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Allopurinol

Pronunciation

Pronunciation

(al oh PURE i nole)

Index Terms

  • Allopurinol Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous, as sodium [strength expressed as base, preservative free]:

Aloprim: 500 mg (1 ea)

Tablet, Oral:

Zyloprim: 100 mg, 300 mg [scored]

Generic: 100 mg, 300 mg

Brand Names: U.S.

  • Aloprim
  • Zyloprim

Pharmacologic Category

  • Antigout Agent
  • Xanthine Oxidase Inhibitor

Pharmacology

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.

Absorption

Oral: 90% from GI tract

Distribution

Vss: IV: 0.84 to 0.87 L/kg

Metabolism

Rapidly oxidized to active metabolites, primarily oxypurinol

Excretion

Urine (76% as oxypurinol, 12% as unchanged drug); feces (~20%)

Onset of Action

Gout: Decrease in serum and urine uric acid: 2 to 3 days; peak effect: 1 week or longer; normal serum urate levels achieved typically within 1 to 3 weeks

Cancer therapy-induced hyperuricemia: Median time to plasma uric acid control: 27 hours (Cortes 2010)

Time to Peak

Plasma: Oral: Allopurinol: 1.5 hours; Oxypurinol: 4.5 hours

Half-Life Elimination

Parent drug: ~1 to 2 hours; Oxypurinol: ~15 hours

Use: Labeled Indications

Oral:

Calcium oxalate calculi (recurrent): Management of recurrent calcium oxalate calculi (with uric acid excretion >800 mg/day in men and >750 mg/day in women)

Cancer therapy-induced hyperuricemia: Management of hyperuricemia associated with cancer treatment for leukemia, lymphoma, and other malignancies

Gout: Management of primary or secondary gout (acute attack, tophi, joint destruction, uric acid lithiasis, and/or nephropathy)

Limitations of use: Allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. Allopurinol reduces serum and urinary uric acid concentrations; its use should be individualized for each patient and requires an understanding of its mode of action and pharmacokinetics.

IV: Cancer therapy-induced hyperuricemia: Management of hyperuricemia associated with cancer treatment for leukemia, lymphoma, or solid tumor malignancies in patients who cannot tolerate oral therapy.

Contraindications

Severe hypersensitivity reaction to allopurinol or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Breast-feeding mothers and children (except those with cancer therapy-induced hyperuricemia or Lesch-Nyhan syndrome)

Dosing: Adult

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

Gout: Oral:

Manufacturer’s labeling: Initial: 100 mg once daily; increase at weekly intervals in increments of 100 mg/day as needed to achieve desired serum uric acid level. Usual dosage range: 200 to 300 mg/day in mild gout; 400 to 600 mg/day in moderate to severe tophaceous gout. Maximum daily dose: 800 mg/day.

Off-label dosing: Initial: 100 mg/day, increasing the dose gradually in increments of 100 mg/day every 2 to 5 weeks as needed to achieve desired serum uric acid level of ≤6 mg/dL (ACR guidelines [Khanna 2012]; EULAR guidelines [Zhang 2006]; McGill 2010). Some patients may require therapy targeted at a serum uric acid level <5 mg/dL to control symptoms. Allopurinol may be initiated during an acute gout attack so long as anti-inflammatory therapy has been initiated as well (ACR guidelines [Khanna 2012]).

Cancer therapy-induced hyperuricemia:

Oral: 600 to 800 mg daily in divided doses for ~2 to 3 days

Off-label dosing: Intermediate risk for tumor lysis syndrome: 10 mg/kg daily divided every 8 hours (maximum: 800 mg/day) or 50 to 100 mg/m2 every 8 hours (maximum: 300 mg/m2/day), begin 1 to 2 days before initiation of induction chemotherapy; may continue for 3 to 7 days after chemotherapy (Coiffier 2008)

IV: Note: Intravenous daily dose can be given as a single infusion or in equally divided doses at 6-, 8-, or 12-hour intervals.

