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ALLOPURINOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Allopurinol is an inhibitor of xanthine oxidase.

Specific Substances

    1) Alopurinol
    2) Allopurinolum
    3) Ketanrifit
    4) BW 56158
    5) HPP
    6) Isopurinol
    7) Sodium allopurinol
    8) CAS 315-30-0
    9) CAS 17795-21-0 (sodium allopurinol)
    10) CAS 2465-59-0 (oxypurinol)
    11) ADENOCK
    12) AL-100
    13) AILURAL
    14) ALLOPUR
    15) ALLO-PUREN
    16) ALLOPURINOL (I)
    17) ALLOPURINOLUM (Latin)
    18) ALLOZYM
    19) ALLURAL
    20) ALOPURINOL (Spanish)
    21) ALORAL
    22) ALOSITOL
    23) ALULINE
    24) ANOPROLIN
    25) ANZIEF
    26) APULONGA
    27) APURIN
    28) APUROL
    29) ATISURIL
    30) BLEMINOL
    31) BLOXANTH
    32) BW 56158
    33) BW 56-158
    34) B.W. 56-158
    35) CAPLENAL
    36) CCRIS 626
    37) CELLIDRIN
    38) COSURIC
    39) DABROSIN
    40) DABROSON
    41) 1,5-DIHYDRO-4H-PYRAZOLO(3,4-d)PYRIMIDIN-4-ONE
    42) 1,5-DIHYDRO-4H-PYRAZOLO(3,4-d)PYRIMIDINE-4-ONE
    43) DRG-0056
    44) DURA AL
    45) EMBARIN
    46) EPIDROPAL
    47) EPURIC
    48) FOLIGAN
    49) GEAPUR
    50) GICHTEX
    51) GOTAX
    52) 1H-PYRAZOLO(3,4-d)PYRIMIDIN-4-OL
    53) H-PYRAZOLO(3,4-d)PYRIMIDIN-4-OL
    54) HAMARIN
    55) HEXANURAT
    56) HEXANURET
    57) 4-HPP
    58) HPP
    59) HYDROXYPYRAZOLOPYRIMIDINE, 4-,3,4-D-
    60) 4'-HYDROXYPYRAZOLO(3,4-d)PYRAMIDINE
    61) 4'-HYDROXYPYRAZOLOL(3,4-d)PYRIMIDINE
    62) 4-HYDROXY-1H-PYRAZOLO(3,4-d)PYRIMIDINE
    63) 4-HYDROXY-3,4-PYRAZOLOPYRIMIDINE
    64) 4-HYDROXYPYRAZOLO(3,4-d)PYRIMIDINE
    65) 4-HYDROXYPYRAZOLOPYRIMIDINE
    66) 4-HYDROXYPYRAZOLYL(3,4-d)PYRIMIDINE
    67) 4H-PYRAZOLO(3,4-d)PYRIMIDIN-4-ONE
    68) 4H-PYRAZOLO(3,4-d)PYRIMIDIN-4-ONE, 1,5-DIHYDRO
    69) 4H-PYRAZOLO(3,4-d)PYRIMIDIN-4-ONE, 1,5-DIHYDRO-
    70) KETANRIFT
    71) KETOBUN-A
    72) LEDOPUR
    73) LOPURIN
    74) LYSURON
    75) MILURIT
    76) MINIPLANOR
    77) MONARCH
    78) NEKTROHAN
    79) NSC 101655
    80) NSC-1390
    81) PROGOUT
    82) REMID
    83) RIBALL
    84) SIGAPUROL
    85) SUSPENDOL
    86) TAKANARUMIN
    87) URBOL
    88) URICEMIL
    89) URIPRIM
    90) URIPURINOL
    91) URITAS
    92) UROBENYL
    93) UROLIT
    94) UROSIN
    95) URTIAS
    96) URTIAS 100
    97) XANTURAT
    98) ZYLOPRIM
    99) ZYLORIC
    1.2.1) MOLECULAR FORMULA
    1) ALLOPURINOL: C5H4N4O
    2) ALLOPURINOL SODIUM: C5H3N4NaO

