Allopurinol is a structural analog of the natural purine base, hypoxanthine and is a xanthine oxidase inhibitor (XOI), a type of uric acid-lowering therapy (ULT). Allopurinol is used in the prevention of gout, renal calculi due to either uric acid or calcium oxalate, and in the prophylaxis and treatment of uric acid nephropathy. In addition, allopurinol is indicated for the prophylaxis of hyperuricemia and its complications associated with radiation and chemotherapy treatment of leukemia, lymphoma, other myeloproliferative disorders, and some solid tumors. For chronic gout management, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) guidelines recommend ULT to achieve a target serum uric acid concentration of less than 6 mg/dL to prevent the formation of crystals and to eliminate crystal deposition, thereby dissolving tophi; a lower target (less than 5 mg/dL) is recommended in the EULAR guidelines for patients with severe disease. Allopurinol is the preferred first-line agents in most patients, including those with moderate-to-severe chronic kidney disease (stage 3 or greater), due to effectiveness and cost considerations, unless contraindications exist. ULTs such as allopurinol are considered more effective than probenecid at achieving treatment goals and are considered less likely to promote uric acid nephrolithiasis. Allopurinol and febuxostat appear relatively similar in lowering serum urate concentrations and reducing gout flares. ACR treatment guidelines recommend switching to a second xanthine oxidase inhibitor (XOI) after failure with the first XOI versus combination therapy with a uricosuric medication plus a XOI. Adding an uricosuric agent to XOI therapy may be an option for patients who have demonstrated a partial response to XOI monotherapy to achieve serum uric acid control. Allopurinol is associated with rash and fatal hypersensitivity reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Persons with the HLA-B*5801 haplotype are more likely to experience serious rashes or other hypersensitivities with allopurinol.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-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.
-Missed dose: Do not double the dose at the next scheduled time if an occasional dose is forgotten.
Extemporaneous Compounding-Oral
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.
Injectable Administration
-For intravenous use only.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Dilute as directed prior to administration.
Reconstitution of Lyophilized Powder:
-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 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.
Dermatologic adverse reactions associated with allopurinol use may involve hypersensitivity, and such reactions can be severe and sometimes fatal. Discontinue use at the first sign of a skin rash or other signs of hypersensitivity; carefully monitor patients for such reactions, especially during treatment initiation or if a patient develops renal impairment. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported in approximately 0.05% of patients taking allopurinol. Other serious hypersensitivity reactions that occurred with allopurinol use include exfoliative, urticarial, and purpuric lesions (purpura), generalized vasculitis, and irreversible hepatotoxicity. DRESS typically presents as fever and rash, which may present as TEN, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis. Organ system involvement including acute hepatocellular injury and worsening renal function, along with hematologic abnormalities (e.g., leukocytosis and eosinophilia) may be present. Many patients developed DRESS 4 to 6 weeks after allopurinol initiation. Accumulation of oxypurinol, the active metabolite of allopurinol, may be an underlying cause for the development of allopurinol-associated DRESS syndrome. Carefully adjusting allopurinol dosages in patients with renal impairment may reduce the incidence of the allopurinol-induced hypersensitivity. The risk of serious skin and hypersensitivity reactions may be associated with renal dysfunction, concurrent use of thiazide diuretics (which could be related to elevated oxypurinol concentrations causing an immune-mediated reaction), concurrent use of ampicillin, amoxicillin, or bendamustine, use of higher allopurinol daily dosages; or presence of HLA-B allele B*5801. The HLA-B*5801 allele is a genetic risk marker for severe skin reactions indicative of hypersensitivity to allopurinol. Consider genomic testing for the HLA-B*5801 allele prior to treatment with allopurinol in populations in which the prevalence of the HLA-B*5801 allele is known to be higher, including individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry. Screening in not generally recommended in patients from populations where the prevalence of the HLA-B*5801 allele is low or in current allopurinol users. The risk of severe hypersensitivity reactions is largely confined to the first few months of therapy. Hypersensitivity reactions have been reported in patients who do not carry the HLA-B*5801 allele. Rash (unspecified) and maculopapular rash were reported in 1% or more of patients treated with oral allopurinol. Rash was reported in 1.5% of patients treated with parenteral allopurinol. Fever was reported in less than 1% of patients treated with oral or parenteral allopurinol. Other dermatologic complications reported during allopurinol use occurring in less than 1% of patients include exfoliative dermatitis, urticaria, purpura, hypersensitivity vasculitis, vesicular bullous dermatitis (bullous rash), eczematoid dermatitis, pruritus, local injection site reaction, furunculosis, cellulitis, alopecia, onycholysis, skin swelling, and lichen planus-like eruption.
