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Allopurinol (Systemic)


VA CLASSIFICATION
Primary: MS400
Secondary: GU900

Commonly used brand name(s): Aloprim; Apo-Allopurinol; Purinol; Zyloprim.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihyperuricemic —

antigout agent—

antiurolithic (uric acid calculi; calcium oxalate calculi).—
Note: Antihyperuricemic is the basic category; the other categories are specific categories of use.



Indications

Note:  Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Gouty arthritis, chronic (treatment)—Allopurinol is indicated for the long-term management of hyperuricemia associated with primary or secondary gout. to reduce the number of acute gout attacks and decrease the risk of uric acid calculi and urate nephropathy in patients with chronic gout. {01} {02}{03} {04} {05} {06} {07}
—Allopurinol is recommended for patients in whom treatment with uricosuric antigout agents such as probenecid or sulfinpyrazone would be ineffective or inadvisable (e.g., patients who are hyperuricemic as a result of overproduction of urate, {35} {36} patients with extensive tophi or who are otherwise at risk for urate nephropathy, {06} {07} and patients with moderate to severe renal function impairment). {07} {35} {36} Both allopurinol and the uricosuric antigout agents are effective in patients whose 24-hour renal excretion of uric acid is 800 mg (4.8 mmol) or less, i.e., individuals who are hyperuricemic as a result of underexcretion of uric acid. {06} {35} {36} However, the uricosuric agents are less toxic than allopurinol and should be considered for use when appropriate {37}.

—Allopurinol has no anti-inflammatory activity and should not be used for the treatment of acute attacks of gouty arthritis. {06} {07} An anti-inflammatory agent, preferably a nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid (preferably via intrasynovial injection, when feasible), should be used to treat acute attacks. {37} Also, initiation of antihyperuricemic therapy may lead to fluctuations in urate concentration that may result in prolongation of an acute attack or initiation of new attacks. {06} {08} The patient should be receiving appropriate anti-inflammatory therapy when allopurinol treatment is initiated. {38}

Hyperuricemia (prophylaxis and treatment)—Allopurinol is indicated to control hyperuricemia secondary to blood dyscrasias {01}( such as polycythemia vera {02} or myeloid metaplasia {02} ), or their treatment. {01} It is also indicated to prevent or treat hyperuricemia secondary to tumor lysis induced by cancer chemotherapy with cytotoxic antineoplastic agents {01} {02} or radiation therapy {02} in patients with leukemias, lymphomas, or other neoplastic disease. {01} {02}{09} [Allopurinol is also used to treat hyperuricemia secondary to the neoplastic disease itself.]{10} Allopurinol prevents complications of hyperuricemia (e.g., acute uric acid nephropathy or renal calculi, tissue urate deposition, or gouty arthritis) in these patients. {01} {10} However, allopurinol may increase the toxicity of several antineoplastic agents, and some clinicians have questioned its routine administration during cancer chemotherapy. {11}
—[Allopurinol is also used to control hyperuricemia in patients with Lesch-Nyhan syndrome {02} {03} . However, it does not improve neurologic or behavioral abnormalities {03} or affect the course of the disease in these patients.] {10}

Nephropathy, uric acid (prophylaxis and treatment)—Allopurinol is indicated in the treatment of primary or secondary uric acid nephropathy (with or without accompanying symptoms of gouty arthritis) to prevent progression of the condition {01}. However, this medicine will not reverse severe renal damage that has already occurred. Allopurinol is also indicated to prevent uric acid nephropathy in certain patients as described under Hyperuricemia, above.

Renal calculi, uric acid (prophylaxis)—Allopurinol is indicated to prevent recurrence of uric acid stone formation in patients{01} {02} . It is also indicated to prevent uric acid calculi in certain other patients as described under Hyperuricemia, above.

Renal calculi, calcium oxalate, (prophylaxis)— Allopurinol is indicated to prevent recurrence of calcium stone formation in patients with a history of recurrent calcium oxalate calculi associated with hyperuricosuria {02} {01}(i.e., uric acid excretion > 800 mg [4.8 mmol] per day in males or 750 mg [4.5mmol] per day in females).{01}

Unaccepted
Allopurinol is not recommended for treatment of asymptomatic hyperuricemia{01} associated with conditions or induced by medications other than those described above.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    A structural analog of hypoxanthine.{01} {02}
Molecular weight—
    Allopurinol: 136.11{14}
    Allopurinol sodium: 158.09{09}

pKa—
    Allopurinol: 10.2
    Allopurinol sodium: 9.31{09}

Mechanism of action/Effect:

Allopurinol and its metabolite, oxipurinol (alloxanthine), decrease the production of uric acid by inhibiting the action of xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. {01} Also, allopurinol increases reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis via an action involving the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). {01} {15} The resultant increase in nucleotide concentration leads to feedback inhibition of de novo purine synthesis.{01}{16} Allopurinol thereby decreases uric acid concentrations in both serum and urine.