Manufacturer’s labeling: 200 to 400 mg/m2 daily (maximum: 600 mg daily) beginning 1 to 2 days before chemotherapy

Off-label dosing: Intermediate risk for tumor lysis syndrome: 200 to 400 mg/m2 daily (maximum: 600 mg/day) in 1 to 3 divided doses beginning 1 to 2 days before the start of induction chemotherapy; may continue for 3 to 7 days after chemotherapy (Coiffier 2008)

Calcium oxalate stones (recurrent): Oral: 200 to 300 mg daily in single or divided doses; may adjust dose as needed to control hyperuricosuria

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Management of hyperuricemia associated with chemotherapy and/or radiation therapy:

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

U.S. labeling:

Children <6 years: 150 mg daily

Children 6 to 10 years: 300 mg daily

Children >10 years: Refer to adult dosing.

Canadian labeling:

Children 6 to 10 years: 10 mg/kg daily (do not exceed adult dosing); adjust dose as necessary after 48 hours

Alternative dosing (off-label; intermediate risk for tumor lysis syndrome): Intermediate risk for tumor lysis syndrome: 10 mg/kg daily divided every 8 hours (maximum dose: 800 mg daily) or 50 to 100 mg/m2 every 8 hours (maximum dose: 300 mg/m2 daily), begin 12 to 24 hours (children) or 1 to 2 days (adults) before initiation of induction chemotherapy; may continue for 3 to 7 days after chemotherapy (Coiffier, 2008)

IV: Note: Intravenous daily dose can be given as a single infusion or in equally divided doses at 6-, 8-, or 12-hour intervals.

Manufacturer’s labeling: Starting dose: 200 mg/m2 daily beginning 1 to 2 days before chemotherapy

Alternative dosing (off-label; intermediate risk for tumor lysis syndrome) 200 to 400 mg/m2 daily (maximum dose: 600 mg daily) in 1 to 3 divided doses beginning 1 to 2 days before the start of induction chemotherapy; may continue for 3 to 7 days after chemotherapy (Coiffier, 2008)

Management of hyperuricemia associated with Lesch-Nyhan syndrome: Canadian labeling (not in U.S. labeling): Children 6 to 10 years: Oral: 10 mg/kg daily in 1 to 3 divided doses; adjust dose as necessary after 48 hours

Dosing: Renal Impairment

Manufacturer’s labeling: Oral, IV: Lower doses are required in renal impairment due to potential for accumulation of allopurinol and metabolites.

CrCl 10 to 20 mL/minute: 200 mg/day

CrCl 3 to 10 mL/minute: Do not exceed 100 mg/day.

CrCl <3 mL/minute: The dosing interval may need to be extended; do not exceed 100 mg/day.

Allopurinol and oxypurinol are dialyzable.

Indication-specific renal dosing (off-label):

Cancer therapy-induced hyperuricemia: Dosage reduction of 50% is recommended in renal impairment (Coiffier 2008)

Gout: Oral:

Initiate therapy with 50 to 100 mg daily, and gradually increase to a maintenance dose to achieve a serum uric acid level of ≤6 mg/dL (with close monitoring of serum uric acid levels and for hypersensitivity) (Dalbeth 2007).

or

In patients with stage 4 CKD or worse, initiate therapy at 50 mg/day, increasing the dose every 2 to 5 weeks to achieve desired uric acid levels of ≤6 mg/dL; doses >300 mg/day are permitted so long as they are accompanied by appropriate patient education and monitoring for toxicity (eg, pruritus, rash, elevated hepatic transaminases). Some patients may require therapy targeted at a serum uric acid level <5 mg/dL to control symptoms (ACR guidelines; Khanna 2012)

Hemodialysis: Initial: 100 mg alternate days given postdialysis, increase cautiously to 300 mg based on response. If dialysis is on a daily basis, an additional 50% of the dose may be required postdialysis (Dalbeth 2007)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute powder for injection with 25 mL SWFI. Further dilution with NS or D5W to a final concentration of ≤6 mg/mL.

Extemporaneously Prepared

A 20 mg/mL oral suspension may be made with tablets and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus® or a 1:4 mixture of cherry syrup concentrate and simple syrup, NF. Crush eight 300 mg tablets in a mortar and reduce to a fine powder. Add small portions of chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well”. Stable for 60 days refrigerated or at room temperature (Allen 1996; Nahata 2004).

Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.8862208Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer fluids sufficient to yield daily urinary output of at least 2 L and to maintain neutral or, preferably, slightly alkaline urine.

