Aloprim

Anti-Gout Agents

Administer orally with food and water. Allopurinol is generally better tolerated if taken following meals.
Instruct patients to stay well hydrated (e.g., drink 2 liters [68 ounces] of fluid daily). The maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

Extemporaneous oral suspension formulation: (not approved by the FDA)
Crush 2,400 mg allopurinol and levigate with glycerin or distilled water.
Add 40 mL methylcellulose (Cologel); then add enough 2:1 simple syrup/cherry syrup mixture to obtain a total volume of 120 mL.
The final concentration will be 20 mg/mL.
Store in the refrigerator and shake well prior to each use. The suspension is stable for 8 weeks.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Allopurinol for injection is available as a single-use 500-mg lyophilized powder vial.
Reconstitution:
Add 25 mL of Sterile Water for injection to the 500-mg lyophilized powder vial for a final concentration of 20 mg/mL.
The reconstituted solution is clear, almost colorless, and has no more than a slight opalescence.
Do not refrigerate the reconstituted vial.
Dilution:
Immediately after reconstitution, withdraw the appropriate dose from the vial and further dilute with 0.9% Sodium Chloride injection or 5% Dextrose for injection to a final admixture concentration less than 6 mg/mL; avoid dilution with sodium bicarbonate-containing solutions.
Storage: The diluted admixture may be stored at room temperature (20 to 25 degrees C; 68 to 77 degrees F) for up to 10 hours after reconstitution (includes infusion time); do not refrigerate.
Intravenous (IV) infusion:
Administer the diluted admixture as an IV infusion; the rate of infusion depends on the volume of infusate.
Do not mix allopurinol with or administer through the same IV line with drugs or solutions that are incompatible with allopurinol.

toxic epidermal necrolysis / Delayed / 0-1.0
erythema multiforme / Delayed / 0-1.0
vasculitis / Delayed / 0-1.0
exfoliative dermatitis / Delayed / 0-1.0
renal failure (unspecified) / Delayed / 0-1.0
Stevens-Johnson syndrome / Delayed / 0-1.0
stroke / Early / 0-1.0
heart failure / Delayed / 0-1.0
bradycardia / Rapid / 0-1.0
pericarditis / Delayed / 0-1.0
respiratory arrest / Rapid / 0-1.0
pulmonary embolism / Delayed / 0-1.0
cardiac arrest / Early / 0-1.0
ventricular fibrillation / Early / 0-1.0
pancreatitis / Delayed / 0-1.0
GI obstruction / Delayed / 0-1.0
GI bleeding / Delayed / 0-1.0
tumor lysis syndrome (TLS) / Delayed / 0-1.0
hemolytic anemia / Delayed / 0-1.0
pancytopenia / Delayed / 0-1.0
agranulocytosis / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
disseminated intravascular coagulation (DIC) / Delayed / 0-1.0
proteinuria / Delayed / 0-1.0
oliguria / Early / 0-1.0
hepatic necrosis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
hyperkalemia / Delayed / 0-1.0
lactic acidosis / Delayed / 0-1.0
water intoxication / Delayed / 0-1.0
optic neuritis / Delayed / 0-1.0
seizures / Delayed / 0-1.0
muscle paralysis / Delayed / 0-1.0
bronchospasm / Rapid / 0-1.0
apnea / Delayed / 0-1.0
acute respiratory distress syndrome (ARDS) / Early / 0-1.0
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known