By lowering both serum and urine concentrations of uric acid below its solubility limits, allopurinol prevents or decreases urate deposition, thereby preventing the occurrence or progression of both gouty arthritis and urate nephropathy. {01} In patients with chronic gout, allopurinol may prevent or decrease tophi formation and chronic joint changes, promote resolution of existing urate crystals and deposits, and, after several months of therapy, reduce the frequency of acute gout attacks.{10}Also, reductions in urine urate concentration prevent or decrease the formation of uric acid {01} or calcium oxalate calculi. {02}


Other actions/effects:

Allopurinol inhibits hepatic microsomal enzyme activity. {02} {15}

Allopurinol increases plasma and urine concentrations of xanthine and hypoxanthine.{01} Although the concentrations of these oxypurines usually remain within their solubility limits, xanthine renal stones have been reported very rarely in patients with HGPRTase deficiency or very high pretreatment uric acid concentrations. {01}

Absorption:

About 80% to 90% {01}{02} {17} of a single 300-mg dose is absorbed from the gastrointestinal tract.

Absolute bioavailability was approximately 50% when compared to IV dosing.{09}

Protein binding:

Neither allopurinol nor its metabolite, oxipurinol, is bound to plasma proteins.

Biotransformation:

Primarily hepatic. About 70% to 76% of a dose is metabolized to the active metabolite, oxipurinol. One study indicates that allopurinol may also be taken up by, and metabolized in, red blood cells. {18}{09}

Half-life:

Allopurinol—1 to 3 hours {01} {02}

Oxipurinol—12 to 30 hours {01} {02} {09} (average about 15 hours); {10} may be greatly prolonged in patients with renal function impairment. {02}

Onset of action:

A significant reduction of serum uric acid concentration usually occurs within 2 or 3 days {01}.

Note: In some patients, especially those with severe tophaceous deposits or those who are underexcretors of uric acid, significant reduction of serum and urine uric acid concentrations may be substantially delayed, {01} {02} possibly because of mobilization of urate from existing tissue deposits. {01}


Time to peak serum concentration

Allopurinol—0.5 to 2 hours following a single 300-mg dose {02} {17}.

Oxipurinol—4.5 to 5 hours {01}{09}

Peak serum concentration

Following a single 300-mg dose—

Allopurinol: About 2 to 3 mcg per mL (14.7 to 22.05 micromoles/L) {09}{01} {17}.

Oxipurinol: About 5 to 6.5 mcg per mL (32.85 to 42.7 micromoles/L) {09}{01} {17}; may be increased to 30 to 50 mcg per mL (197.1 to 328.5 micromoles/L) in patients with renal function impairment {20}.

Time to peak effect

Reduction of serum uric acid concentration to normal range—1 to 3 weeks {01} {02}.

Reduction of frequency of acute gout attacks—Several months of therapy may be required, even though the serum uric acid concentration returns to normal values, possibly because of mobilization and recrystallization of urate as serum concentrations fluctuate.

Duration of action:

The serum uric acid concentration usually returns to the pretreatment value 1 to 2 weeks after discontinuation of therapy {01} {02}.

Elimination:
    Renal—Up to 12% of a dose is excreted as unchanged allopurinol {02} {17} {20} and about 70% to 76% as oxipurinol {02} {09} {17} .
    Fecal—About 20% of a dose {01} .
    In dialysis—Both allopurinol and oxipurinol are dialyzable {01}{09} .


Precautions to Consider

Carcinogenicity/Mutagenicity

Life-time dosing in mice and rats at doses equivalent to 1/6 to 1/3 recommended human doses (mg per square meter basis) showed no carcinogenic potential. Human lymphocytes harvested after a mean of 40 months treatment with allopurinol showed no evidence of clastogenicity duringin vitroassays.{09}

Pregnancy/Reproduction
Fertility—
No impairment of fertility was observed in rats or rabbits given up to 20 times the usual human dose.{01}

Pregnancy—
Although adequate and well-controlled studies in humans have not been done, 3 reports indicate no evidence of birth defects in offspring of women receiving allopurinol during pregnancy.{09}

In a study in mice, administration of 100 mg of allopurinol per kg of body weight (mg/kg) intraperitoneally on Day 10 or Day 13 of gestation caused an increased number of fetal deaths; no such effect was seen with a dose of 50 mg/kg.{01} In the same study, 50 or 100 mg/kg caused external fetal malformations when administered intraperitoneally on Day 10 of gestation and skeletal malformations when administered intraperitoneally on Day 13 of gestation. Whether these effects were due to maternal toxicity or a direct effect on the fetus has not been determined. However, other studies in rats and rabbits given up to 20 times the usual human dose have not shown that allopurinol affects the fetus adversely. {09}

