrift® (JP); Ketobun-A® (JP); Llanol® (ID); Lonol® (ZA); Masaton® (JP); Medoric® (TH); Mephanol® (CH, HK); Milurit® (CZ, DE, HU, PL, RO, RU); Neufan® (JP); Nilapur® (ID); No-Uric® (EG, JO, KW, LB); Progout® (AU, NZ, SG); Proxuric® (ID); Puricemia® (ID); Puricin® (TH); Puricos® (ZA); Puride® (TH); Purinol® (AT, CZ, IE, RU); Puritenk® (AR); Redurate® (ZA); Remid® (DE); Reucid® (ID); Riball® (JP); Rimapurinol® (GB); Rinolic® (ID); Rolab-Allopurinol® (ZA); Serviprinol® (CH); Sigapurol® (CH); Takanarumin® (JP); Talol® (CL); Tipuric® (IE); Tylonic® (ID); Uribenz® (DE); Uricad® (TH); Urica® (ID); Uricemil® (IT); Uriconorm® (CH); Urikoliz® (TR); Urinol-300® (ZA); Uriprim® (PT); Uripurinol® (DE); &uuml;rkoliz® (TR); Urogotan A® (CL); Uroquad® (AR, ID); Urosin® (AT, LU); Urozyl-SR® (ZA); Urtias® (DE); Valeric® (SG, TH); Xanol® (TH); Xanthomax® (GB); Xanturic® (FR, ID); Zurim® (PT); Zylol® (IL); Zyloprim® (AU, CA, MX, NZ, ZA); Zyloric® (AT, BE, BR, CH, CL, DE, ES, FI, FR, GB, HK, ID, IE, IL, IN, IT, KW, LU, NL, NO, PL, PT, RO, SE, SG, SI, TH)


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