Available Forms Sources

    A) FORMS
    1) Allopurinol is available in the United States as 100 and 300 mg tablets for oral use and 30 mL glass vials containing allopurinol sodium equivalent to 500 mg of allopurinol for intravenous infusion (Prod Info allopurinol oral tablet, 2011; Prod Info allopurinol sodium intravenous solution, 2004).
    B) USES
    1) Allopurinol is used to manage patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy). It is also used to manage patients with cancer (leukemia, lymphoma, and solid-tumor malignancies) receiving cancer therapy which causes an increase in serum and urinary uric acid concentrations and patients with recurrent calcium oxalate calculi and excessive uric acid excretion (800 mg/day in men and 750 mg/day in women) (Prod Info allopurinol oral tablet, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Allopurinol is used to reduce serum and/or urinary uric acid concentrations in patients with primary or secondary gout, cancer (leukemia, lymphoma, and solid-tumor malignancies) receiving cancer therapy which causes an increase in serum and urinary uric acid concentrations, and patients with recurrent calcium oxalate calculi and excessive uric acid excretion.
    B) PHARMACOLOGY: Allopurinol and its metabolite, oxipurinol (alloxanthine), decrease the production of uric acid by inhibiting the action of xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Skin rash is the most common adverse effect in patients receiving allopurinol. Allopurinol hypersensitivity reactions manifest by varying kinds of skin rash in association with fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, and pruritus. Cases of skin rash that can be severe and sometimes fatal have been reported following allopurinol use. In some cases, a skin rash may progress to severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death. The incidence of skin rash may be higher in the presence of renal insufficiency and/or the concomitant use of ampicillin or amoxicillin.
    2) Hypersensitivity reactions have been reported in patients taking allopurinol. They are thought to be immune complex mediated and may include all or one of the following effects:
    a) DERMATOLOGIC: Mild maculopapular eruptions, exfoliative dermatitis, epidermal necrolysis, or Stevens-Johnson syndrome may develop. These reactions often occur with fever, arthralgias, eosinophilia, hepatomegaly, renal dysfunction, or other signs of hypersensitivity.
    b) HEMATOLOGIC: Leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression (especially with concurrent administration of chemotherapeutic agents) have been reported. Rarely, mild reticulocytosis, lymphocytosis, agranulocytosis, pancytopenia, anemia, hemolytic anemia, aplastic anemia, pure red cell aplasia, decreased prothrombin levels and eosinophilic fibrohistiocytic bone marrow lesions have also occurred.
    c) HEPATIC: Elevated liver enzymes, cholestatic jaundice, granulomatous hepatitis, hepatic necrosis, hepatomegaly, and hyperbilirubinemia may be seen.
    d) RENAL: Deterioration of renal function due to interstitial nephritis or glomerular involvement may be more prevalent in patients with preexisting renal disease.
    e) OTHER: Alopecia, arteritis, peripheral neuritis, and macular eye lesions have been reported.
    3) OTHER REPORTED ADVERSE EFFECTS: Nausea, vomiting, diarrhea, anorexia, anorexia, peripheral neuropathy, headache, somnolence, aseptic meningitis, and cerebral vasculitis. Rhabdomyolysis suspected due to allopurinol has been reported in a single case.
    E) WITH POISONING/EXPOSURE
    1) In one case of massive acute overdose (22.5 grams), no adverse effects were noted. A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed.
    0.2.20) REPRODUCTIVE
    A) Allopurinol has been classified as FDA pregnancy category C. Allopurinol is excreted into breast milk. Although there are no human studies, allopurinol has resulted in a low incidence of major malformation in one case series, as well as fetal external and skeletal malformations and fetal death in animal studies.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for allopurinol in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor renal function and liver enzymes after significant overdose.
    C) Monitor CBC with differential and platelet count after significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Hematopoietic effects have also been reported, including leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression; however, these effects may be the result of concomitant use of other myelosuppressive drugs. Treat severe neutropenia with filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding.
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) ENHANCED ELIMINATION
    1) Although allopurinol and oxypurinol are removed during hemodialysis, the value of this in overdose has yet to be established.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be evaluated in a healthcare facility. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe hypersensitivity reactions should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected allopurinol overdose, the possibility of multidrug involvement should be considered. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable followup is imperative.
    K) PHARMACOKINETICS
    1) About 80% to 90% of an oral dose is absorbed. Allopurinol is rapidly converted in the body to oxypurinol (alloxanthine). Allopurinol and its metabolites are not bound to serum proteins. Vd: 2 L/kg. Renal excretion: 10% of a single acute dose and approximately 30% of a chronically administered dose is excreted unchanged in the urine. Allopurinol half-life is 2 hours or less. Oxypurinol: 18 to 30 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.
    0.4.6) PARENTERAL EXPOSURE
    A) Please refer to ORAL sections for information on specific treatment.

Range Of Toxicity

    A) TOXICITY: A 15-year-old girl ingested 22.5 g (416 mg/kg) of allopurinol and did not experience any toxicity. A woman with a medical history of gout (taking allopurinol 100 mg/day), hypertension, hypercholesterolemia, and advanced chronic kidney disease, did not experience any adverse clinical effects after ingesting 10 g of allopurinol. A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed.
    B) THERAPEUTIC DOSES: ADULTS: ORAL: Varies by indication: 100 to 800 mg/day orally as a single dose or divided doses. INTRAVENOUS: 200 to 400 mg/m(2)/day IV; MAX: 600 mg/day. CHILDREN: ORAL: 6 TO 10 YEARS OF AGE: 300 mg/day orally. YOUNGER THAN 6 YEARS OF AGE: 150 mg/day orally. INTRAVENOUS: 200 mg/m(2)/day IV.