FDA Pregnancy Category C. {09}

Breast-feeding

Allopurinol and oxipurinol are distributed into breast milk. Whether this toxic medication may cause adverse effects in the nursing infant has not been determined. However, problems in humans have not been documented. {09}

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of allopurinol in children. However, use of allopurinol in pediatric patients has been limited to children with certain rare inborn errors of purine metabolism or hyperuricemia secondary to a malignancy or cancer therapy. {09} {01}


Geriatrics


No information is available on the relationship of age to the effects of allopurinol in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of the dose and/or dosing interval in patients receiving allopurinol.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid
Potassium or sodium phosphate    (urinary acidification by these medications may increase the possibility of allopurinol-induced xanthine kidney stone formation)


Alcohol or
Diazoxide or
Mecamylamine or
Pyrazinamide    (these medications may increase serum uric acid concentrations; dosage adjustment of allopurinol may be necessary to control hyperuricemia and gout)


Amoxicillin{01}{05} or
Ampicillin or {01}{05}
Bacampicillin or
Hetacillin    (concurrent use with allopurinol may significantly increase the possibility of skin rash; however, it has not been established that allopurinol, rather than the presence of hyperuricemia, is responsible for this effect {02} {22} {23})


» Anticoagulants, coumarin- or indandione-derivative    (allopurinol may inhibit enzymatic metabolism of the anticoagulant, leading to potentiation of the anticoagulant effect; dosage adjustments based on increased monitoring of prothrombin time may be necessary during and after concurrent use)


Antineoplastics, such as:
Bleomycin or{05}
Cyclophosphamide or{05}
Doxorubicin or{05}
Procarbazine or{05}
Mechlorethamine{05}    (rapidly cytolytic antineoplastic agents may increase serum uric acid concentrations; prophylactic administration of allopurinol may be indicated to prevent complications associated with antineoplastic agent–induced hyperuricemia; also, patients receiving allopurinol to treat pre-existing hyperuricemia or gout may require allopurinol dosage adjustment during and following concurrent therapy with one of these agents)

    (concurrent use of allopurinol with cyclophosphamide and possibly other antineoplastic agents may increase the potential for bone marrow depression; although studies of this possibility have reported conflicting results, it is recommended that patients receiving allopurinol concurrently with antineoplastic agents, especially cyclophosphamide, be carefully monitored {03}{05}{09} {11} {25}{41})


» Azathioprine or
» Mercaptopurine    (allopurinol-induced inhibition of xanthine oxidase decreases metabolism of these medications and may potentiate therapeutic and toxic effects, especially bone marrow depression {01} {02} {26}{42}; the effect on azathioprine metabolism is especially critical in renal transplant patients because of the high risk of oxipurinol accumulation and consequent azathioprine toxicity if the transplanted kidney is rejected {27}; if concurrent use is essential, it is recommended that azathioprine or mercaptopurine dosage be reduced to one-third to one-fourth of the usual dosage, that the patient be carefully monitored, and that subsequent dosage adjustments be based on patient response and evidence of toxicity {01})

    (mercaptopurine may increase serum uric acid concentration in some patients; patients receiving allopurinol to treat pre-existing hyperuricemia or gout may require allopurinol dosage adjustment when mercaptopurine therapy is initiated or discontinued)


Chlorpropamide    (allopurinol may inhibit renal tubular secretion of chlorpropamide; patients receiving the medications concurrently should be monitored for possible increased hypoglycemic effect {02} {05}{01} )


Cyclosporine    (decreased cyclosporine metabolism {05}; monitoring of cyclosporine levels is recommended and dosage adjustment may be necessary{01})


Dacarbazine    (dacarbazine inhibits xanthine oxidase and may cause additive hypouricemic effects when used concurrently with allopurinol {28})


Diuretics, thiazide    (caution and careful monitoring of the patient are advised when allopurinol and thiazide diuretics are used concurrently, especially in patients with known or possible renal function impairment, because severe hypersensitivity reactions to allopurinol may occur {01}; although it has been suggested that compromised renal function, rather than the combination of medications, may be responsible for the adverse reactions, it has also been proposed that thiazide diuretics may increase serum oxipurinol concentrations by decreasing its renal excretion {02} {29})


Probenecid    (probenecid increases urinary excretion of oxipurinol; however, the antihyperuricemic effects of the medications are additive, and increased therapeutic benefit has been reported with concurrent use {01}{05} )