bullous rash / Early / 0-1.0
eosinophilia / Delayed / 0-1.0
hepatitis / Delayed / 0-1.0
edema / Delayed / 0-1.0
phlebitis / Rapid / 0-1.0
bleeding / Early / 0-1.0
hypotension / Rapid / 0-1.0
hypervolemia / Delayed / 0-1.0
hypertension / Early / 0-1.0
hyperlipidemia / Delayed / 0-1.0
proctitis / Delayed / 0-1.0
constipation / Delayed / 0-1.0
gastritis / Delayed / 0-1.0
stomatitis / Delayed / 0-1.0
splenomegaly / Delayed / 0-1.0
hypotonia / Delayed / 0-1.0
myopathy / Delayed / 0-1.0
lymphocytosis / Delayed / 0-1.0
neutropenia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
lymphadenopathy / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
anemia / Delayed / 0-1.0
hematuria / Delayed / 0-1.0
hepatomegaly / Delayed / 0-1.0
jaundice / Delayed / 0-1.0
elevated hepatic enzymes / Delayed / 0-1.0
hyperbilirubinemia / Delayed / 0-1.0
cholestasis / Delayed / 0-1.0
cataracts / Delayed / 0-1.0
amblyopia / Delayed / 0-1.0
iritis / Delayed / 0-1.0
conjunctivitis / Delayed / 0-1.0
infertility / Delayed / 0-1.0
impotence (erectile dysfunction) / Delayed / 0-1.0
hypomagnesemia / Delayed / 0-1.0
hypocalcemia / Delayed / 0-1.0
hypercalcemia / Delayed / 0-1.0
glycosuria / Early / 0-1.0
hyperphosphatemia / Delayed / 0-1.0
hypernatremia / Delayed / 0-1.0
hyperuricemia / Delayed / 0-1.0
hyperglycemia / Delayed / 0-1.0
hypokalemia / Delayed / 0-1.0
metabolic acidosis / Delayed / 0-1.0
hyponatremia / Delayed / 0-1.0
neuritis / Delayed / 0-1.0
peripheral neuropathy / Delayed / 0-1.0
confusion / Early / 0-1.0
amnesia / Delayed / 0-1.0
dystonic reaction / Delayed / 0-1.0
depression / Delayed / 0-1.0
myoclonia / Delayed / 0-1.0
tachypnea / Early / 0-1.0
nephrolithiasis / Delayed / Incidence not known

nausea / Early / 0-1.3
vomiting / Early / 0-1.2
lichen planus-like eruption / Delayed / 0-1.0
fever / Early / 0-1.0
injection site reaction / Rapid / 0-1.0
onycholysis / Delayed / 0-1.0
purpura / Delayed / 0-1.0
pruritus / Rapid / 0-1.0
urticaria / Rapid / 0-1.0
leukocytosis / Delayed / 0-1.0
alopecia / Delayed / 0-1.0
flushing / Rapid / 0-1.0
flatulence / Early / 0-1.0
dyspepsia / Early / 0-1.0
anorexia / Delayed / 0-1.0
abdominal pain / Early / 0-1.0
chills / Rapid / 0-1.0
headache / Early / 0-1.0
infection / Delayed / 0-1.0
diaphoresis / Early / 0-1.0
myalgia / Early / 0-1.0
arthralgia / Delayed / 0-1.0
malaise / Early / 0-1.0
ecchymosis / Delayed / 0-1.0
drowsiness / Early / 0-1.0
gynecomastia / Delayed / 0-1.0
libido decrease / Delayed / 0-1.0
dizziness / Early / 0-1.0
asthenia / Delayed / 0-1.0
tinnitus / Delayed / 0-1.0
paresthesias / Delayed / 0-1.0
tremor / Early / 0-1.0
vertigo / Early / 0-1.0
agitation / Early / 0-1.0
insomnia / Early / 0-1.0
epistaxis / Delayed / 0-1.0
pharyngitis / Delayed / 0-1.0
rhinitis / Early / 0-1.0
dysgeusia / Early / 0-1.0
rash / Early / 1.0
maculopapular rash / Early / 1.0
diarrhea / Early / 1.0

Aloprim, Zyloprim

Rx

Purine analog; a xanthine oxidase inhibitor (XOI)
Used in the chronic management of gout and gouty arthritis and prophylaxis of hyperuricemia due to radiation and chemotherapy
Commonly causes rash; fatal hypersensitivity may occur; persons with the HLA-B*5801 haplotype are at risk for serious side effects; must also adjust doses for renal dysfunction

50 to 100 mg PO once daily, initially. Increase the dose by 50 to 100 mg/day weekly until the serum uric acid concentration is 6 mg/dL or less. Doses more than 300 mg/day are given in divided doses. Usual dose: 200 to 300 mg/day for mild gout and 400 to 600 mg/day for moderately severe tophaceous gout. Max: 800 mg/day in divided doses. When adjusting the allopurinol dosage in persons who are being treated with colchicine and/or anti-inflammatory agents, continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months. When switching from an uricosuric agent to allopurinol, gradually reduce the dose of the uricosuric agent over several weeks and increase the dose of allopurinol to the required dose needed to maintain a normal serum uric acid concentration.

