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    Anti-gout Preparations, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Purine analog used for gout, renal calculi due to uric acid or calcium oxalate, or for prophylaxis of hyperuricemia associated with radiation and chemotherapy for myeloproliferative disorders. Doses must be adjusted for renal dysfunction.

    COMMON BRAND NAMES

    Aloprim, Zyloprim

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of signs and symptoms of primary or secondary gout (i.e., acute attacks, tophi, joint destruction, uric acid lithiasis, and/or uric acid nephropathy).
    NOTE: The lowest effective dose of allopurinol should be used to decrease the incidence of side effects.
    NOTE: In transferring a patient from a uricosuric agent to allopurinol, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the allopurinol dose gradually increased to the required dose needed to maintain a normal serum uric acid concentration.
    NOTE: Continuation of colchicine and/or anti-inflammatory agents is recommended during adjustment of the allopurinol dose until the serum uric acid concentration has been normalized and no acute gouty attacks have occurred for several months.
    Oral dosage
    Adults

    Adjust dosage according to patient tolerance and response. Recommended initial dose is 100 mg PO once daily, increased by 100 mg PO weekly until serum urate concentrations decrease to 6 mg/dL or less, or until reaching a maximum daily dose of 800 mg/day. Less severe cases of gout typically require 200—300 mg/day. Tophaceous gout typically requires 400—600 mg/day. The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. Allopurinol therapy should be constant, otherwise serum urate concentrations may increase. The serum uric acid concentration should be used to indicate the lowest effective dose. Normal serum urate concentrations are usually achieved in 1—3 weeks. The upper limit of normal is about 7 mg/dL for men and postmenopausal women and 6 mg/dL for premenopausal women.

    For the prevention of acute hyperuricemia during chemotherapy or radiation treatment of leukemia, lymphoma, or solid tumors that may cause tumor lysis syndrome.
    NOTE: Intravenous allopurinol has been designated an orphan drug by the FDA for this indication.
    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 concentration as an index. Allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. Discontinue allopurinol when the potential for overproduction of uric acid is no longer present.
    Intravenous dosage

    NOTE: Allopurinol sodium for injection is only indicated for patients who cannot tolerate oral therapy.

    Adults

    200—400 mg/m2/day IV as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. Start treatment 24—48 hours prior to the start of chemotherapy, when possible. Doses > 600 mg/day IV do not seem to be more effective than lower doses.

    Children

    200 mg/m2/day IV as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. Start treatment 24—48 hours prior to the start of chemotherapy, when possible.

    Oral dosage
    Adults, Adolescents and Children > 10 years of age

    600—800 mg PO per day in 2—3 divided doses for 2—3 days along with a high fluid intake.

    Children 6—10 years of age

    300 mg/day PO. Adjust dose after 48 hours, according to patient response.

    Children < 6 years of age

    150 mg/day PO. Adjust dose after 48 hours, according to patient response.

    For the treatment of recurrent calcium oxalate nephrolithiasis (renal calculus) in males whose daily uric acid excretion exceeds 800 mg/day and in females whose daily uric acid excretion exceeds 750 mg/day.
    NOTE: Carefully assess each patient's situation initially and periodically to determine if treatment is beneficial and if the benefits outweigh the risks.
    NOTE: Patients may also benefit from dietary changes such as an increased intake of oral fluids and dietary fiber and a decreased intake of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium.
    Oral dosage
    Adults

    200—300 mg PO once daily or in divided doses. Dosage should be adjusted according to patient response as evidenced by 24-hour urinary urate excretion assays.

    MAXIMUM DOSAGE

    Adults

    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.