Oral: Administer after meals.

IV: The rate of infusion depends on the volume of the infusion; infuse maximum single daily doses (600 mg/day) over ≥30 minutes. Whenever possible, therapy should be initiated at 24 to 48 hours before the start of chemotherapy known to cause tumor lysis (including adrenocorticosteroids). IV daily dose can be administered as a single infusion or in equally divided doses at 6-, 8-, or 12-hour interval.

Dietary Considerations

Fluid intake should be administered to yield neutral or slightly alkaline urine and an output of ~2 L (in adults).

Compatibility

Stable in D5W, NS, SWFI.

Y-site administration: Incompatible with 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, ondansetron, prochlorperazine edisylate, promethazine, sodium bicarbonate, streptozocin, tobramycin, vinorelbine.

Storage

Powder for injection: Store at 20°C to 25°C (68°F to 77°F). Following preparation, intravenous solutions in NS or D5W 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 15°C to 25°C (59°F to 77°F). Store in a dry place. Protect from light.

Drug Interactions

ACE Inhibitors: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Amoxicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Amoxicillin. Monitor therapy

Ampicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Monitor therapy

Antacids: May decrease the absorption of Allopurinol. Exceptions: Sodium Bicarbonate. Consider therapy modification

AzaTHIOprine: Allopurinol may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Management: Reduce the azathioprine dose to one third to one quarter of the usual dose if used concomitantly with allopurinol, and monitor closely for systemic toxicity (particularly hematologic toxicity, nausea, and vomiting). Consider therapy modification

Bendamustine: Allopurinol may enhance the adverse/toxic effect of Bendamustine. Specifically, the risk of severe skin reactions may be enhanced. Monitor therapy

CarBAMazepine: Allopurinol may increase the serum concentration of CarBAMazepine. Monitor therapy

ChlorproPAMIDE: Allopurinol may increase the serum concentration of ChlorproPAMIDE. Monitor therapy

Cyclophosphamide: Allopurinol may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, bone marrow suppression. Monitor therapy

Didanosine: Allopurinol may increase the serum concentration of Didanosine. Avoid combination

Doxofylline: Allopurinol may increase the serum concentration of Doxofylline. Monitor therapy

Loop Diuretics: May enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Mercaptopurine: Allopurinol may increase the serum concentration of Mercaptopurine. Allopurinol may also promote formation of active thioguanine nucleotides. Management: Reduce the mercaptopurine dose to one third to one quarter of the usual dose if used with allopurinol, and monitor closely for systemic toxicity. US labeling for mercaptopurine oral suspension (Purixan brand) recommends avoiding allopurinol. Consider therapy modification

Pegloticase: Allopurinol may enhance the adverse/toxic effect of Pegloticase. Specifically, Allopurinol may blunt increases in serum urate that would signal an increased risk of anaphylaxis and infusion reactions. Avoid combination

Tegafur: Allopurinol may diminish the therapeutic effect of Tegafur. Avoid combination

Theophylline Derivatives: Allopurinol may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Allopurinol may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

Most commonly reported:

Dermatologic: Skin rash

Endocrine & metabolic: Gout (acute)

Gastrointestinal: Diarrhea, nausea

Hepatic: Increased liver enzymes, increased serum alkaline phosphatase

<1% (Limited to important or life-threatening): Ageusia, agranulocytosis, alopecia, angioedema, aplastic anemia, cataract, cholestatic jaundice, ecchymoses, eczematoid dermatitis, eosinophilia, exfoliative dermatitis, hepatic necrosis, hepatitis, hepatomegaly, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperbilirubinemia, hypersensitivity reaction, leukocytosis, leukopenia, lichen planus, macular retinitis, myopathy, necrotizing angiitis, nephritis, neuritis, neuropathy, onycholysis, pancreatitis, purpura, renal failure, skin granuloma (annulare), Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, toxic pustuloderma, uremia, vasculitis, vesicobullous dermatitis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Bone marrow suppression has been reported in patients receiving allopurinol, most of whom received concomitant medications with a potential for hematologic toxicity. The onset occurs between 6 weeks to 6 years after allopurinol initiation. Varying degrees of bone marrow depression affecting one or more cell lines may occur (rare) in patients receiving allopurinol alone.