Clinical Effects

Summary Of Exposure

    A) USES: Allopurinol is used to reduce serum and/or urinary uric acid concentrations in patients with primary or secondary gout, cancer (leukemia, lymphoma, and solid-tumor malignancies) receiving cancer therapy which causes an increase in serum and urinary uric acid concentrations, and patients with recurrent calcium oxalate calculi and excessive uric acid excretion.
    B) PHARMACOLOGY: Allopurinol and its metabolite, oxipurinol (alloxanthine), decrease the production of uric acid by inhibiting the action of xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Skin rash is the most common adverse effect in patients receiving allopurinol. Allopurinol hypersensitivity reactions manifest by varying kinds of skin rash in association with fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, and pruritus. Cases of skin rash that can be severe and sometimes fatal have been reported following allopurinol use. In some cases, a skin rash may progress to severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death. The incidence of skin rash may be higher in the presence of renal insufficiency and/or the concomitant use of ampicillin or amoxicillin.
    2) Hypersensitivity reactions have been reported in patients taking allopurinol. They are thought to be immune complex mediated and may include all or one of the following effects:
    a) DERMATOLOGIC: Mild maculopapular eruptions, exfoliative dermatitis, epidermal necrolysis, or Stevens-Johnson syndrome may develop. These reactions often occur with fever, arthralgias, eosinophilia, hepatomegaly, renal dysfunction, or other signs of hypersensitivity.
    b) HEMATOLOGIC: Leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression (especially with concurrent administration of chemotherapeutic agents) have been reported. Rarely, mild reticulocytosis, lymphocytosis, agranulocytosis, pancytopenia, anemia, hemolytic anemia, aplastic anemia, pure red cell aplasia, decreased prothrombin levels and eosinophilic fibrohistiocytic bone marrow lesions have also occurred.
    c) HEPATIC: Elevated liver enzymes, cholestatic jaundice, granulomatous hepatitis, hepatic necrosis, hepatomegaly, and hyperbilirubinemia may be seen.
    d) RENAL: Deterioration of renal function due to interstitial nephritis or glomerular involvement may be more prevalent in patients with preexisting renal disease.
    e) OTHER: Alopecia, arteritis, peripheral neuritis, and macular eye lesions have been reported.
    3) OTHER REPORTED ADVERSE EFFECTS: Nausea, vomiting, diarrhea, anorexia, anorexia, peripheral neuropathy, headache, somnolence, aseptic meningitis, and cerebral vasculitis. Rhabdomyolysis suspected due to allopurinol has been reported in a single case.
    E) WITH POISONING/EXPOSURE
    1) In one case of massive acute overdose (22.5 grams), no adverse effects were noted. A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER is a commonly reported side effect with therapeutic administration (Medline et al, 1978).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CATARACTS: Cataracts have been associated with chronic allopurinol ingestion (Garbe et al, 1998; Liu et al, 1988). Morphologically, they frequently consist of an unusual thinning of the anterior clear zone of the lens (Liu et al, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ARTERITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One study reported a case of a 57-year-old woman who received allopurinol 100 mg twice daily for up to one year who developed severe arteritis accompanied by erythema multiform with exfoliative dermatitis. After six weeks of therapy the patient developed a rash, fever, giddiness, muscle weakness, and morning stiffness. Anorexia, hypotension, pleuritic pain, and worsening of renal function subsequently developed with severe bitemporal headache, photophobia, fever, and weight loss. It was also noted that the patient had tenderness over both temporal arteries and her vision became very impaired with funduscopic examination revealing vascular changes and cotton-wool spots. Biopsy of artery and skin lesions confirmed the diagnosis of severe arteritis. Discontinuation of the drug did not result in immediate improvement of the clinical features but administration of prednisone resulted in dramatic clinical improvement with the erythrocyte sedimentation rate decreasing from 55 to 7 mL/hour (Bailey et al, 1976).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has been seen with long term (i.e., 14 years) ingestion of allopurinol therapeutically. The 79-year-old woman had stocking and glove sensation loss (Worth & Hussein, 1985). This neuropathy was reversible, but 2 others, in uremic patients, were not (Glyn & Crofts, 1966).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Weakness and malaise were seen in a 66-year-old patient taking allopurinol therapeutically for 18 months (Calin, 1978).
    C) CATATONIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Catatonia was seen in a 67-year-old patient taking 300 mg/day for 8 weeks. This was thought to be part of a hypersensitivity reaction which included a maculopapular rash and reduced renal function (Collins et al, 1991).
    D) ASEPTIC MENINGITIS
    1) WITH THERAPEUTIC USE
    a) Several cases of aseptic meningitis and cerebral vasculitis have been reported (Duchene et al, 2000) Greenberg et al, 2001; (Rothwell & Grant, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may occur with either acute or chronic ingestion (Kuzell et al, 1966).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may be seen with either acute or chronic ingestion (Kuzell et al, 1966; Yu & Gutman, 1964).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Anorexia and severe weight loss were seen in a 66-year-old man who had been taking allopurinol for 18 months (Calin, 1978).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice, granulomatous hepatitis, hepatic necrosis, hepatomegaly, and hyperbilirubinemia have occurred in less than 1% of patients receiving allopurinol in early clinical studies. These cases were reversible (Prod Info allopurinol oral tablet, 2011; Ohsawa & Ohtsubo, 1985; McInnes et al, 1981; Al-Kawas et al, 1981; Phanichphant & Boonpucknavig, 1980; Young et al, 1974; Jarzobski et al, 1970; Lidsky & Sharp, 1967; Ogryzlo et al, 1966).
    b) In the majority of cases reporting hepatic failure, symptoms developed while receiving allopurinol 300 mg/day for 1 to 4 weeks. The most common findings included fever, hepatomegaly, elevated liver enzymes, left upper quadrant pain, splenomegaly, jaundice, asterixis, fatigue, anorexia, drowsiness, eosinophilia, arthralgias, myalgias, dermatitis, and diplopia. Liver biopsy revealed focal necrosis, fatty changes, noncaseating granulomas, fibrin ring granulomas, and toxic hepatic centrilobular necrosis. Allopurinol-induced liver injury appears to be enhanced in patients receiving thiazide diuretics or in patients with renal insufficiency. In severe cases, pulmonary edema and hypotension developed and proved fatal. However, in the majority of cases, discontinuation of allopurinol lead to prompt improvement (Tam & Carroll, 1989a; Vanderstigel et al, 1986; Ohsawa & Ohtsubo, 1985; Raper et al, 1984; Chawla et al, 1977; Simmons et al, 1972; Espiritu et al, 1976; Al-Kawas et al, 1981).
    c) CASE REPORT: Mild elevations in transaminase levels (AST 115 International Units/L, ALT 446 International Units/L) were reported in a 42-year-old woman with hypertension, insulin-dependent diabetes, and gout who developed allopurinol hypersensitivity syndrome (Elasy et al, 1995a).