Sulfinpyrazone    (the antihyperuricemic effects of allopurinol and sulfinpyrazone are additive; increased therapeutic benefit has been reported with concurrent use {05} )


Vidarabine, systemic    (concurrent use with allopurinol may increase the risk of neurotoxicity and other side effects such as anemia, nausea, pain, and pruritus; caution is recommended if concurrent use is necessary {39}{40})


Xanthines, such as:
Aminophylline
Oxtriphylline
Theophylline    (concurrent use of large doses [600 mg per day] of allopurinol with the xanthines [except dyphylline] may decrease theophylline clearance, resulting in increased serum theophylline concentrations; when steady-state theophylline concentration is 13 mcg per mL [72.15 micromoles/L] or higher and 600 mg of allopurinol per day is required, serum theophylline concentrations should be monitored and theophylline dosage adjusted if necessary)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase activity, serum and
Bilirubin concentrations, serum and
Transaminase activity, serum    (may be increased {30} {31}, indicating hepatotoxicity {31}, especially in patients with pre-existing hepatic or renal {30} disease)


Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be increased, indicating nephrotoxicity, especially in patients with pre-existing renal disease {01} {31})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Renal function impairment or any illness that may predispose to a change in renal function, such as:
Congestive heart disease {05}
Diabetes mellitus
Hypertension    (oxipurinol may accumulate; risk of severe allergic reactions and other adverse effects is increased; a reduction in dosage may be required {01}{02} {29} {30})

    (risk of renal failure may be increased, especially when allopurinol is being used for hyperuricemia secondary to neoplastic disease or urate nephropathy; monitoring of renal function may be especially important when these conditions exist{01} )


Sensitivity to allopurinol, history of

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Complete blood counts and
Hepatic function determinations and
Renal function determinations    (recommended at periodic intervals during therapy, especially during the first few months {01})


Prothrombin time    (recommended periodically in patients receiving dicumarol{01}{09})


» Uric acid, serum    (monitoring may be required for proper dosing; the upper limit of normal is about 7 mg per 100 mL [416.36 micromoles/L] for males and postmenopausal females and about 6 mg per 100 mL [356.88 micromoles/L] for premenopausal females but may vary, depending on the patient and laboratory methodology {10})




Side/Adverse Effects

Note: Following initiation of allopurinol therapy for gouty arthritis, the most commonly encountered adverse effect is a temporary increase in the frequency of acute gout attacks. The occurrence of such reactions may be reduced by initiating therapy with a low dose that is gradually increased until the desired effect is obtained {01}{09} and by administration of prophylactic doses of colchicine or a nonsteroidal anti-inflammatory drug. {06} {07} {01}{05}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Dermatitis, allergic (skin rash, hives, or itching)
Note: Maculopapular skin rash occurs most often; however, eczematoid, exfoliative, urticarial, vesicular bullous, or purpuric lesions and lichen planus have also been reported rarely {01} {05} .
Very rarely, skin rash may be followed by more severe allergic reactions, usually in patients with renal function impairment and/or those receiving thiazide diuretics. Generalized vasculitis, hepatotoxicity, and/or acute renal failure may occur. Laboratory studies may indicate eosinophilia and leukopenia or leukocytosis. Several deaths have been attributed to these reactions. {05} {29} {32}



Incidence rare {01}
    
Agranulocytosis (fever with or without chills; sores, ulcers, or white spots on lips or in mouth; sore throat )
    
anemia ( unusual tiredness and/or weakness)
    
angiitis [vasculitis], hypersensitivity (chills, fever, and sore throat ; muscle aches, pains, or weakness; shortness of breath, troubled breathing, tightness in chest, or wheezing)
    
aplastic anemia (shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sores, ulcers, or white spots on lips or in mouth; swollen and/or painful glands; unusual bleeding or bruising; unusual tiredness or weakness)
    
dermatitis, exfoliative (possible prodrome of chills, fever, sore throat, muscle aches or pains, and/or nausea with or without vomiting; red, thickened, scaly skin)
    
erythema multiforme (possible prodrome of chills, fever, sore throat, muscle aches or pains, and/or nausea with or without vomiting; sores, ulcers, or white spots in mouth or on lips; skin rash or sores, hives, and/or itching)
    
hepatotoxicity (swelling in upper abdominal area; yellow eyes or skin)
    
hypersensitivity reaction, allopurinol-induced (initially skin rash immediately preceding or concurrent with chills, fever, and sore throat; muscle aches or pains; and/or nausea with or without vomiting ; followed by signs and symptoms of angiitis [vasculitis], hepatotoxicity, and/or acute renal failure)
    
loosening of fingernails
    
necrolysis, toxic epidermal (possible prodrome of chills, fever, sore throat, muscle aches or pains, and/or nausea with or without vomiting; redness, tenderness, itching, burning, or peeling of skin; red or irritated eyes )
    
neuritis, peripheral (numbness, tingling, pain, or weakness in hands or feet)
    
renal calculus, xanthine ( blood in urine, difficult or painful urination, pain in lower back and/or side)
    
renal failure, acute (sudden decrease in amount of urine; swelling of face, fingers, feet, and/or lower legs; weight gain, rapid )
    