Adverse cardiovascular effects have been reported during allopurinol therapy. Such effects noted in less than 1% of patients include cardiovascular disorder (unspecified), heart failure, cardiorespiratory arrest (i.e., cardiac arrest, respiratory arrest), stroke, septic shock, ECG abnormality, ventricular fibrillation, bradycardia, hypertension, hypotension, decreased venous pressure, peripheral vascular disease, vasodilation, pulmonary embolism, pericarditis, thrombo-phlebitis, flushing, hemorrhage (bleeding), necrotizing angiitis, hypervolemia, and vasculitis.
The most frequent adverse gastrointestinal effects reported in patients during allopurinol use include nausea (1.3%; 1% or more), vomiting (1.2%; less than 1%), and diarrhea (1% or more; less than 1%). Gastritis, dyspepsia, flatulence, constipation, GI bleeding, GI obstruction, splenomegaly, mucositis, proctitis, intermittent abdominal pain, hemorrhagic pancreatitis, stomatitis, salivary gland swelling, tongue or facial swelling, hyperlipidemia, anorexia, and enlarged abdomen were each reported in less than 1% of patients treated with allopurinol during clinical trials.
Exacerbation of gout or acute gouty attacks were identified as one of the most frequent adverse events following initiation of oral allopurinol therapy, occurring in more than 1% of patients. A more gradual initiation of therapy may reduce acute gout attacks. Pain (unspecified), arthralgia, myalgia, headache, hyperhidrosis (sweating), chills, malaise, myopathy, hypotonia, infection (unspecified), and sepsis occurred at an incidence of less than 1% in patients receiving either parenteral or oral allopurinol.
Adverse hematologic and lymphatic effects have been reported during allopurinol therapy. Hematologic effects noted in less than 1% of patients include anemia, hemolytic anemia, reticulocytosis, agranulocytosis, pancytopenia, blast crisis, tumor lysis syndrome (TLS), ecchymosis, decreased prothrombin, thrombocytopenia, disseminated intravascular coagulation (DIC), eosinophilic fibrohistiocytic lesion of bone marrow, leukopenia, neutropenia, aplastic anemia, bone marrow suppression, marrow aplasia, eosinophilia, and leukocytosis. The majority of cases of bone marrow suppression occurred in patients who were concomitantly receiving other myelosuppressive drugs. Lymphatic effects such as lymphadenopathy and lymphocytosis were reported in less than 1% of patients.
Renal failure or renal insufficiency has been reported in up to 1.2% of patients during parenteral allopurinol use. Other adverse renal effects reported in less than 1% of patients during oral or parenteral allopurinol therapy include hematuria, increased serum creatinine (azotemia), oliguria, urinary tract infection, uremia, glomerulonephritis, primary hematuria, albuminuria (proteinuria), and other unspecified renal abnormalities. Measure renal function prior to allopurinol initiation and monitor renal function frequently throughout the early stages of therapy in patients receiving allopurinol for gout or the management of recurrent calcium oxalate calculi. Monitor renal function at least daily during the early stages of allopurinol treatment for the management of tumor lysis syndrome. Patients with renal impairment or renal failure require allopurinol dosage adjustments. Renal impairment has been observed in some patients who received allopurinol due to formation of xanthine calculi (xanthine nephrolithiasis) or due to precipitation of urates in patients receiving concomitant uricosuric medications.
Adverse hepatic effects have been reported during allopurinol therapy. The following have been reported in less than 1% of allopurinol recipients: hepatomegaly, hepatic necrosis, granulomatous hepatitis, hepatic failure, hyperbilirubinemia, and cholestatic jaundice (cholestasis). Cases of reversible clinical hepatotoxicity have occurred in patients taking allopurinol. Asymptomatic elevations of hepatic enzymes, such as alkaline phosphatase or serum transaminase (AST or ALT), also occurred. Overall, elevated hepatic enzymes have been reported in 1% or more of patients. Patients with preexisting hepatic disease have an increased risk of developing these complications. Liver function monitoring is recommended periodically during therapy in patients with pre-existing liver disease and in patients who develop signs and symptoms of hepatotoxicity (e.g., anorexia, weight loss, or pruritus). Discontinue allopurinol if patients develop elevated hepatic enzymes.