    Children

    > 10 years: 800 mg/day PO. Any single oral dose should not exceed 300 mg PO; higher daily dosages should be administered in divided doses. Maximum dosage information is not available for IV dosing.
    6—10 years: 300 mg/day PO; maximum dosage information is not available for IV dosing.
    < 6 years: 150 mg/day PO; maximum dosage information is not available for IV dosing.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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 (see Adverse Events).
    CrCl 121-140 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 400 mg/day PO or IV has also been suggested.
    CrCl 101-120 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 350 mg/day PO or IV has also been suggested.
    CrCl 81-100 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 300 mg/day PO or IV has also been suggested.
    CrCl 61-80 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 250 mg/day PO or IV has also been suggested.
    CrCl 41-60 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 200 mg/day PO or IV has also been suggested.
    CrCl 21-40 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 150 mg/day PO or IV has also been suggested.
    CrCl 10—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—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 < 3 ml/min: According to the manufacturer, 100 mg PO or IV q24 hours or longer; 100 mg PO or IV every third day has also been suggested.

    ADMINISTRATION

    Oral Administration

    Administer after meals and with plenty of fluids. If possible, maintain urine output of at least 2 L/day.
    The maintenance of a neutral or, preferably, slightly alkaline urine is desirable.

    Extemporaneous Compounding-Oral

    Extemporaneous oral suspension formulation:
    This route of administration is not FDA-approved.
    Crush 2400 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 use. The suspension is stable for 8 weeks.

    Injectable Administration

    Administer intravenously. Do not inject intramuscularly.
    If possible, maintain urine output of at least 2 L/day.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Reconstitute the 30 ml vial with 25 ml Sterile Water for Injection. The reconstituted solution is clear, almost colorless, and has no more than a slight opalescence. Do not use if discoloration or particulate matter are present.
    Further dilute with NS or D5W to a final concentration of <= 6 mg/ml. Avoid sodium bicarbonate-containing solutions.
    Use reconstituted solution within 10 hours; reconstituted vial and infusion solutions may be stored at 20—25 degrees C (68—77 degrees F). Do not refrigerate.
    Intermittent IV infusion:
    Do not mix allopurinol with or administer the drug through the same intravenous port with agents that are incompatible in solution with allopurinol such as amikacin sulfate, hydroxyzine HCl, amphotericin B, idarubicin HCl, carmustine, imipenem-cilastatin sodium, cefotaxime sodium, mechlorethamine HCl, chlorpromazine HCl, meperidine HCl, cimetidine HCl, metoclopramide HCl, clindamycin phosphate, methylprednisolone sodium succinate, cytarabine, minocycline HCl, dacarbazine, nalbuphine HCl, daunorubicin HCl, netilmicin sulfate, diphenhydramine HCl, ondansetron HCl, doxorubicin HCl, prochlorperazine edisylate, doxycycline hyclate, promethazine HCl, droperidol, sodium bicarbonate, floxuridine, streptozocin, gentamicin sulfate, tobramycin sulfate, haloperidol lactate, and vinorelbine tartrate.
    The rate of infusion depends on the volume of infusate.

    STORAGE

    Aloprim:
    - Store unreconstituted product at 68 to 77 degrees F
    Zyloprim:
    - Protect from light
    - Store between 59 to 77 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Serious rash

    Allopurinol is contraindicated in patients with a known hypersensitivity to allopurinol, including previous occurrence of skin rash or serious rash. Patients who have developed a severe reaction to allopurinol should not be restarted on the drug. Skin rash is a frequently reported adverse reaction in patients receiving allopurinol. The skin rash may be followed by more severe hypersensitivity reactions associated with exfoliation, fever, lymphadenopathy, arthralgia, and/or eosinophilia including Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and toxic epidermal necrolysis. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal dysfunction, seizures, and on rare occasions, death. The HLA-B*5801 allele is a genetic risk marker for severe skin reactions indicative of hypersensitivity to allopurinol. Allopurinol should be discontinued immediately at the first appearance of skin rash or other signs which may indicate an allergic reaction, and additional medical care should be provided as needed. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazide diuretics and allopurinol concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.[28048] [32197]

    Renal disease, renal failure, renal impairment

    An increase in BUN has been observed in some patients with renal disease receiving allopurinol. Patients with renal impairment require dosage adjustments. Serious toxicity has occurred in patients who received standard doses in the presence of renal insufficiency. With extreme renal impairment (creatinine clearance less than 3 mL/minute, such as end-stage renal disease, renal failure, and patients on dialysis) the interval between doses may also need to be lengthened. Patients should maintain a urine output of 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.