Stevens-Johnson syndrome (possible prodrome of chills, fever, sore throat, muscle aches and pains, and/or nausea with or without vomiting; sores, ulcers, or white spots in mouth or on lips; bleeding sores on lips )
    
thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
    
unexplained nosebleeds
Note: Bone marrow depression has been reported to occur 6 weeks to 6 years after initiation of allopurinol therapy. Most of the affected patients were also receiving other medications with the potential for causing this reaction. However, bone marrow depression affecting one or more cell lines has rarely occurred in patients receiving allopurinol alone. {01}
Hepatotoxicity may be hypersensitivity-mediated; hepatic necrosis, granulomatous hepatitis, and cholestatic jaundice have been reported.
Renal failure associated with allopurinol therapy has been reported in patients being treated for hyperuricemia secondary to neoplastic diseases or gouty nephropathy as well as in patients experiencing hypersensitivity reactions to the medication. {01}





Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare {01}
    
Diarrhea
    
drowsiness
    
headache
    
indigestion
    
nausea or vomiting without symptoms of skin rash, chills or fever, or muscle aches and pains
    
stomach pain
    
unusual hair loss





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Treatment of overdose
Immediate discontinuation of allopurinol.

To decrease absorption—Gastric lavage, if very large quantities have been ingested {05}.

To enhance elimination—Although allopurinol and oxipurinol are dialyzable, the value of hemodialysis or peritoneal dialysis in the management of allopurinol overdose has not been established {05}{09} .

Monitoring—Renal function and urinalysis if chronic toxicity (stone formation) is suspected. Symptomatic treatment only for emergent adverse reactions; no specific antidotes are available.{05}

Supportive care—Maintaining hydration. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Allopurinol (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Other medications, especially coumarin- or indandione-derivative anticoagulants, azathioprine, and mercaptopurine

Proper use of this medication
Taking after meals, if necessary, to minimize gastrointestinal irritation

» Compliance with therapy

Importance of high fluid intake during therapy and compliance with therapy for alkalinization of urine, if prescribed, to help prevent kidney stones

Several months of continuous therapy may be required for maximum effectiveness in patients with chronic gout

» Medication helps prevent, but does not relieve, acute gout attacks; need to continue taking allopurinol with medication prescribed for gout attacks

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy; possible need for periodic blood tests to determine efficacy of therapy and/or occurrence of side effects

Avoiding large amounts of alcohol, which may increase uric acid concentrations and reduce effectiveness of medication

Possibility that vitamin C taken in large amounts may increase the potential for kidney stone formation

» Notifying physician immediately if skin rash occurs or if influenza-like symptoms (chills, fever, muscle aches and pains, or nausea or vomiting) occur concurrently with or shortly after skin rash; these symptoms may rarely indicate onset of severe hypersensitivity reaction

» Caution if drowsiness occurs


Side/adverse effects
Signs of potential adverse effects, especially allergic dermatitis, agranulocytosis, anemia, angiitis, aplastic anemia, exfoliative dermatitis, erythema multiforme, hepatotoxicity, hypersensitivity reaction, loosening of fingernails, toxic epidermal necrolysis, peripheral neuritis, renal caluli, renal failure, Stevens-Johnson syndrome, thrombocytopenia, and unexplained nosebleeds


For oral dosing forms:
Allopurinol may be administered after meals to lessen gastrointestinal irritation. {01}

An increase in the frequency of acute attacks of gouty arthritis may occur during the early months of allopurinol therapy. The risk of precipitating acute gout attacks may be reduced by initiating allopurinol therapy with 100 to 200 milligrams, with weekly increases by 100– mg increments until the desired effect is obtained.{01}{05}Prophylactic doses of colchicine (or, if the patient cannot take colchicine, a nonsteroidal anti-inflammatory drug [NSAID]) are recommended concurrently during the first 3 to 6 months of allopurinol therapy.{01}{33}

Acute attacks of gout may occur during allopurinol therapy, even with colchicine or NSAID prophylactic therapy. During an attack, allopurinol therapy should be continued at the same dose {05} while an appropriate anti-inflammatory agent (preferably an NSAID or a corticosteroid [preferably via intrasynovial injection, when feasible]) {33} is administered to relieve the attack. Because of the toxicity associated with therapeutic doses of colchicine, its use for treatment of an acute attack of gout should be reserved for patients in whom the preferred medications are contraindicated or ineffective.{33}

The total daily dose may be administered in divided doses or as a single dose. Each single dose should not exceed 300 mg. Daily dosage requirements exceeding 300 mg should be administered in divided doses.{01}

Monitoring of serum uric acid concentrations may be necessary for proper dosing. {01}

To reduce the risk of xanthine calculi formation, and to help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents, a high fluid intake {01} {05}(no less than 2.5 to 3 liters daily) and maintenance of a neutral, or preferably slightly alkaline, urine{01} are recommended.

