ZYLOPRIM Allopurinol 100mg Tablet 1's
RXDRUG-DR-273-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
For reducing urate/uric acid formation in conditions where urate/uric acid deposition has already occurred (eg, gouty arthritis, skin tophi, nephrolithiasis) or is a predictable clinical risk (eg, treatment of malignancy potentially leading to acute uric acid nephropathy).
The main clinical conditions where urate/uric acid deposition may occur are: Idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate eg, hypoxanthine-guanine phosphoribosyltransferase including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage disease; phosphoribosylpyrophosphate synthetase; phosphoribosylpyrophosphate amidotransferase; and adenine phosphoribosyltransferase.
Management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.
Management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria when fluid, dietary and similar measures have failed.
The main clinical conditions where urate/uric acid deposition may occur are: Idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate eg, hypoxanthine-guanine phosphoribosyltransferase including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage disease; phosphoribosylpyrophosphate synthetase; phosphoribosylpyrophosphate amidotransferase; and adenine phosphoribosyltransferase.
Management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.
Management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria when fluid, dietary and similar measures have failed.
Dosage/Direction for Use
The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Adults: Zyloprim should be introduced at low dosage eg, 100 mg/day to reduce the risk of adverse reactions and increased only if the serum urate response is unsatisfactory. Extra caution should be exercised if renal function is poor (see Renal Impairment as follows and Precautions).
The following dosage schedules are suggested: Mild Conditions: 100-200 mg daily; moderately severe conditions: 300-600 mg daily. Severe Conditions: 700-900 mg daily.
If dosage on a mg/kg body weight basis is required, 2-10 mg/kg body weight/day should be used. When available, Zyloprim granules should be used in preference to the halving of tablets.
Children <15 years: 10-20 mg/kg body weight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukemia) and certain enzyme disorders eg, Lesch-Nyhan syndrome.
Elderly: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. (See also Renal Impairment as follows and Precautions.)
Renal Impairment: Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of plasma t½. In severe renal insufficiency, it may be advisable to use <100 mg/day or to use single doses of 100 mg at longer intervals than 1 day.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels <100 micromol/L (15.2 mg/L).
Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required 2-3 times/week, consideration should be given to an alternative dosage schedule of Zyloprim 300-400 mg immediately after each dialysis with none in the interim.
Hepatic Impairment: Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.
Treatment of High Urate Turnover Conditions eg, Neoplasia, Lesch-Nyhan Syndrome: It is advisable to correct existing hyperuricemia and/or hyperuricosuria with Zyloprim before starting cytotoxic therapy. Adequate hydration is important to maintain optimum diuresis and alkalinization of the urine is advisable to increase solubility of urinary urate/uric acid. Dosage of Zyloprim should be at the lower end of the recommended dosage schedule.
If urate nephropathy or other pathology has compromised renal function, the advice previously given in Renal Impairment should be followed. These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation (see Interactions and Adverse Reactions).
Administration: Zyloprim may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and GI intolerance be manifested, a divided dose regimen may be appropriate.
Adults: Zyloprim should be introduced at low dosage eg, 100 mg/day to reduce the risk of adverse reactions and increased only if the serum urate response is unsatisfactory. Extra caution should be exercised if renal function is poor (see Renal Impairment as follows and Precautions).
The following dosage schedules are suggested: Mild Conditions: 100-200 mg daily; moderately severe conditions: 300-600 mg daily. Severe Conditions: 700-900 mg daily.
If dosage on a mg/kg body weight basis is required, 2-10 mg/kg body weight/day should be used. When available, Zyloprim granules should be used in preference to the halving of tablets.
Children <15 years: 10-20 mg/kg body weight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukemia) and certain enzyme disorders eg, Lesch-Nyhan syndrome.
Elderly: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. (See also Renal Impairment as follows and Precautions.)
Renal Impairment: Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of plasma t½. In severe renal insufficiency, it may be advisable to use <100 mg/day or to use single doses of 100 mg at longer intervals than 1 day.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels <100 micromol/L (15.2 mg/L).
Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required 2-3 times/week, consideration should be given to an alternative dosage schedule of Zyloprim 300-400 mg immediately after each dialysis with none in the interim.
Hepatic Impairment: Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.