NOTE: Intravenous allopurinol has been designated an orphan drug by the FDA for this indication.

200 to 400 mg/m2 per day (maximum daily dose, 600 mg) IV as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. Start treatment 24 to 48 hours prior to the start of chemotherapy known to cause tumor cell lysis. Only use IV allopurinol in patients who cannot take oral therapy. Use the serum uric acid concentration as an index to guide dosing and dose frequency. Discontinue IV allopurinol when the patient can take oral therapy or when the risk of tumor cell lysis is over.

200 mg/m2 per day (maximum daily dose, 400 mg) IV as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. Start treatment 24 to 48 hours prior to the start of chemotherapy known to cause tumor cell lysis. Only use IV allopurinol in patients who cannot take oral therapy. Use the serum uric acid concentration as an index to guide dosing and dose frequency. Discontinue IV allopurinol when the patient can take oral therapy or when the risk of tumor cell lysis is over.

600 to 800 mg/day PO in 2 to 3 divided doses for 2 to 3 days. Discontinue when the potential for overproduction of uric acid is no longer present.

600 to 800 mg/day PO in 2 to 3 divided doses for 2 to 3 days. Alternatively, 50 to 100 mg/m2/dose PO every 8 hours or 10 mg/kg/DAY divided every 8 hours (Max: 300 mg/dose and 800 mg/DAY) is recommended for patients with intermediate-risk for developing tumor lysis syndrome. Discontinue when the potential for overproduction of uric acid is no longer present.

300 mg/day PO. Alternatively, 50 to 100 mg/m2/dose PO every 8 hours or 10 mg/kg/DAY divided every 8 hours (Max: 300 mg/dose and 800 mg/DAY) is recommended for patients with intermediate-risk for developing tumor lysis syndrome. Discontinue when the potential for overproduction of uric acid is no longer present.

150 mg/day PO. Alternatively, 50 to 100 mg/m2/dose PO every 8 hours or 10 mg/kg/DAY divided every 8 hours (Max: 300 mg/dose and 800 mg/DAY) is recommended for patients with intermediate-risk for developing tumor lysis syndrome. Discontinue when the potential for overproduction of uric acid is no longer present.

200 to 300 mg PO once daily or in divided doses. Adjust dose according to control of hyperuricosuria using 24-hour urinary urate determinations.[28048] Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes (e.g., reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, and an increase in oral fluids and dietary fiber).

Allopurinol is primarily metabolized by hepatic oxidation. The drug is known to rarely cause hepatotoxicity, especially if there is preexisting hepatic and/or renal disease. However, specific recommendations for allopurinol dosage adjustment in patients with hepatic impairment are not available.

NOTE: The correct dose and frequency of dosage for maintaining the serum uric acid concentration within the normal range are best determined by using the serum uric acid level as an index. Allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. Serious toxicity may occur, especially in patients with impaired renal function.
CrCl 121 to 140 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 400 mg/day PO or IV has also been suggested.
CrCl 101 to 120 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 350 mg/day PO or IV has also been suggested.
CrCl 81 to 100 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 300 mg/day PO or IV has also been suggested.
CrCl 61 to 80 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 250 mg/day PO or IV has also been suggested.
CrCl 41 to 60 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 200 mg/day PO or IV has also been suggested.
CrCl 21 to 40 mL/min: No specific dosage adjustments are recommended by the manufacturer ; 150 mg/day PO or IV has also been suggested.
CrCl 10 to 20 mL/min: According to the manufacturer, 200 mg/day PO or IV; 100 mg/day PO or IV has also been suggested.
CrCl 3 to 9 mL/min: According to the manufacturer, 100 mg/day PO or IV; 100 mg PO or IV every other day has also been suggested.
CrCl less than 3 mL/min: According to the manufacturer, 100 mg PO or IV every 24 hours or longer; 100 mg PO or IV every third day has also been suggested.
Dialysis: 50 mg IV every 12 hours or 100 mg IV every 24 hours; IV allopurinol has not been studied in pediatric patients with severe renal impairment or on dialysis.

