Allopurinol

Pronunciation (al oh PURE i nole)

• Antacid Drug Interactions

U.S. Brand Names Aloprim^TM; Zyloprim®

Synonyms Allopurinol Sodium Injection

Generic Available Yes

Canadian Brand Names Apo®-Allopurinol; Zyloprim®

Pharmacologic Category Xanthine Oxidase Inhibitor

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

Orphan drug: I.V.: 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

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/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.

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%:

<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.

Decreased effect: Ethanol decreases effectiveness, uricosurics

Increased toxicity:

Ethanol/Nutrition/Herb Interactions Ethanol: Avoid ethanol (may decrease effectiveness).

Stability 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.

Y-site 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, metoclopramide, methylprednisolone sodium succinate, minocycline, nalbuphine, netilmicin, ondansetron, prochlorperazine, promethazine, sodium bicarbonate, streptozocin, tobramycin, vinorelbine

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.

Onset of action: Peak effect: 1-2 weeks

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

Distribution: V_d: ~1.6 L/kg; V_ss: 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:

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

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

Allopurinol and oxypurinol are dialyzable

Oral:

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.

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

Administration 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 6 mg/mL.

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:

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.

Patient Information 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 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); 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.

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

Anesthesia and Critical Care Concerns/Other Considerations Allopurinol does not require more frequent dosing than once daily; however, GI intolerance may occasionally necessitate a more frequent dosing interval

Dental Health: Effects on Dental Treatment No 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

Injection, powder for reconstitution, as sodium (Aloprim^TM): 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.

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.

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International Brand Names Abburic (ZA); Abopur® (DK); Adenock® (JP); Allo (DE); Allo 1A Pharma® (DE); Allo-300-Tablinen® (DE); Allo-300-Tablinen (CH); Allo AbZ® (DE); Allo-basan® (DE); allo-basan (CH); Allobeta® (DE); Alloboxal® (AR); Allo-Efeka (DE); Allogut® (TR); Allohexal® (AU); Allohexal (DE); Allohexan® (DE); Allonol® (FI); Allop.-Gry® (DE); Allopin® (TR); Alloprim® (TR); Alloprin® (CA); Allopur® (DK, NO, CH); Allo-Puren® (DE); Allopurin (ES); Allopurinol 300 Craveri® (AR); Allopurinol 300 Lacefa® (AR); Allopurinol AL® (DE); Allopurinol Aliud® (AT); Allopurinol Bayer® (FR); Allopurinol-BC® (AU); Allopurinol Fabra® (AR); Allopurinol Genericon® (AT); Allopurinol GNR® (FR); Allopurinol Heumann® (DE); Allopurinol Hexal® (DE); Allopurinol-Inca® (AR); Allopurinol Lindo® (DE); Allopurinol L.U.T.® (DE); Allopurinol MSD® (FR); Allopurinol Nordic® (SE); Allopurinol Nycomed® (SE); Allopurinolo® (IT); Allopurinol Phoenix® (AR); Allopurinol-ratiopharm® (FR, DE, LU, PL); Allopurinol Stada® (DE); Allopurinol Tika® (FI); Alloratio® (PL); Alloremed (AU); Allorin® (AU, HK, NZ); Allostad (AT); Allotyrol (AT); Allo-Uerik® (TR); allo von ct® (DE); Allozym® (JP); Allpargin® (DE, LU); Allupol® (PL); Allural (ES); Allurit (IT); Alopron® (CY); Alopurinol® (CL, HR, YU); Alopurinol L.CH.® (CL); Alopurinol Mundogen® (ES); Alopurinol ratiopharm® (ES); Alopurinol Richet® (AR); Aloral® (CH); Alosfar (PT); Alositol® (JP); Alpuric® (BE, LU); Anoprolin® (JP); Antigut® (TR); Anzief® (JP); Apo-Allopurinol® (CA, NZ, PL); Apulonga (DE); Apurin® (AT, DK, FI); Apurin (NL); Apurin® [inj.] (DK, NL); Arturic® (FI, NO); Atisuril® (MX); Be-Uric (ZA); Bleminol® (DE); Burmadon® (PL); Caplenal® (CZ, GB, HK, IE); Capurate® (AU); Cellidrin® (CH); Cellidrine (CH); Cosuric® (GB); Ethipurinol (ZA); Foligan (CH); Geapur® (DK); Gewapurol (AT); Gichtex (AT); Gotir® (AR); Hamarin® (GB); Hexanurat (DK); Huma-Purol® (HU); Ketanrift® (JP); Ketobun-A® (JP); Lonol (ZA); Lo-Uric (ZA); Lysuron (CH); Masaton® (JP); Mephanol® (HK, CH); Milurit® (CZ, HU, PL); Monarch® (JP); Neufan® (JP); Novopurol® (CA); Progout (AU, NZ); Puricos (ZA); Purinol (AT, CA, CZ, IE); Pyrazol (ZA); Ranpuric (ZA); Redurate (ZA); Riball® (JP); Rimapurinol® (GB); Roucol® (CA); Serviprinol® (CH); Sigapurol (CH); Tipuric® (IE); Uerikoliz® (TR); Unizuric 300 (MX); Urbol® (DK); Uredimin® (CH); Uricemil (BR, IT); Uriconorm® (CH); Uriconorme (CH); Uridocid® (ES); Urikoliz® (TR); Urinol (ZA); Uriprim® (PT); Urolit® (IT); Uroquad® (AR, ID); Urosin® (AT, LU); Urozyl-SR (ZA); Vedatan® (IT); Xanthomax® (GB); Xanturic® (FR); Zurim® (PT); Zygout (AU); Zylol® (IL); Zyloprim (AU, CA, MX, ZA); Zyloric® (AT, BE); Zyloric (BR, CZ, DK, FI, FR, GB, HK, IN, ID, IE, IT, LU, NL, NO, PL, PT, ES, SE, CH)