    d) CASE REPORT: A 79-year-old man taking allopurinol of unknown dosage and duration developed general malaise, weakness, and anorexia. The initial impression was acute hepatitis. Laboratory results revealed the elevated liver enzymes: total bilirubin 1.3 mg/dL, LDH 1,957 International Units/L, SGOT (AST) 1,487 International Units/L, SGPT (ALT) 535 International Units/L, and alkaline phosphatase 331 International Units/L. Despite aggressive treatment, the patient died on the third hospital day. Autopsy revealed hepatic toxic centrilobular necrosis. An antemortem blood sample was found to contain allopurinol 230.8 mcg/mL; normal peak serum levels after a typical 300 mg dose are 3 to 9 mcg/mL (Tam & Carroll, 1989).
    e) DRUG INTERACTION: TAMOXIFEN has been shown to potentiate allopurinol hepatotoxicity (Shah et al, 1982).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal failure has been reported in less than 1% of patients treated with allopurinol in clinical trials (Prod Info allopurinol oral tablet, 2011).
    b) Rare cases of acute tubular necrosis and renal failure, which may have been part of a generalized hypersensitivity reaction, have been reported during allopurinol therapy (McInnes et al, 1981; Boyer et al, 1977). Several cases of acute granulomatous interstitial nephritis have been reported in association with allopurinol therapy. At least one case may have been part of a generalized hypersensitivity reaction (Martinez-Vea et al, 1996; Parra et al, 1995; Magner et al, 1986; Gelbart et al, 1977).
    c) CASE REPORT: A case report described toxic epidermal necrolysis (TEN) and acute renal failure in a 74-year-old woman 3 weeks after allopurinol 300 mg/day was prescribed. The patient, who had chronic renal failure, type 2 diabetes, hypertension, and hereditary angioedema, was admitted to the hospital 2 days and 7 days after developing oliguria and extensive skin blistering, respectively. Three weeks prior to hospitalization, her serum creatinine, creatinine clearance, and uric acid were 2.7 mg/dL, 19.6 mL/min, and 7.3 mg/dL, respectively. Subsequently, she was initiated on allopurinol 300 mg/day. After 2 weeks of allopurinol treatment, she experienced an episode of fever, cough, sore throat, mucous membrane lesions, and widespread blistering of the skin. Upon admission, her serum creatinine and creatinine clearance were 6.6 mg/dL and 8.7 mL/minute, respectively. Based on surface area of the skin lesions and internal organ involvement, TEN was diagnosed and confirmed with skin biopsy. She was treated with saline solution infusions, multiple red blood cell transfusions, and fresh frozen plasma. Intravenous immunoglobulins (IVIg) 0.75 g/kg/day were administered for 4 days with recrudescence of skin lesions noted 3 days after IVIg was discontinued. Daily hemodialysis was initiated due to acute renal failure and persistent oliguria. Seven days later, hemodialysis was changed to albumin dialysis due to worsening cholestatic jaundice and confused mental status. After 4 treatments, bilirubin levels decreased and cognitive status improved. The skin lesions improved and resolved within 45 days. Kidney function returned to baseline. Subsequently, dialysis was discontinued after a few weeks and the patient was discharged after 2 months of hospitalization (Fagugli et al, 2008).
    d) PEDIATRIC: An 11-year-old boy with acute lymphoblastic leukemia presented in renal failure after having been treated with allopurinol 900 mg/day for 3 months. He failed to respond to peritoneal dialysis, and died on the seventh day post-admission. Autopsy revealed an obstructive uropathy, focal nephrocalcinosis, and multiple small stones in the calyces of both kidneys. The stones were found to contain 82 percent xanthine, 15 percent oxypurinol, and 3 percent hypoxanthine. Uric acid and allopurinol were not detected (Potter & Silvidi, 1987).
    B) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Oxypurinol (the metabolite of allopurinol) and xanthine renal stones have been rarely reported (Green et al, 1969; Band et al, 1970; Stote et al, 1980; Potter & Silvidi, 1987). These are consistent with chronic ingestion.
    b) PEDIATRIC: An 11-year-old boy with acute lymphoblastic leukemia presented in renal failure after having been treated with allopurinol 900 mg/day for 3 months. He failed to respond to peritoneal dialysis, and died on the seventh day post-admission. Autopsy revealed an obstructive uropathy, focal nephrocalcinosis, and multiple small stones in the calyces of both kidneys. The stones were found to contain 82 percent xanthine, 15 percent oxypurinol, and 3 percent hypoxanthine. Uric acid and allopurinol were not detected (Potter & Silvidi, 1987).
    C) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Worsening renal insufficiency (creatinine 9 mg/dL in a patient with mild underlying renal insufficiency) developed in a 42-year-old woman with hypertension, insulin-dependent diabetes and gout who developed allopurinol hypersensitivity syndrome (Elasy et al, 1995a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Hematopoietic effects have also been reported, including leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression; however, these effects may be the result of concomitant use of other myelosuppressive drugs. Rarely, mild reticulocytosis, lymphocytosis, agranulocytosis, pancytopenia, anemia, hemolytic anemia, aplastic anemia, pure red cell aplasia, decreased prothrombin levels and eosinophilic fibrohistiocytic bone marrow lesions have also occurred (Prod Info allopurinol oral tablet, 2011; Anon, 2001; Shinohara et al, 1990; McInnes et al, 1981; Rosenbloom & Gilbert, 1981; Wilkinson, 1977). These reactions have occurred as early as 6 weeks to as long as 6 years after the initiation of allopurinol treatment. Cases of bone marrow depression of varying degrees and affecting more than one cell line have been reported rarely in patients treated with allopurinol alone (Prod Info allopurinol oral tablet, 2011).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 15-year-old boy with Williams syndrome developed anemia 6 weeks after beginning allopurinol (hemoglobin 6.5 grams/decaliter). Bone marrow biopsy revealed red cell aplasia and he improved when allopurinol was discontinued (Lin et al, 1999).
    C) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Several cases of aplastic anemia, including fatalities, have been reported in patients with renal insufficiency. Severe pancytopenia developed 11 days to 4 months after administration of allopurinol (Shinohara et al, 1990).
    b) Six fatal cases of aplastic anemia among 69 blood-related adverse events were reported to the Swedish ADR database through November 2000. Patient characteristics included a predominance of women (4 vs 2), age greater than 70 years of age in 5, allopurinol doses between 100 to 300 mg daily, and onset between 3 to 5 months after therapy in 4 patients. Signs and symptoms leading to diagnosis included thrombocytopenia (severe and dominant), hematoma, fainting, chest pain, anemia, purpura, fatigue, and epistaxis. Death occurred as soon as 2 days and as late as 4 months from diagnosis (Anon, 2001).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in less than 1% of patients treated with allopurinol in clinical trials (Prod Info allopurinol oral tablet, 2011). Leukopenia has occurred with or without thrombocytopenia during allopurinol therapy (McInnes et al, 1981; Rosenbloom & Gilbert, 1981; Gilbert, 1972).
    2) WITH POISONING/EXPOSURE