Drowsiness has been reported in less than 1% of patients using allopurinol. Instruct patients to use caution when driving or operating machinery until they know how allopurinol affects them.
Neurologic adverse effects have been noted during allopurinol therapy. Neurologic events reported in less than 1% of patients receiving oral therapy include peripheral neuropathy, paresthesias, neuritis, depression, amnesia, confusion, dizziness, tinnitus, asthenia, vertigo, foot drop, insomnia, and optic neuritis. Additional neurologic complications reported with parenteral allopurinol include seizures and status epilepticus, dystonic reaction, myoclonia, twitching, tremor, muscle paralysis, agitation, mental status changes, cerebral infarction, and coma.
Adverse ocular effects have been reported during allopurinol therapy. Cataracts, macular retinitis, iritis, conjunctivitis, and amblyopia have been reported in less than 1% of patients receiving allopurinol; no causal relationship has been established.
Loss or perversion of taste (dysgeusia) has occurred in less than 1% of patients receiving allopurinol.
Impotence (erectile dysfunction), gynecomastia, male infertility, and libido decrease were reported in less than 1% of patients during allopurinol use.
Reported electrolyte abnormalities reported in less than 1% of patients who received parenteral allopurinol include hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, hyperphosphatemia, hyperuricemia, hypercalcemia, hypernatremia, and hyperkalemia. Other metabolic complications reported in less than 1% of patients receiving either parenteral or oral allopurinol include metabolic acidosis, lactic acidosis, hyperglycemia, glycosuria, water intoxication, and edema.
Adverse pulmonary effects have been noted during allopurinol therapy. Pharyngitis, rhinitis, bronchospasm, asthma, tachypnea, respiratory failure or insufficiency, acute respiratory distress syndrome (ARDS), epistaxis, and apnea were reported in less than 1% of patients who received oral or parenteral allopurinol.
Gout flares may occur after initiation of urate lowering therapy, such as allopurinol, due to changing serum uric acid concentrations resulting in mobilization of urate from tissue deposits. If a gout flare occurs during treatment, allopurinol does not need to be discontinued. Manage the flare concurrently, as appropriate for the individual patient.
Allopurinol is contraindicated in patients with a known hypersensitivity to allopurinol, including previous occurrence of skin rash or serious rash. Discontinue allopurinol immediately at the first appearance of skin rash or other signs which may indicate an allergic reaction, and provide additional medical care as needed. Inform patients of the potential for serious hypersensitivity reactions and the importance of informing their health care provider if signs or symptoms develop. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and other serious hypersensitivity reactions have been reported in patients taking allopurinol. The HLA-B*5801 allele is a genetic risk marker for severe skin reactions indicative of hypersensitivity to allopurinol. Consider genomic testing for the HLA-B*5801 allele prior to treatment with allopurinol in populations in which the prevalence of the HLA-B*5801 allele is known to be higher, including African American patients, Asian patients (e.g., Han Chinese, Korean, Thai), and patients with Native Hawaiian/Pacific Islander ancestry. Screening in not generally recommended in patients from populations where the prevalence of the HLA-B*5801 allele is low or in current allopurinol users. The risk of severe hypersensitivity reactions is largely confined to the first few months of therapy. Hypersensitivity reactions have been reported in patients who do not carry the HLA-B*5801 allele. The risk of serious skin and hypersensitivity reactions may also be associated with renal dysfunction, concurrent use of thiazide diuretics (which could be related to elevated oxypurinol concentrations causing an immune-mediated reaction), concurrent use of ampicillin, amoxicillin, or bendamustine, or use of higher allopurinol daily dosages. Carefully adjusting allopurinol dosages in patients with impaired renal function may reduce the incidence of the allopurinol-induced hypersensitivity.