Aluminum Hydroxide: (Minor) Aluminum hydroxide decreases the oral bioavailability of allopurinol, possibly by inhibiting gastrointestinal absorption of allopurinol. Allopurinol should be administered no less than 3 hours before doses of aluminum hydroxide to avoid inhibition of allopurinol absorption.
Aluminum Hydroxide; Magnesium Carbonate: (Minor) Aluminum hydroxide decreases the oral bioavailability of allopurinol, possibly by inhibiting gastrointestinal absorption of allopurinol. Allopurinol should be administered no less than 3 hours before doses of aluminum hydroxide to avoid inhibition of allopurinol absorption.
Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Aluminum hydroxide decreases the oral bioavailability of allopurinol, possibly by inhibiting gastrointestinal absorption of allopurinol. Allopurinol should be administered no less than 3 hours before doses of aluminum hydroxide to avoid inhibition of allopurinol absorption.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Aluminum hydroxide decreases the oral bioavailability of allopurinol, possibly by inhibiting gastrointestinal absorption of allopurinol. Allopurinol should be administered no less than 3 hours before doses of aluminum hydroxide to avoid inhibition of allopurinol absorption.
Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Aluminum hydroxide decreases the oral bioavailability of allopurinol, possibly by inhibiting gastrointestinal absorption of allopurinol. Allopurinol should be administered no less than 3 hours before doses of aluminum hydroxide to avoid inhibition of allopurinol absorption.
Amoxicillin: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Amoxicillin; Clavulanic Acid: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Ampicillin: (Minor) Use of ampicillin with allopurinol can increase the incidence of drug-related skin rash.
Ampicillin; Sulbactam: (Minor) Use of ampicillin with allopurinol can increase the incidence of drug-related skin rash.
Azathioprine: (Major) Concomitant use of allopurinol with azathioprine can result in a large increase in azathioprine activity and toxicity (e.g., bone marrow suppression, leukopenia, pancytopenia). The interaction is well-documented (i.e., multiple case reports over the course of decades) and can be potentially life-threatening. The increase in azathioprine activity is due to the ability of allopurinol to inhibit xanthine oxidase-controlled metabolism, thereby decreasing the elimination of azathioprine. When possible, this drug combination should be avoided. If avoidance of cotherapy is not possible, a reduced dosage of azathioprine (e.g., reduce to one-third to one-quarter of the original dose and close hematologic monitoring are required. Further azathioprine dosage reduction or use of an alternative therapy is recommended for patients who have low or absent thiopurine methyltransferase activity, as both the thiopurine methyltransferase and xanthine oxidase pathways are affected.
Capecitabine: (Major) Avoid coadministration of allopurinol with capecitabine due to the risk of decreased exposure to the active metabolites of capecitabine, which may decrease capecitabine efficacy. Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP; however, the clinical significance was not fully characterized.
Chlorpropamide: (Minor) Limited evidence suggests that concurrent allopurinol can interfere with chlorpropamide elimination. It is proposed that allopurinol interferes with renal tubular secretion of chlorpropamide. If allopurinol is added to chlorpropamide therapy, patients should be monitored for hypoglycemia.
Cyclophosphamide: (Moderate) Monitor for evidence of myelosuppression if cyclophosphamide is coadministered with allopurinol. Coadministration of allopurinol with cytotoxic agents, such as cyclophosphamide, may increase the risk of myelosuppression in patients with neoplastic disease (with the exception of leukemia). Routinely obtain complete blood cell counts.
Cyclosporine: (Moderate) Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are used together. Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol.
Diazoxide: (Moderate) Diazoxide can cause hyperuricemia. Dosages of concomitantly administered antigout medications, including allopurinol, may require adjustment.