    a) A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed (NTP , 2001; RTECS , 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Allopurinol hypersensitivity reactions manifest by varying kinds of skin rash in association with fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, and pruritus. Dermatological complications related to allopurinol therapy are common and may occur in up to 10% to 15% of cases (Prod Info allopurinol oral tablet, 2011; Yale et al, 1996; Elasy et al, 1995; Walz-LeBlanc et al, 1991; Lang, 1979; Rundles et al, 1966), particularly if allopurinol is used concurrently with ampicillin or amoxicillin (Anon, 1972; Jick & Porter, 1981). Cases of skin rash that can be severe and sometimes fatal have been reported following allopurinol use. In an earlier study, pruritic maculopapular skin eruption, sometimes scaly or exfoliative, was reported in 3% of patients with gout treated with allopurinol. Current usage analyses suggest an incidence of skin reactions of less than 1%. In some cases, a skin rash may progress to severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death. The incidence of skin rash may be higher in the presence of renal insufficiency and/or the concomitant use of ampicillin or amoxicillin (Prod Info allopurinol oral tablet, 2011).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) TOXIC EPIDERMAL NECROLYSIS as well as other moderate to severe skin reactions have been seen as part of a hypersensitivity syndrome (Ellman et al, 1975).
    b) CASE REPORT: A case report described toxic epidermal necrolysis (TEN) and acute renal failure in a 74-year-old woman 3 weeks after allopurinol 300 mg/day was prescribed. The patient, who had chronic renal failure, type 2 diabetes, hypertension, and hereditary angioedema, was admitted to the hospital 2 days and 7 days after developing oliguria and extensive skin blistering, respectively. Three weeks prior to hospitalization, her serum creatinine, creatinine clearance, and uric acid were 2.7 mg/dL, 19.6 mL/min, and 7.3 mg/dL, respectively. Subsequently, she was initiated on allopurinol 300 mg/day. After 2 weeks of allopurinol treatment, she experienced an episode of fever, cough, sore throat, mucous membrane lesions, and widespread blistering of the skin. Upon admission, her serum creatinine and creatinine clearance were 6.6 mg/dL and 8.7 mL/minute, respectively. Based on surface area of the skin lesions and internal organ involvement, TEN was diagnosed and confirmed with skin biopsy. She was treated with saline solution infusions, multiple red blood cell transfusions, and fresh frozen plasma. Intravenous immunoglobulins (IVIg) 0.75 g/kg/day were administered for 4 days with recrudescence of skin lesions noted 3 days after IVIg was discontinued. Daily hemodialysis was initiated due to acute renal failure and persistent oliguria. Seven days later, hemodialysis was changed to albumin dialysis due to worsening cholestatic jaundice and confused mental status. After 4 treatments, bilirubin levels decreased and cognitive status improved. The skin lesions improved and resolved within 45 days. Kidney function returned to baseline. Subsequently, dialysis was discontinued after a few weeks and the patient was discharged after 2 months of hospitalization (Fagugli et al, 2008)
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has been reported in less than 1% of patients receiving allopurinol (Prod Info allopurinol oral tablet, 2011).
    b) CASE REPORT: Stevens Johnson syndrome was observed in one case report (Bashir et al, 2000).
    c) The combination therapy of allopurinol and captopril has also been associated with the development of Stevens-Johnson syndrome. In 3 reported cases, the syndrome developed within 3 to 5 weeks of initiation of the combined therapy. In one patient, despite receiving high-dose steroids, the condition continued to worsen and the patient eventually died (Pennell et al, 1984).
    D) DRUG-INDUCED TOXIC PUSTULODERMA
    1) WITH THERAPEUTIC USE
    a) Several cases of allopurinol-induced toxic pustuloderma have been reported. Patients have developed a generalized pustular eruption associated with fever, neutrophilia, and eosinophilia following 1 to 4 weeks of treatment with allopurinol (200 to 300 mg/day). Symptoms resolved following discontinuation of allopurinol (Fitzgerald et al, 1994; Boffa & Chalmers, 1994; Yu & Chu, 1993).
    E) GRANULOMA ANNULARE
    1) WITH THERAPEUTIC USE
    a) Two cases of generalized granuloma annulare occurring in patients treated for hyperuricemia with long-term (13 years and 18 months) allopurinol 300 mg/day have been reported. Neither patient exhibited accompanying illnesses which might have induced granuloma annulare (eg, diabetes mellitus) and symptoms in each case cleared quickly without relapse upon discontinuation of allopurinol; a causal connection between the drug and the adverse effect is suggested (Becker et al, 1995).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Rhabdomyolysis suspected due to allopurinol has been reported in a single case (Terawaki et al, 2002).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DIABETES MELLITUS
    1) WITH THERAPEUTIC USE
    a) Allopurinol hypersensitivity apparently precipitating new-onset diabetes mellitus has been reported in a single case (Sommers & Schoene, 2002).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allopurinol hypersensitivity reactions manifest by varying kinds of skin rash in association with fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, and pruritus. Dermatological complications related to allopurinol therapy are common and may occur in up to 10% to 15% of cases (Prod Info allopurinol oral tablet, 2011; Yale et al, 1996; Elasy et al, 1995; Walz-LeBlanc et al, 1991; Lang, 1979; Rundles et al, 1966), particularly if allopurinol is used concurrently with ampicillin or amoxicillin (Anon, 1972; Jick & Porter, 1981). Cases of skin rash that can be severe and sometimes fatal have been reported following allopurinol use. In an earlier study, pruritic maculopapular skin eruption, sometimes scaly or exfoliative, was reported in 3% of patients with gout treated with allopurinol. Current usage analyses suggest an incidence of skin reactions of less than 1%. In some cases, a skin rash may progress to severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death. The incidence of skin rash may be higher in the presence of renal insufficiency and/or the concomitant use of ampicillin or amoxicillin (Prod Info allopurinol oral tablet, 2011).
    b) The incidence of hypersensitivity reactions is about 10% (Anon, 1972a) and usually occur within 2 to 6 weeks after initiation of therapy but range from 2 days to over 1 year. Fatalities are reported (Hammer et al, 2001).
    c) Hypersensitivity reactions (which are thought to be immune complex mediated) may include all or one of the following (Lang, 1979a; Lupton & Odom, 1979; Young et al, 1974a; Ellman et al, 1975; Elasy et al, 1995a):
    1) DERMATOLOGIC: Mild maculopapular eruptions, exfoliative dermatitis, epidermal necrolysis, or Stevens-Johnson syndrome may develop. These reactions often occur with fever, arthralgias, eosinophilia, hepatomegaly, renal dysfunction, or other signs of hypersensitivity (Lang, 1979a).
    2) HEMATOLOGIC: Bone marrow suppression, including agranulocytosis, leukopenia, and thrombocytopenia (especially with concurrent administration of chemotherapeutic agents) have been reported (Lupton & Odom, 1979; Band et al, 1970) Cummins et al, 1997; Greenberg & Zambrano, 1972; (Young et al, 1974a). Acute red cell aplasia has been reported (Lin et al, 1999).
    3) HEPATIC: Mild transient abnormalities in liver function tests, hepatomegaly, granulomatous hepatitis, hepatic necrosis, and intrahepatic obstructive jaundice may be seen (Shah et al, 1982; Young et al, 1974a; Elasy et al, 1995a).
    4) RENAL: Deterioration of renal function due to interstitial nephritis or glomerular involvement may be more prevalent in patients with pre-existing renal disease (Lupton & Odom, 1979; Elasy et al, 1995a).
    5) OTHER: Alopecia, arteritis, peripheral neuritis, and macular eye lesions have been reported (Lupton & Odom, 1979; Auerbach & Orentrich, 1968; Pinnas, 1968).
    6) DESENSITIZATION: Multiple reports suggest that desensitization regimens may successfully overcome allopurinol hypersensitivity and may be safe if carefully monitored (Dominguez Ortega et al, 2001; Fam et al, 2001).