When uricosuric therapy is being changed to allopurinol therapy, the dose of the uricosuric agent should be reduced gradually over a period of several weeks and the dose of allopurinol increased gradually to the dose required for maintenance of normal serum uric acid concentrations. {01}

It is recommended that allopurinol therapy be discontinued at once if a skin rash or any other sign of adverse reaction occurs. Skin rash may be followed by more severe hypersensitivity reactions. After a severe reaction, therapy should be discontinued permanently. However, after a mild reaction, it may be possible to reinstate therapy at a lower dosage (50 mg per day initially and increased very gradually) after the reaction has subsided. If skin rash recurs, therapy should be discontinued permanently. {01} {02} {05}

For parenteral dosing forms:
Initiate therapy 24 to 48 hours before chemotherapy regimens known to cause tumor cell lysis.{09}

Maintain at least 2 liters daily of neutral to (preferably) slightly alkaline urinary output in adults.{09}

Many parenteral drugs which might be used concurrently in cancer chemotherapy, including analgesics, anti-infectives, and antinauseants may be physically incompatible with allopurinol sodium for injection, and should not be mixed in the same container or administered through common intravenous access ports.{09}

Daily doses may be given as a single daily infusion or divided into infusions given every 6–, 8–, or 12–hours for both adults and children.{09}

The final concentration of the administered fluid should not exceed 6 milligrams per milliliter.{09}

Monitoring of serum uric acid to maintain concentrations within the normal range is necessary for proper dosing. {09}

For treatment of adverse effects
Hypersensitivity reactions—Administer glucocorticoids . Prolonged administration may be required after a severe reaction. If after recovery from mild episodes, allopurinol is reinstated and is followed by the recurrence of any rash, permanent withdrawal of allopurinol is recommended. {05}


Oral Dosage Forms

ALLOPURINOL TABLETS USP

Usual adult and adolescent dose
Antigout agent
Initial—Oral, 100 mg once a day, to be increased by 100 mg per day at one-week intervals until the desired serum uric acid concentration is attained, not to exceed the maximum recommended dosage of 800 mg per day {01} {05}.

Maintenance—Oral, 100 to 200 mg two or three times a day; or 300 mg as a single dose once a day. The usual maintenance dose is 200 to 300 mg per day in mild gout or 400 to 600 mg per day in moderately severe tophaceous gout. {01}

Neoplastic disease therapy:
Initial—Oral, 600 to 800 mg per day starting twelve hours to three days (preferably two to three days) prior to initiation of chemotherapy or radiation therapy {01} {05} .

Maintenance—Dosage should be based on serum uric acid determinations performed approximately forty-eight hours after initiation of allopurinol therapy and periodically thereafter {01} {05}. Allopurinol should be discontinued following the period of tumor regression {34}.

Antiurolithic (uric acid calculi)
Oral, 100 to 200 mg one to four times a day; or 300 mg as a single dose once a day {01}.

Antiurolithic (calcium oxalate calculi)
Oral,

200 to 300 mg a day as a single dose or in divided doses {01}.

Note: Because oxipurinol is excreted primarily by the kidneys, accumulation may occur in patients with renal failure. Patients receiving dialysis may require usual therapeutic doses of allopurinol; however, in patients not receiving dialysis, it is recommended that the dosage be reduced as follows:

Creatinine Clearance
(mL/min)
Dose
10 to 20
200 mg daily
3 to 10
no more than {01} 100 mg daily
< 3
100 mg at intervals of more than 24 hours may be necessary
Some patients with renal function impairment may require even lower doses or longer intervals between doses. In some cases, 300 mg twice a week, or even less, may suffice.



Usual adult prescribing limits
300 mg per dose; 800 mg per day {01}.

Usual pediatric dose
Antihyperuricemic, in neoplastic disease therapy
Children up to 6 years of age: Oral, 50 mg three times a day {01}.

Children 6 to 10 years of age: Oral, 100 mg three times a day; or 300 mg as a single dose once a day {01}.