Dichlorphenamide: (Moderate) Use dichlorphenamide and allopurinol together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Didanosine, ddI: (Contraindicated) Concurrent use of allopurinol and didanosine, ddI is contraindicated. Coadministration may result in increased concentrations of didanosine and may increase the incidence of pancreatitis. In 14 healthy volunteers, the mean AUC of didanosine increased approximately 2-fold when given with allopurinol. This interaction was more pronounced in 2 patients with renal impairment, as coadministration resulted in elevated didanosine AUC and Cmax of 312% and 232%, respectively. The effects of allopurinol in patients with normal renal function is not known.
Floxuridine: (Minor) Allopurinol can interfere in the activation of fluorouracil, 5-FU, and thus impair its activity. Because floxuridine is metabolized to fluorouracil, a similar interaction can occur with floxuridine. Theoretically, this may provide protection to host tissues and preserve anti-tumor activity since host tissues, but not all tumors, rely on the effected activation pathway. However, the reduction of 5-FU toxicity, specifically mucositis, by allopurinol has been inconsistent in clinical trials. In some animal models, allopurinol has decreased the effectiveness of 5-FU.
Fluorouracil, 5-FU: (Minor) Allopurinol may interfere with the activation of fluorouracil, 5-FU, and decrease the effectiveness of 5-FU.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Because pyrazinamide, PZA can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including allopurinol, may need to be adjusted.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Mercaptopurine, 6-MP: (Major) The concomitant use of mercaptopurine and allopurinol may result in increased mercaptopurine toxicity (e.g., bone marrow suppression, nausea, and vomiting). If these drugs are used together, reduce the mercaptopurine dose to one-third to one-quarter of the usual dose to avoid severe toxicity. Allopurinol inhibits xanathine oxidase; mercaptopurine is inactivated via the xanathine oxidase enzyme.
Methotrexate: (Minor) In vitro studies have shown that allopurinol administered one hour prior to methotrexate may decrease the therapeutic effects of methotrexate.
Methoxsalen: (Minor) Preclinical data suggests that allopurinol may decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Pegloticase: (Major) Allopurinol may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with allopurinol. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Pretomanid: (Major) Avoid coadministration of pretomanid with allopurinol, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Probenecid: (Minor) Uricosuric agents are likely to increase the excretion of the active metabolite of allopurinol, oxypurinol. Although uricosuric agents increase the renal excretion of oxypurinol, the antihyperuricemic effects of allopurinol may be additive when administered with either probenecid or sulfinpyrazone.
Probenecid; Colchicine: (Minor) Uricosuric agents are likely to increase the excretion of the active metabolite of allopurinol, oxypurinol. Although uricosuric agents increase the renal excretion of oxypurinol, the antihyperuricemic effects of allopurinol may be additive when administered with either probenecid or sulfinpyrazone.
Pyrazinamide, PZA: (Minor) Because pyrazinamide, PZA can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including allopurinol, may need to be adjusted.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and allopurinol. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Theophylline, Aminophylline: (Minor) Allopurinol in large doses can decrease aminophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol. (Minor) Allopurinol in large doses can decrease theophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol.
Thiazide diuretics: (Moderate) Monitor renal function and for signs and symptoms of hypersensitivity and skin rash during concomitant use of allopurinol and thiazide diuretics; reduce the allopurinol dose in persons with renal impairment and concomitant thiazide diuretic use. Concomitant use may increase the risk of severe skin rash and renal impairment may further increase the risk. Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a hypersensitivity when using these drugs concomitantly.
Uricosuric Agents: (Minor) Uricosuric agents are likely to increase the excretion of the active metabolite of allopurinol, oxypurinol. Although uricosuric agents increase the renal excretion of oxypurinol, the antihyperuricemic effects of allopurinol may be additive when administered with either probenecid or sulfinpyrazone.
Vonoprazan; Amoxicillin: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with allopurinol is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