    B) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 47-year-old man developed recurrent palpable purpura, lower extremity edema, malaise and night sweats after beginning allopurinol. Biopsy revealed leukocytoclastic vasculitis and tests for circulating antineutrophil cytoplasmic antibodies and antimyeloperoxidase antibodies were strongly positive. The patient improved when allopurinol was discontinued (Choi et al, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Allopurinol has been classified as FDA pregnancy category C. Allopurinol is excreted into breast milk. Although there are no human studies, allopurinol has resulted in a low incidence of major malformation in one case series, as well as fetal external and skeletal malformations and fetal death in animal studies.
    3.20.2) TERATOGENICITY
    A) Congenital Anomalies
    1) In prospective study conducted from 1991 until June 2012 of 31 pregnant women exposed to allopurinol during the first trimester, there were 2 spontaneous abortions, 2 elective terminations of pregnancy, and 27 live births with an overall rate of major malformations of 3.7% (1 out of 27). In addition, there were 4 infants with minor malformations and one with congenital hypoparathyroidism (autosomal-dominant). While the rates of major malformations and spontaneous abortions (cumulative incidence, 11%; 95% CI, 3 to 40) were within the expected range, the 1 child who had multiple, severe malformations had strikingly similar anomalies (eg, microphthalmia, cleft lip and palate, microtia), as another case reported elsewhere by Kozenko, et al. This rare combination of malformations present in 2 infants after first-trimester exposure to allopurinol suggests it may be the source of these teratogenic effects. The authors recommend caution with allopurinol therapy in the first trimester of pregnancy and high-resolution ultrasound to confirm normal fetal development, if inadvertent, first-trimester exposure occurs (Hoeltzenbein et al, 2013).
    B) LACK OF EFFECT
    1) A case report described an infant born without congenital abnormalities to a 25-year-old woman treated for left-sided ulcerative colitis throughout her entire pregnancy with combination therapy of allopurinol 100 mg and low-dose mercaptopurine 25 mg. During routine gestational follow-ups, no fetal abnormalities or growth restrictions were seen, and an uncomplicated cesarean section was performed at 39 weeks gestational age. The infant had a birth weight of 3550 g and had an Apgar score of 9/10/10 at 1, 5, and 10 minutes. At the time of delivery, the level of 6-thioguanine nucleotides (6-TGN) in the umbilical cord vein was 88 picomoles (pmol)/8 x 10(8) and the level of 6-methylmercaptopurine (6-MMP) was undetectable, while the maternal level of 6-TGN was 112 pmol/8 x 10(8) and 6-MMP was 160 pmol/8 x 10(8) (Seinen et al, 2013).
    2) Two unpublished reports and published paper revealed cases of women giving birth to normal offspring after exposure to oral forms of allopurinol during pregnancy (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    C) ANIMAL STUDIES
    1) MICE: On gestation days 10 and 13, there was an increased incidence of fetal external malformations (eg, cleft palate, harelip, and digital defects) and fetal skeletal malformations, respectively, when mice were given 50 or 100 mg/kg/day doses (about one-third and three-fourths the human dose on a mg/m(2) basis) intraperitoneally (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    2) RATS, RABBITS: There were no teratogenic effects observed in rats or rabbits administered doses up to 20 times the usual human dose of 5 mg/kg/day or at oral doses of up to 200 mg/kg/day or 100 mg/kg/day (about 3 times the human dose on a mg/m(2) basis), respectively, during organogenesis (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified allopurinol as FDA pregnancy category C (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    B) LACK OF EFFECT
    1) Two unpublished reports and published paper revealed cases of women giving birth to normal offspring after exposure to oral forms of allopurinol during pregnancy (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    2) A case report described an infant born without congenital abnormalities to a 25-year-old woman treated for left-sided ulcerative colitis throughout her entire pregnancy with combination therapy of allopurinol 100 mg and low-dose mercaptopurine 25 mg. During routine gestational follow-ups, no fetal abnormalities or growth restrictions were seen, and an uncomplicated cesarean section was performed at 39 weeks gestational age. The infant had a birth weight of 3550 g and had an Apgar score of 9/10/10 at 1, 5, and 10 minutes. At the time of delivery, the level of 6-thioguanine nucleotides (6-TGN) in the umbilical cord vein was 88 picomoles (pmol)/8 x 10(8) and the level of 6-methylmercaptopurine (6-MMP) was undetectable, while the maternal level of 6-TGN was 112 pmol/8 x 10(8) and 6-MMP was 160 pmol/8 x 10(8) (Seinen et al, 2013).
    3) Allopurinol was safely used during pregnancy in 3 women with inflammatory bowel disease. Two women (both 29-years-old) were diagnosed with ulcerative colitis and were treated with allopurinol 100 mg daily in combination with azathioprine. The pregnancies progressed unremarkably and resulted in the birth of healthy infants via caesarean section. In a third case, a 28-year-old woman with ileocecal Crohn's disease was treated with allopurinol 100 mg daily in combination with azathioprine and adalimumab. Upon becoming pregnant, the patient discontinued treatment with adalimumab but continued as usual with allopurinol and azathioprine. The pregnancy progressed uneventfully and the patient delivered a healthy infant via caesarean section (Fazal et al, 2013).
    C) ANIMAL STUDIES
    1) MICE: There was an increased rate of fetal mortality in pregnant mice administered 100 mg/kg doses (about three-fourths the human dose on a mg/m(2) basis) intraperitoneally on gestation days 10 or 13 (Prod Info allopurinol oral tablets, 2013).
    2) RATS, RABBITS: There were no fetotoxic effects observed in rats or rabbits administered doses up to 20 times the usual human dose of 5 mg/kg/day or at oral doses of up to 200 mg/kg/day or 100 mg/kg/day (about 3 times the human dose on a mg/m(2) basis), respectively, during organogenesis (Prod Info allopurinol oral tablets, 2013; Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) CASE REPORT: One case was reported in which a woman breastfed while taking 300 mg/day of allopurinol. Milk and plasma samples were taken from mother and infant after four weeks of therapy. The oxypurinol level in the maternal plasma peaked at 53.7 mcg/mL two hours after maternal intake. Four hours after maternal intake, allopurinol was undetectable in the infant plasma, and the oxypurinol level was 6.6 mcg/mL in the infant plasma. The infant received an estimated dose of 8 mg/kg of oxypurinol per day; the therapeutic dose for infants is 10 to 20 mg/kg/day (Kamilli et al, 1991).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: There was no effect on male or female fertility in rats or rabbits administered oral doses of 20 mg/kg/day (about one-third or one-half the human dose on a mg/m(2) basis, respectively) (Prod Info allopurinol oral tablets, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS315-30-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for allopurinol in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity when mice and rats were given allopurinol at doses up to 20 mg/kg/day (about one-sixth or one-third the recommended human dose on a mg/m(2) basis, respectively) for most of their life span (Prod Info allopurinol sodium IV injection, 2004).