Measure renal function prior to allopurinol initiation and monitor renal function frequently throughout the early stages of therapy in patients receiving allopurinol for gout or the management of recurrent calcium oxalate calculi. Monitor renal function at least daily during the early stages of allopurinol treatment for the management of tumor lysis syndrome. Patients with renal impairment or renal failure require allopurinol dosage adjustments. Adults should maintain a urine output at least 2 L/day or more to attempt to avoid the formation of xanthine calculi under the influence of allopurinol therapy and to help prevent renal precipitation of urates in patients receiving concurrent uricosuric agents. Pediatric patients with tumor lysis syndrome should maintain a urine output of at least 2 L/m2/day (100 mL/m2/hour). Patients with pre-existing renal disease, including renal impairment, renal failure, or a history of nephrolithiasis, may be at increased risk for worsening renal function due to xanthine calculi or precipitation of urates. Decrease the allopurinol dose or stop allopurinol therapy if increased abnormalities in renal function appear and persist in gout patients with chronic kidney disease.
Periodic liver function tests (LFTs) are recommended during allopurinol treatment for patients with hepatic disease. If anorexia, weight loss, or pruritus develops in patients on allopurinol treatment, evaluation of hepatic function should be performed. Discontinue allopurinol in patients with elevated hepatic enzymes. A few cases of reversible clinical hepatotoxicity have been reported in patients taking allopurinol, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminases have been observed.
Measure complete blood counts prior to allopurinol initiation. Bone marrow suppression, manifested as anemia, leukopenia, or thrombocytopenia, has been reported as early as 6 weeks to as long as 6 years after the initiation of therapy. Monitor blood counts more frequently when cytotoxic medications are used concomitantly with allopurinol.
In some patients allopurinol may cause drowsiness. Patients should exercise caution when driving or operating machinery until they know how allopurinol affects them.
Based on findings in animals, allopurinol may cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been described in exposed animals. Limited data regarding allopurinol use during human pregnancy do not demonstrate a clear pattern or increase in frequency of adverse developmental outcomes. Experience with allopurinol use during 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. Allopurinol and its metabolite, oxypurinol, cross the placenta. Among approximately 50 pregnancies described in published literature, two infants with major congenital malformations have been reported with following maternal allopurinol exposure. 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. An observational study of 31 women who received allopurinol during the first trimester of pregnancy 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 1 child was born with severe birth defects including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis.
Breast-feeding should be avoided during allopurinol treatment and for 1 week following the last dose due to the potential for serious adverse reactions in the breastfed child. Allopurinol and oxypurinol have been detected in human milk. The estimated relative infant dose for allopurinol was between 0.14 to 0.2 mg/kg and for oxypurinol was between 7.2 and 8 mg/kg when a mother received 300 mg of allopurinol daily for 5 weeks postpartum. There were no reports on the effect of allopurinol on the breastfed infant or milk production.
General dosage information:
-Measure serum uric acid concentration, complete blood count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, serum creatinine, and estimated glomerular filtration rate (eGFR), and other serum chemistries prior to initiaion of allopurinol.
For the treatment of primary or secondary gout (i.e., acute attacks, tophi, gouty arthritis or joint destruction, uric acid lithiasis, and/or uric acid nephropathy):
Oral dosage:
Adults: 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.
For the prevention of acute hyperuricemia during chemotherapy or radiation treatment of leukemia, lymphoma, or solid tumors that may cause tumor lysis syndrome:
NOTE: Administer fluids sufficient to yield a daily urinary output of at least 2 liters in adults (at least 100 mL/m2/hour in pediatric patients) with a neutral or, preferably, slightly alkaline urine.
Intravenous dosage:
NOTE: Intravenous allopurinol has been designated an orphan drug by the FDA for this indication.
Adults: 200 to 400 mg/m2 IV daily as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. The maximum recommended dose is 600 mg/day. 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.
Children and Adolescents: 200 mg/m2 IV daily as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. The maximum recommended dose is 400 mg/day. 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.
Oral dosage:
Adults: 300 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.
Children and Adolescents: 50 to 100 mg/m2 PO every 8 hours or 100 mg/m2 PO every 12 hours. The recommended maximum dose is 300 mg/m2/day. Alternatively, 10 mg/kg/day PO divided every 8 hours. The recommended maximum dose is 300 mg/dose and 800 mg/day. Consider using an alternative allopurinol formulation in patients with a body surface area less than 0.5 m2. Discontinue when the potential for overproduction of uric acid is no longer present.