Note: Dosage adjustment may be necessary after approximately forty-eight hours of therapy, depending on the patient"s response.{01}



Strength(s) usually available
U.S.—


100 mg (Rx) [Zyloprim (scored)][Generic]


300 mg (Rx) [Zyloprim (scored)][Generic]

Canada—


100 mg (Rx) [Apo-Allopurinol (scored)] [Purinol (scored)] [Zyloprim ( scored)]


200 mg (Rx) [Apo-Allopurinol (scored)] [Purinol (scored)] [Zyloprim ( scored)][Generic]


300 mg (Rx) [Apo-Allopurinol (scored)] [Purinol (scored)] [Zyloprim ( scored)][Generic]

Packaging and storage:
Store at 15 to 25 °C (59 and 77 °F) in a dry place and protect from light.{01}

Auxiliary labeling:
   • Drink large amounts of fluids.



Parenteral Dosage Forms

ALLOPURINOL SODIUM INJECTION

Usual Adult Dose
Neoplastic disease therapy:
Initial—Intravenous, 200 to 400 milligrams per square meter per day starting 24 to 48 hours prior to initiation of chemotherapy therapy known to cause tumor cell lysis. The daily dose can be given as a single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals at the recommended final concentration of not greater than 6 mg per mL. The rate of infusion depends on the volume of infusate. {09}

Maintenance—Dosage should be based on serum uric acid determinations performed approximately forty-eight hours after initiation of allopurinol therapy and periodically thereafter . The dosage of intravenous allopurinol to lower serum and urinary uric acid levels to normal or near-normal varies with the severity of the disease. {09} {05} Allopurinol should be discontinued following the period of tumor regression. {34}

Note: Because oxipurinol is excreted primarily by the kidneys, accumulation may occur in patients with renal failure. Patients receiving dialysis may require usual therapeutic doses of allopurinol; however, in patients not receiving dialysis, it is recommended that the dosage be reduced as follows{09}:

Creatinine Clearance
(mL/min)
Dose
10 to 20
200 mg daily
3 to 10
100 mg daily
< 3
100 mg daily at extended intervals




Usual adult prescribing limits
Up to 600 mg daily

Usual Pediatric Dose
Neoplastic disease therapy:
Initial—Intravenous, 200 milligrams per square meter per day starting 24 to 48 hours prior to initiation of chemotherapy therapy known to cause tumor cell lysis. The daily dose can be given as a single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals at the recommended final concentration of not greater than 6 mg per mL. The rate of infusion depends on the volume of infusate. {09}

Maintenance—Dosage should be based on serum uric acid determinations performed approximately forty-eight hours after initiation of allopurinol therapy and periodically thereafter . The dosage of intravenous allopurinol to lower serum and urinary uric acid levels to normal or near-normal varies with the severity of the disease. {09} {05} Allopurinol should be discontinued following the period of tumor regression. {34}

Note: See Usual adult dose for dose adjustment recommendations for renal impairment



Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


Allopurinol sodium equivalent to 500 mg of allopurinol per 30-mL vial of lyophilized powder (Rx) [Aloprim ( preservative free)]

Packaging and storage:
Store unreconstituted powder at 25 °C (77 °F), with excursions permitted to 15°-30° C (59°-86° F) .{09}

Preparation of dosage form:
Allopurinol for injection must be reconstituted and diluted. The 30–mL vials of allopurinol powder should be reconstituted with 25 mL of sterile water for injection. The reconstituted solution (pH of 11.1 to 11.8) 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 per mL is recommended. The solution should not be used if particulate matter or discoloration is present. See the manufacturer's package insert for a detailed list of specific drugs which are physically incompatible in solution with allopurinol.{09}

Stability:
Following reconstitution and dilution, the final solution should be stored at 20° to 25° C (68° to 77° F) and administration should begin within 10 hours after reconstitution. The reconstituted and/or diluted solution should NOT be refrigerated.{09}

Incompatibilities:
See the manufacturer's package insert for a detailed list of specific drugs which are physically incompatible in solution with allopurinol.{09}


Caution:
During intravenous allopurinol therapy, a fluid intake sufficient to yield a daily urinary output of at least two liters and maintenance of a neutral or slightly alkaline urine are suggested.{09}