Allopurinol/Allopurinol Sodium/Aloprim Intravenous Inj Pwd F/Sol: 500mg
Allopurinol/Zyloprim Oral Tab: 100mg, 200mg, 300mg

800 mg/day PO or 600 mg/day IV. Any single oral dose should not exceed 300 mg PO; higher daily dosages should be administered in divided doses.

300 mg/dose and 800 mg/DAY PO; 200 mg/m2/day (Max: 400 mg/day) IV.

300 mg/dose and 800 mg/DAY PO; 200 mg/m2/day (Max: 400 mg/day) IV.

Unlike uricosuric agents, which increase the urinary excretion of uric acid, allopurinol interferes with the catabolism of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding uric acid formation. Concentrations of uric acid in the blood and urine are thereby lowered. Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine to xanthine and of xanthine to uric acid. In addition, secondary to elevated concentrations of oxypurine, allopurinol indirectly inhibits purine biosynthesis by stimulating negative feedback. Oxypurinol, an allopurinol metabolite, also inhibits xanthine oxidase. Allopurinol also facilitates the incorporation of hypoxanthine and xanthine into DNA and RNA, resulting in further reductions of serum uric acid concentrations. Although hypoxanthine and xanthine serum concentrations increase, their renal clearance is at least 10 times that of uric acid. The serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol is usually in the range of 0.3 to 0.4 mg/dL compared to normal level of approximately 0.15 mg/dL. Precipitation is expected to occur with concentrations above 7 mg/dL. A secondary result of decreased renal tubular transport of uric acid is increased nephron reabsorption of calcium ions.

Allopurinol may be administered orally or intravenously. Allopurinol distributes throughout the body tissues and into breast milk. Allopurinol is rapidly metabolized by hepatic oxidation to the active compound oxypurinol (alloxanthine). The rapid conversion of allopurinol to oxypurinol was not significantly different after repeated allopurinol dosing. The plasma half-life of allopurinol is 1 to 2 hours. Oxypurinol half-life is approximately 24 hours; thus, effective xanthine oxidase inhibition is maintained over a 24-hour period with single daily allopurinol doses. Similar half-lives of allopurinol and oxypurinol were obtained after either oral or intravenous administration. Administration of 100 mg orally and intravenously produced nearly superimposable oxypurinol plasma concentration versus time profiles. Nearly superimposable oxypurinol plasma concentration-versus-time profiles were also obtained after oral and IV administration of a single 300 mg dose. Allopurinol is cleared essentially by glomerular filtration, but oxypurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. Within 48 to 72 hours, approximately 12% of the drug is excreted as allopurinol, 76% is excreted as oxypurinol, and the remaining dose is excreted as riboside conjugates in the urine.
 
Serum urate concentrations usually begin to decrease within 24 to 48 hours, although significant reductions may not be immediately evident due to the constant dissolution of uric acid deposits. Normal serum urate concentrations are usually achieved within 1 to 3 weeks. If allopurinol is discontinued, uric acid concentrations may return to pretreatment levels, which usually occurs 7 to 10 days after allopurinol cessation.

Approximately 90% of an orally administered dose is absorbed from the gastrointestinal tract. Peak allopurinol plasma concentrations generally occur 1.5 hours after oral administration. Peak plasma concentrations of the active metabolite, oxypurinol, generally occur 3 to 4 hours after oral administration.

Peak allopurinol plasma concentrations generally occur within 30 minutes after IV administration. Peak plasma concentrations of the active metabolite, oxypurinol, generally occur 3 to 4 hours after IV administration. The Cmax and systemic exposure (AUC) for both allopurinol and oxypurinol after IV administration were dose-proportional over the dose range of 100 to 300 mg.

Limited data regarding allopurinol use during pregnancy do not demonstrate a clear pattern or increase in frequency of adverse developmental outcomes. Experience with allopurinol during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol. The potential risks to the fetus must be weighed against the potential benefits to the mother. There is a published case report on a child born with multiple, complex birth defects following a full-term pregnancy in a 35-year-old woman; the child died 8 days after birth. Hoeltzenbien M, et al., conducted an observational study of 31 women who received allopurinol during the first trimester of pregnancy and found that the overall rate for major fetal malformations (3.7%) and spontaneous abortions (cumulative incidence 11%, 95% CI 3 to 40) was within the normal, expected range. The authors reported that one child was born with severe birth defects including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. Animal reproduction studies at doses up to 20 times the usual human dose (i.e., 5 mg/kg/day) have shown no adverse effects to the fetus; however, animal reproduction studies are not always predictive of human response.[28048] [63805]

Allopurinol and oxipurinol have been found in the milk of a mother who was receiving allopurinol. Since the effect of allopurinol on the breast-fed infant is unknown, caution should be exercised when allopurinol is administered during breast-feeding. If allopurinol is used in a breast-feeding mother, infants should be monitored. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.