For the treatment of recurrent calcium oxalate nephrolithiasis (renal calculus) in those whose uric acid excretion exceeds 800 mg/day (males) or 750 mg/day (females):
Oral dosage:
Adults: 200 to 300 mg PO once daily or in divided doses. Adjust dose according to control of hyperuricosuria using 24-hour urinary urate determinations. 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).
Maximum Dosage Limits:
-Adults
300 mg/dose and 800 mg/day PO; 600 mg/day IV.
-Geriatric
300 mg/dose and 800 mg/day PO; 600 mg/day IV.
-Adolescents
100 mg/m2/dose and 300 mg/m2/day PO, alternatively 300 mg/dose and 800 mg/day PO; 400 mg/day IV.
-Children
100 mg/m2/dose and 300 mg/m2/day PO, alternatively 300 mg/dose and 800 mg/day PO; 400 mg/day IV.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Gout (allopurinol tablets):
eGFR more than 60 mL/minute: No dosage adjustment required.
eGFR 31 to 60 mL/minute: 50 mg PO daily, initially. Increase the dose by 50 mg/day every 2 to 4 weeks.
eGFR 16 to 30 mL/minute: 50 mg PO every other day, initially. Increase the dose by 50 mg/day every 2 to 4 weeks.
eGFR 5 to 15 mL/minute: 50 mg PO twice weekly, initially. Increase the dose by 50 mg/day every 2 to 4 weeks.
eGFR less than 5 mL/minute: 50 mg PO once weekly, initially. Increase the dose by 50 mg/day every 2 to 4 weeks.
Specific guidelines for maximum dosage at various stages of renal impairment are not available.
Hyperuricemia associated with cancer therapy in adults (allopurinol tablets or injection):
eGFR more than 21 mL/minute: No dosage adjustment required.
eGFR 10 to 20 mL/minute: 200 mg PO/IV daily.
eGFR less than 10 mL/minute: 100 mg PO/IV daily.
On dialysis: 50 mg PO/IV every 12 hours or 100 mg PO/IV every 24 hours.
Specific guidelines for dosage adjustments in pediatric patients with renal impairment or who are on dialysis are not available.
Recurrent calcium oxalate renal calculi (allopurinol tablets):
Specific guidelines for dosage adjustments in renal impairment are not available.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Aliskiren; Hydrochlorothiazide, HCTZ: (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.
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.
Amiloride; Hydrochlorothiazide, HCTZ: (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.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (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.
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.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Atenolol; Chlorthalidone: (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.
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.
Azilsartan; Chlorthalidone: (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.
Benazepril; Hydrochlorothiazide, HCTZ: (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.
Bendamustine: (Major) Consider the use of an alternative therapy if allopurinol treatment is needed in patients receiving bendamustine. Concomitant use of allopurinol may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
Bisoprolol; Hydrochlorothiazide, HCTZ: (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.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with allopurinol is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Caffeine; Sodium Benzoate: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Candesartan; Hydrochlorothiazide, HCTZ: (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.
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. Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP.
Captopril; Hydrochlorothiazide, HCTZ: (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.
Chlorothiazide: (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.
Chlorthalidone: (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.
Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if concomitant use of allopurinol is necessary; a clomipramine dose reduction may be necessary. Concomitant use may increase clomipramine exposure; clomipramine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with allopurinol and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate; allopurinol is a weak CYP1A2 inhibitor.
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.
Enalapril; Hydrochlorothiazide, HCTZ: (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.
Eprosartan; Hydrochlorothiazide, HCTZ: (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.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of allopurinol is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and allopurinol is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; allopurinol is a weak CYP1A2 inhibitor. Concomitant use with another weak CYP1A2 inhibitor increased fezolinetant overall exposure by 100%.
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.
Fosinopril; Hydrochlorothiazide, HCTZ: (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.
Hydrochlorothiazide, HCTZ: (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.
Hydrochlorothiazide, HCTZ; Moexipril: (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.
Irbesartan; Hydrochlorothiazide, HCTZ: (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.
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.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with allopurinol is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with allopurinol is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with allopurinol is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lisinopril; Hydrochlorothiazide, HCTZ: (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.