Revised: 03/30/2000



References
  1. Product Information: Zyloprim, allopurinol. Faro Pharmaceuticals, Bedminster, NJ, (PI revised 2/99) reviewed 2/2000
  1. AHFS Drug information 99. Bethesda, MD: American Society of Hospital Pharmacists, 1999:3221–3224.
  1. Lesch M & Nyhan WL: A familial disorder of uric acid metabolism and central nervous system function. Am J Med 1964; 36:561-570.
  1. Not used.
  1. Product Information: Zyloprim, allopurinol. Glaxo Wellcome, Inc., Mississauga, Ontario, Canada ,(PI revised 8/99) reviewed 02/2000.
  1. Rakel RE, editor. Conn's current therapy. Philadelphia: W.B. Saunders; 1991: 501-4.
  1. Kelley WN, Harris ED Jr, Ruddy S et al (eds). Textbook of rheumatology. 2nd ed. Philadelphia: W.B. Saunders; 1985: 857-860.
  1. Panel responses to Probenecid monograph revision 3/92.
  1. Product Information: Aloprim, allopurinol sodium for injection. Nabi, Boca Raton, FL, (PI revised 6/99) reviewed 02/2000.
  1. Panel responses to monograph revision 3/84.
  1. Boston Collaborative Drug Surveillance Program. Allopurinol and cytotoxic drugs. JAMA 1974; 227: 1036-40.
  1. 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: 1386-1389.
  1. Not used.
  1. Fleeger CA, editor. USAN 1993. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 31.
  1. Bluestone R: Choosing the right therapy for hyperuricemia. Drug Therapy (Hosp) 1978: 40-57.
  1. Edwards NL, Recker D, Airozo D et al:. Enhanced purine salvage during allopurinol therapy: an important pharmacologic property in humans. J Lab Clin Med 1981; 98: 673-683.
  1. Breithaupt H & Tittel M: Kinetics of allopurinol after single intravenous and oral doses. Noninteraction with benzbromarone and hydrochlorothiazide. Eur J Clin Pharmacol 1982; 22: 77-84.
  1. Thomas G, Feldman S & Kramer WG: Interaction of allopurinol with human blood. Biochem Pharmacol 1982; 31: 1937-1940.
  1. Not used
  1. Anderson RJ, Gambertoglio JG & Schrier RW: Clinical use of drugs in renal failure. Springfield, IL: CC Thomas, 1978: 111-112.
  1. Not used


  1. Boston Collaborative Drug Surveillance Program. Excess of ampicillin rashes associated with allopurinol or hyperuricemia. N Engl J Med. 1972; 286: 505-507.
  1. Jick H & Porter JB: Potentiation of ampicillin skin reactions by allopurinol or hyperuricemia. J Clin Pharmacol 1981; 21: 436-438.
  1. Not used.
  1. Stolbach L, Begg C, Bennett JMet al: Evaluation of bone marrow toxic reaction in patients treated with allopurinol. JAMA 1982; 247: 334-336.
  1. Brooks RJ, Dorr RT & Durie BGM: Interaction of allopurinol with 6-mercaptopurine and azathioprine. Biomedicine 1982; 36: 217-222.
  1. Panelist comment, monograph revision 8/86.
  1. Dorr RT& Fritz WL: Cancer chemotherapy handbook. New York: Elsevier; 1980: 362-367.
  1. Lupton GP & Odom RB: The allopurinol hypersensitivity syndrome. J Am Acad Dermatol 1979; 1: 365-374.
  1. Anderson RJ & Schrier RW (eds). Clinical use of drugs in patients with kidney and liver disease. Philadelphia: W.B. Saunders, 1981: 254, 327.
  1. Al-Kawas FH, Seeff LB, Berendson RA et al: Allopurinol hepatotoxicity. Report of two cases and review of the literature. Ann Intern Med 1981; 95: 588-590.
  1. Rosenbloom D &, Gilbert R: Reversible flu-like syndrome, leukopenia, and thrombocytopenia induced by allopurinol. Drug Intell Clin Pharm 1981; 15: 286-287.
  1. Panel response to Colchicine monograph revision 10/93.
  1. Panel response to monograph revision 8/86.
  1. AMA drug evaluations annual. Chicago: American Medical Association; 1992: 1413, 1820, 1829, 1831-3, 1837-8, 1899.
  1. Speight TM, editor. Avery's drug treatment. Principals and practice of clinical pharmacology and therapeutics. 3rd ed. Baltimore: Williams and Wilkins; 1987: 542, 944-7, 1377, 1399.
  1. Panelist comment, draft 4/94.
  1. Panelist comment, draft 4/94.
  1. Collignon PJ & Sorrell TC: Neurological toxicity associated with vidarabine therapy. Aust N Z J Med 1983; 13:627.
  1. Friedman HM & Grasela T: Adenine arabinoside and allopurinol: possible adverse drug interaction (letter). N Engl J Med 1981; 304:423.
  1. Anon: Boston Collaborative Drug Surveillence Program: Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. JAMA 1974; 227:1036.
  1. Rundles RW, Wyngaarden JB & Hitchings GH: Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Trans Assoc Am Physicians 1963; 76:126.
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