Genotoxicity

    A) Allopurinol was not incorporated into rapidly replicating intestinal DNA following IV administration of 50 mg/kg to rats. There was no evidence of clastogenicity in the following tests: an in vivo micronucleus test in rats, lymphocytes taken from patients treated with allopurinol for a mean duration of 40 months, and an in vitro assay with human lymphocytes (Prod Info allopurinol sodium IV injection, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor renal function and liver enzymes after significant overdose.
    C) Monitor CBC with differential and platelet count after significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor renal and hepatic function in symptomatic patients.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) HEMATOLOGIC
    1) Monitor CBC with differential and platelet count after significant overdose.

Methods

    A) CHROMATOGRAPHY
    1) May be isolated by column chromatography (Green et al, 1969).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe hypersensitivity reactions should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be evaluated in a healthcare facility. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor renal function and liver enzymes after significant overdose.
    C) Monitor CBC with differential and platelet count after significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor renal function and liver enzymes in symptomatic patients.
    3) Monitor CBC with differential and platelet count after significant overdose.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    13) Prednisone has been used in doses of 40 to 200 mg/day for periods of two weeks to five months to treat severe reactions (Lang, 1979a).
    C) MYELOSUPPRESSION
    1) Hematopoietic effects have also been reported, including leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression; however, these effects may be the result of concomitant use of other myelosuppressive drugs. Rarely, mild reticulocytosis, lymphocytosis, agranulocytosis, pancytopenia, anemia, hemolytic anemia, aplastic anemia, pure red cell aplasia, decreased prothrombin levels and eosinophilic fibrohistiocytic bone marrow lesions have also occurred (Prod Info allopurinol oral tablet, 2011; Anon, 2001; Shinohara et al, 1990; McInnes et al, 1981; Rosenbloom & Gilbert, 1981; Wilkinson, 1977).
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    3) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Although allopurinol and oxypurinol are removed during hemodialysis, the value of this in overdose has yet to be established (Prod Info allopurinol oral tablet, 2011).

Abstracts

Case Reports

    A) ADOLESCENT: A 15-year-old girl who ingested 22.5 grams (416 mg/kg) of allopurinol received gastric lavage within 3 hours of ingestion and 50 grams of activated charcoal. No signs of toxicity developed. Minor increases in plasma phosphate (to 1.43 mmoL/L) and alkaline phosphatase (to 129 International Units) were noted over the next 4 days. The half-life of allopurinol was 3.6 hours, and oxypurinol 26 hours (Ferner et al, 1988).
    B) PEDIATRIC: An 11-year-old boy with acute lymphoblastic leukemia presented in renal failure after having been treated with allopurinol 900 mg/day for 3 months. He failed to respond to peritoneal dialysis, and died on the seventh day post-admission. Autopsy revealed an obstructive uropathy, focal nephrocalcinosis, and multiple small stones in the calyces of both kidneys. The stones were found to contain 82 percent xanthine, 15 percent oxypurinol, and 3 percent hypoxanthine. Uric acid and allopurinol were not detected (Potter & Silvidi, 1987).
    C) ADULT: A 79-year-old man taking allopurinol of unknown dosage and duration developed general malaise, weakness, and anorexia. The initial impression was acute hepatitis. Liver function tests revealed the following: total bilirubin 1.3 mg/dL, LDH 1,957 International Units/L, SGOT (AST) 1,487 International Units/L, SGPT (ALT) 535 International Units/L, and alkaline phosphatase 331 International Units/L. Despite aggressive treatment, the patient died on the third hospital day. Autopsy revealed hepatic toxic centrilobular necrosis. An antemortem blood sample was found to contain allopurinol 230.8 mcg/mL; normal peak serum levels after a "typical" 300 mg dose are 3 to 9 mcg/mL (Tam & Carroll, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: A 15-year-old girl ingested 22.5 g (416 mg/kg) of allopurinol and did not experience any toxicity. A woman with a medical history of gout (taking allopurinol 100 mg/day), hypertension, hypercholesterolemia, and advanced chronic kidney disease, did not experience any adverse clinical effects after ingesting 10 g of allopurinol. A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed.
    B) THERAPEUTIC DOSES: ADULTS: ORAL: Varies by indication: 100 to 800 mg/day orally as a single dose or divided doses. INTRAVENOUS: 200 to 400 mg/m(2)/day IV; MAX: 600 mg/day. CHILDREN: ORAL: 6 TO 10 YEARS OF AGE: 300 mg/day orally. YOUNGER THAN 6 YEARS OF AGE: 150 mg/day orally. INTRAVENOUS: 200 mg/m(2)/day IV.

Therapeutic Dose

    7.2.1) ADULT
    A) ORAL
    1) Varies by indication: 100 to 800 mg/day orally as a single dose or divided doses (Prod Info allopurinol oral tablet, 2011).
    B) INTRAVENOUS
    1) The recommended dose is 200 to 400 mg/m(2) as a single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals. MAX dose: 600 mg/day (Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013)
    7.2.2) PEDIATRIC
    A) HYPERURICEMIA - TUMOR LYSIS SYNDROME
    1) ORAL
    a) 6 TO 10 YEARS OF AGE: 300 mg/day orally (Prod Info allopurinol oral tablet, 2011).
    b) YOUNGER THAN 6 YEARS OF AGE: 150 mg/day orally (Prod Info allopurinol oral tablet, 2011).
    2) INTRAVENOUS
    a) The recommended starting dose is 200 mg/m(2) as a single infusion or in equally divided infusions at 6-, 8-, or 12-hour intervals (Prod Info ALOPRIM(R) intravenous injection lyophilized powder for solution, 2013).