Losartan; Hydrochlorothiazide, HCTZ: (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.
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.
Metolazone: (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.
Metoprolol; Hydrochlorothiazide, HCTZ: (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.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with allopurinol. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (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.
Olmesartan; Hydrochlorothiazide, HCTZ: (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.
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.
Pimozide: (Moderate) Monitor for pimozide-related adverse reactions, including QT prolongation and ventricular arrhythmias, if coadministered with allopurinol. Coadministration may result in elevated pimozide concentrations. Pimozide is metabolized primarily through CYP3A, and to a lesser extent CYP1A2 and CYP2D6; allopurinol is a weak CYP1A2 inhibitor.
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.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if concomitant use of allopurinol is necessary. Concomitant use may increase propafenone exposure; propafenone is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
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.
Quinapril; Hydrochlorothiazide, HCTZ: (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.
Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and allopurinol. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; allopurinol is a weak CYP1A2 inhibitor.
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.
Spironolactone; Hydrochlorothiazide, HCTZ: (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.
Telmisartan; Hydrochlorothiazide, HCTZ: (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.
Theophylline, Aminophylline: (Moderate) Monitor theophylline concentrations and watch for an increase in aminophylline-related adverse reactions if coadministration with allopurinol is necessary; an aminophylline dose reduction may be necessary. Aminophylline is a CYP1A2 substrate with a narrow therapeutic index and allopurinol is a CYP1A2 inhibitor. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with allopurinol is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and allopurinol is a CYP1A2 inhibitor.
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.
Tizanidine: (Major) Avoid concomitant use of tizanidine and allopurinol as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
Triamterene; Hydrochlorothiazide, HCTZ: (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.
Valsartan; Hydrochlorothiazide, HCTZ: (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.
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.
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. 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. 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.
Allopurinol may be administered orally or intravenously. Steady-state volume of distribution (mean +/- standard deviation) is approximately 0.87 +/- 0.13 L/kg following intravenous administration. Allopurinol and its active metabolite, oxypurinol, are present in breast milk. Oxypurinol is present in systemic circulation at higher concentrations and for a longer period of time compared to allopurinol. The ratio of systemic exposure (AUC0-inf) between oxypurinol and allopurinol was approximately 30 to 40. Allopurinol is rapidly metabolized by hepatic oxidation to oxypurinol (alloxanthine). 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. Approximately 12% of the drug was excreted as allopurinol, 76% was excreted as oxypurinol, and the remaining dose was excreted as riboside conjugates in the urine following intravenous administration. Approximately 20% of allopurinol is excreted in the feces. The half-lives of allopurinol and oxypurinol are 1 to 2 hours and 15 hours, respectively, following oral administration. The half-lives (mean +/- standard deviation) of allopurinol and oxypurinol are approximately 1.21 +/- 0.33 and 23.5 +/- 4.5 hours following intravenous administration.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2
Allopurinol is a weak inhibitor of CYP1A2.
-Route-Specific Pharmacokinetics
Oral Route
Approximately 90% of an orally administered dose is absorbed from the gastrointestinal tract. Peak allopurinol and oxypurinol plasma concentrations generally occur 1.5 hours and 4.5 hours, respectively, following oral administration. Maximum plasma concentrations of approximately 3 mcg/mL and 6.5 mcg/mL for allopurinol and oxypurinol occurred following a single 300 mg oral dose of allopurinol.
Intravenous Route
The maximum concentration (Cmax) and systemic exposure (AUC0-inf) for both allopurinol and oxypurinol after intravenous administration were dose-proportional over the dose range of 100 to 300 mg. The relative intravenous Cmax was approximately 3-fold to 3.8-fold and AUC0-inf was approximately 1.9-fold higher for allopurinol following intravenous and oral administration of 100 mg and 300 mg single doses. Administration of 100 mg and 300 mg orally and intravenously produced nearly superimposable oxypurinol plasma concentration versus time profiles.
-Special Populations
Hepatic Impairment
The pharmacokinetics of allopurinol in patients with hepatic impairment are not available.
Renal Impairment
The pharmacokinetics of allopurinol in patients with renal impairment are not available. Accumulation of allopurinol can occur in patients with renal impairment.