• CNS effects: May occasionally cause drowsiness; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Hepatotoxicity: Cases of hepatotoxicity (reversible) have been reported. Asymptomatic elevations of serum alkaline phosphatase or serum transaminases have been observed. Monitor for signs/symptoms of hepatotoxicity and evaluate liver function if they occur. Periodic liver function tests are recommended during the early stages of therapy in patients with preexisting hepatic impairment.

• Hypersensitivity: Allopurinol has been associated with hypersensitivity reactions. In some instances a skin rash may be followed by more severe hypersensitivity reactions, including exfoliative, urticarial, and purpuric lesions, Stevens-Johnson syndrome, generalized vasculitis, and/or hepatotoxicity (irreversible); some reactions have been fatal (rare). Discontinue at first sign of skin rash or other signs indicative of allergic reaction. Consider HLA-B*5801 testing in patients at a higher risk for allopurinol hypersensitivity syndrome (eg, Korean patients with stage 3 or worse CKD and Han Chinese and Thai descent regardless of renal function) prior to initiation of therapy (ACR guidelines [Khanna 2012]).

Disease-related concerns:

• Acute gout attacks: Even when normal or subnormal serum uric acid levels have been attained, an increase in acute gout attacks has been reported during the early stages of allopurinol administration. When allopurinol is initiated, maintenance colchicine doses should generally be administered as prophylaxis. Additionally, it is recommended to initiate with a low allopurinol dose (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained (do not exceed the maximum recommended dose of 800 mg/day). In some cases, colchicine or anti-inflammatory agents may be required to suppress gouty attacks. After several months of therapy, attacks usually decrease in duration and severity. These episodes may be due to mobilization of urates from tissue deposits, causing fluctuations in the serum uric acid levels. Even with adequate allopurinol therapy, several months may be required to deplete the uric acid pool enough to achieve control of the acute attacks.

• Renal impairment: Dose reductions are recommended in patients with renal impairment; monitor closely. Patients with reduced renal function receiving thiazide diuretics in combination with allopurinol may be at increased risk for hypersensitivity reactions. Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN with allopurinol. Patients with renal impairment should be carefully monitored during the early stages of allopurinol treatment; reduce the dose or withdraw therapy if increased renal function abnormalities appear and persist. Renal failure associated with allopurinol has been observed in patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions including multiple myeloma and congestive myocardial disease were present among patients whose renal dysfunction increased after allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with allopurinol. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Concomitant medications: Concomitant use of allopurinol (at doses of 300 to 600 mg/day) with mercaptopurine or azathioprine will require a reduction in the mercaptopurine or azathioprine dose to approximately one-third to one-fourth of the usual dose. Subsequent dose adjustments may be necessary based on therapeutic response and toxicity.

Other warnings/precautions:

• Appropriate use: Do not use to treat asymptomatic hyperuricemia.

• Hydration: Fluid intake sufficient to yield a daily urinary output of at least 2 L and maintenance of a neutral or (preferably) a slightly alkaline urine are desirable in order to avoid possible formation of xanthine calculi due to allopurinol therapy and to help prevent renal urate precipitation in patients receiving concomitant uricosuric agents.

Monitoring Parameters

CBC, serum uric acid levels every 2 to 5 weeks during dose titration until desired level is achieved and every 6 months thereafter (ACR guidelines [Khanna 2012]), liver function tests (periodically in patients with preexisting hepatic disease), renal function (BUN, serum creatinine or creatinine clearance [periodically], prothrombin time [periodically in patients receiving warfarin]); consider HLA-B*5801 testing prior to initiation of therapy in patients at a higher risk for allopurinol hypersensitivity syndrome (ACR guidelines [Khanna 2012]). Monitor hydration status, for signs and symptoms of hypersensitivity, hepatotoxicity.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Allopurinol crosses the placenta (Torrance 2009). An increased risk of adverse fetal events has not been observed (limited data) (Hoeltzenbein 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, or injection site irritation. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), painful urination, hematuria, burning or numbness feeling, urinary retention, change in amount of urine passed, chills, pharyngitis, eye irritation, severe joint pain, bruising, bleeding, muscle pain, muscle weakness, severe loss of strength and energy, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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