Minimum Lethal Exposure

    A) A woman died after ingesting a dose of 88 mg/kg intermittently over the course of 22 days. Leukopenia was observed (NTP , 2001; RTECS , 2002).
    B) ADULT: A 79-year-old man taking allopurinol of unknown dosage and duration developed general malaise, weakness, and anorexia. The initial impression was acute hepatitis. Liver function tests revealed the following: total bilirubin 1.3 mg/dL, LDH 1,957 International Units/L, SGOT (AST) 1,487 International Units/L, SGPT (ALT) 535 International Units/L, and alkaline phosphatase 331 International Units/L. Despite aggressive treatment, the patient died on the third hospital day. Autopsy revealed hepatic toxic centrilobular necrosis. An antemortem blood sample was found to contain allopurinol 230.8 mcg/mL; normal peak serum levels after a "typical" 300 mg dose are 3 to 9 mcg/mL (Tam & Carroll, 1989).
    C) PEDIATRIC: An 11-year-old boy with acute lymphoblastic leukemia presented in renal failure after having been treated with allopurinol 900 mg/day for 3 months. He failed to respond to peritoneal dialysis, and died on the seventh day post-admission. Autopsy revealed an obstructive uropathy, focal nephrocalcinosis, and multiple small stones in the calyces of both kidneys. The stones were found to contain 82 percent xanthine, 15 percent oxypurinol, and 3 percent hypoxanthine. Uric acid and allopurinol were not detected (Potter & Silvidi, 1987).

Maximum Tolerated Exposure

    A) A 36-year-old transgender woman with a medical history of gout (taking allopurinol 100 mg/day), hypertension, hypercholesterolemia, and advanced chronic kidney disease, did not experience any adverse clinical effects after ingesting 10 g of allopurinol. The longer oxypurinol half-life of 65 hours was attributed to the impaired renal function of this patient. Following an ingestion of allopurinol 300 mg, the Cmax is about 3 mg/L. In this patient, the Cmax of allopurinol and oxypurinol were 29 mg/L and 106 mg/L, respectively (Kannangara et al, 2011).
    B) ADOLESCENT: A 15-year-old girl who ingested 22.5 grams (416 mg/kg) of allopurinol received gastric lavage within 3 hours of ingestion and 50 grams of activated charcoal. No signs of toxicity developed. Minor increases in plasma phosphate (to 1.43 mmoL/L) and alkaline phosphatase (to 129 International Units) were noted over the next 4 days. The half-life of allopurinol was 3.6 hours, and oxypurinol 26 hours (Ferner et al, 1988).
    C) A man developed muscle weakness, jaundice, and thrombocytopenia after taking oral doses of allopurinol 21.4 mg/kg intermittently for 5 days (RTECS , 2002).
    D) Patients receiving 500 to 600 mg of allopurinol daily experienced a rise in serum iron levels and a decrease in total iron binding capacity. These effects were not observed when dosage levels were reduced to 300 mg (HSDB , 2002).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) In a fatal case of allopurinol-induced hepatitis, blood allopurinol concentration was 230.8 mcg/mL (Tam & Carroll, 1989).
    b) CASE REPORT: A 36-year-old transgender woman with a medical history of gout (taking allopurinol 100 mg/day), hypertension, hypercholesterolemia, and advanced chronic kidney disease, did not experience any adverse clinical effects after ingesting 10 g of allopurinol. The longer oxypurinol half-life of 65 hours (allopurinol: 4.4 hours) was attributed to the impaired renal function of this patient. Following an ingestion of allopurinol 300 mg, the Cmax is about 3 mg/L. In this patient, the Cmax of allopurinol and oxypurinol were 29 mg/L and 106 mg/L, respectively (Kannangara et al, 2011).

Workplace Standards

    A) ACGIH TLV Values for CAS315-30-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS315-30-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS315-30-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS315-30-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Lewis, 2000 NTP, 2001 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 214 mg/kg -- food/fluid intake affected, ataxia
    2) LD50- (ORAL)MOUSE:
    a) 78 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 298 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 900 mg/kg
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 2450 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Allopurinol is a xanthine oxidase inhibitor which prevents the de novo formation of uric acid. Within less than 2 hours, most of the ingested allopurinol is oxidized to oxypurinol, a less potent inhibitor of xanthine oxidase. Both allopurinol and oxypurinol inhibit the catalytic xanthine oxidase system and the conversion of hypoxanthine to xanthine to uric acid (O'Sullivan, 1974). The source of allopurinol's adverse reactions has been postulated to be oxypurinol because of the latter's possible accumulation in renal insufficiency. Allopurinol has also been shown to be a non-competitive inhibitor of deoxythymidine phosphorylase and pyrimidine deoxyribosyltransferase in human leukocytes (O'Sullivan, 1974).

Physicochemical

Physical Characteristics

    A) Allopurinol is a "fluffy," white to off-white, odorless, powder or crystals, with a metallic or bitter taste (Budavari, 2000; HSDB , 2002). It has also been reported as being tasteless (HSDB , 2002; NTP , 2001). It is very slightly soluble in water; 0.48 mg/mL (at 25 degrees C) (Budavari, 2000; HSDB , 2002); 80 mg/dL (at 37 degrees C); solubility is greater in an alkaline solution. It has a pKa of 10.2 (Prod Info allopurinol oral tablet, 2011).
    B) Allopurinol sodium is a white amorphous mass with a pKa of 9.31 (Prod Info allopurinol sodium IV injection, 2004).

Ph

    A) ALLOPURINOL SODIUM: 11.1 to 11.8: reconstituted, concentrated solution (Prod Info allopurinol sodium IV injection, 2004)

Molecular Weight

    A) ALLOPURINOL: 136.11 (Prod Info allopurinol oral tablet, 2011)
    B) ALLOPURINOL SODIUM: 158.09 (Prod Info allopurinol sodium IV injection, 2004)

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