    Hepatic disease, hepatotoxicity

    Periodic liver function tests (LFTs) are recommended during the initial stages of allopurinol treatment for patients with hepatic disease. 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. If anorexia, weight loss, or pruritus develops in patients on allopurinol treatment, evaluation of liver function tests (LFTs) should be performed.

    Anticoagulant therapy, bone marrow suppression

    Bone marrow suppression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of therapy of allopurinol. Rarely, a patient may develop varying degrees of bone marrow depression, affecting 1 or more cell lines, while receiving allopurinol alone. It has also been reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant. The prothrombin time/INR should be reassessed periodically in patients receiving coumarin anticoagulant therapy (dicumarol, warfarin) concomitantly with allopurinol.

    Driving or operating machinery

    In some patients allopurinol may cause drowsiness. Patients should exercise caution when driving or operating machinery until they know how allopurinol affects them.

    Pregnancy

    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]

    Breast-feeding

    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.

    Infants

    Allopurinol is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism. Allopurinol has also been rarely used off-label in infants using weight-based dosing.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    vasculitis / 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

    Moderate

    eosinophilia / Delayed / 0-1.0
    bullous rash / Early / 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

    Mild

    nausea / Early / 0-1.3
    vomiting / Early / 0-1.2
    urticaria / Rapid / 0-1.0
    leukocytosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    fever / Early / 0-1.0
    lichen planus-like eruption / Delayed / 0-1.0
    onycholysis / Delayed / 0-1.0
    injection site reaction / Rapid / 0-1.0
    alopecia / Delayed / 0-1.0
    purpura / 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
    maculopapular rash / Early / 1.0
    rash / Early / 1.0
    diarrhea / Early / 1.0

    DRUG INTERACTIONS

    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; Lansoprazole: (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.
    Colchicine; 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.
    Cyclosporine: (Minor) Allopurinol may increase concentrations of cyclosporine. Close monitoring of cyclosporine concentrations is required when allopurinol is given concurrently with cyclosporine.
    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: (Severe) 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.
    Mercaptopurine, 6-MP: (Major) Avoid the concomitant use of mercaptopurine oral suspension and allopurinol. The concomitant use of mercaptopurine and allopurinol may result in increased mercaptopurine toxicity (e.g., bone marrow suppression, nausea, and vomiting). If allopurinol is coadministered with mercaptopurine tablets, 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.
    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.
    Photosensitizing agents: (Minor) Allopurinol may decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Porfimer: (Minor) Allopurinol may decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    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.
    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.
    Sulfinpyrazone: (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.
    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) The occurrence of certain hypersensitivity reactions may be increased in patients with renal impairment who receive allopurinol and thiazide diuretics in combination. The precise mechanism for such events is unclear but likely immune-mediated and may be related to an effect of oxypurinol; elevated oxypurinol concentrations appear to be associated with hypersensitivity reactions; decreased clearance of this metabolite may occur with renal impairment and with the concurrent use of thiazide diuretics. Severe skin reactions include exfoliative dermatitis, toxic epidermal necrolysis and Steven's Johnson syndrome; some reactions have been fatal. In addition, thiazide diuretics, like hydrochlorothiazide, can cause hyperuricemia. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia may have exacerbations of their disease.
    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.
    Verteporfin: (Minor) Allopurinol may decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Warfarin: (Minor) Allopurinol may interfere with the metabolism of warfarin. The INR should be monitored carefully in patients receiving oral anticoagulants when allopurinol therapy is added.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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—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—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—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—3 weeks. If allopurinol is discontinued, uric acid concentrations may return to pretreatment levels, which usually occurs 7—10 days after allopurinol cessation.

    Oral Route

    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—4 hours after oral administration. 

    Intravenous Route

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