Treatment of High Urate Turnover Conditions eg, Neoplasia, Lesch-Nyhan Syndrome: It is advisable to correct existing hyperuricemia and/or hyperuricosuria with Zyloprim before starting cytotoxic therapy. Adequate hydration is important to maintain optimum diuresis and alkalinization of the urine is advisable to increase solubility of urinary urate/uric acid. Dosage of Zyloprim should be at the lower end of the recommended dosage schedule.
If urate nephropathy or other pathology has compromised renal function, the advice previously given in Renal Impairment should be followed. These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation (see Interactions and Adverse Reactions).
Administration: Zyloprim may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and GI intolerance be manifested, a divided dose regimen may be appropriate.
Overdosage
Ingestion of up to allopurinol 22.5 g without adverse effect has been reported. Nausea, vomiting, diarrhea and dizziness have been reported in a patient who ingested allopurinol 20 g. Recovery followed general supportive measures.
Massive absorption of Zyloprim may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with 6-mercaptopurine (6-MP) and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary, hemodialysis may be used.
Massive absorption of Zyloprim may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with 6-mercaptopurine (6-MP) and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary, hemodialysis may be used.
Administration
Should be taken with food.
Contraindications
Hypersensitivity to allopurinol or to any of the excipients of Zyloprim.
Special Precautions
Zyloprim should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrosis (see Immune System Disorders and Skin and Subcutaneous Tissue Disorders under Adverse Reactions).
Reduced doses should be used in patients with hepatic or renal impairment. Patients under treatment for hypertension or cardiac insufficiency eg, with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and Zyloprim should be used with care in this group.
Asymptomatic hyperuricemia per se is generally not considered an indication for use of Zyloprim. Fluid and dietary modification with management of the underlying cause may correct the condition.
Acute Gouty Attacks: Zyloprim treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.
In the early stages of treatment with Zyloprim, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore, it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for a few months.
If acute attacks develop in patients receiving Zyloprim, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.
Xanthine Deposition: In conditions where the rate of urate formation is greatly increased (eg, malignant disease and its treatment, Lesch-Nyhan syndrome), the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be minimized by adequate hydration to achieve optimal urine dilution.
Impaction of Uric Acid Renal Stones: Adequate therapy with Zyloprim will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Effects on the Ability to Drive or Operate Machinery: Since adverse reactions eg, somnolence, vertigo and ataxia have been reported in patients receiving Zyloprim, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Zyloprim does not adversely affect performance.
Use in pregnancy: There is inadequate evidence of safety of Zyloprim in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child (see also Teratogenicity under Actions).
Use in lactation: Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of allopurinol 1.4 mg/L and oxipurinol 53.7 mg/L have been demonstrated in breast milk from a woman taking Zyloprim 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breastfed baby.
Reduced doses should be used in patients with hepatic or renal impairment. Patients under treatment for hypertension or cardiac insufficiency eg, with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and Zyloprim should be used with care in this group.
Asymptomatic hyperuricemia per se is generally not considered an indication for use of Zyloprim. Fluid and dietary modification with management of the underlying cause may correct the condition.
Acute Gouty Attacks: Zyloprim treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.
In the early stages of treatment with Zyloprim, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore, it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for a few months.
If acute attacks develop in patients receiving Zyloprim, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.
Xanthine Deposition: In conditions where the rate of urate formation is greatly increased (eg, malignant disease and its treatment, Lesch-Nyhan syndrome), the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be minimized by adequate hydration to achieve optimal urine dilution.
Impaction of Uric Acid Renal Stones: Adequate therapy with Zyloprim will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Effects on the Ability to Drive or Operate Machinery: Since adverse reactions eg, somnolence, vertigo and ataxia have been reported in patients receiving Zyloprim, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Zyloprim does not adversely affect performance.
Use in pregnancy: There is inadequate evidence of safety of Zyloprim in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child (see also Teratogenicity under Actions).
Use in lactation: Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of allopurinol 1.4 mg/L and oxipurinol 53.7 mg/L have been demonstrated in breast milk from a woman taking Zyloprim 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breastfed baby.
Use In Pregnancy & Lactation
Use in pregnancy: There is inadequate evidence of safety of Zyloprim in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child (see also Teratogenicity under Actions).
Use in lactation: Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of allopurinol 1.4 mg/L and oxipurinol 53.7 mg/L have been demonstrated in breast milk from a woman taking Zyloprim 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breastfed baby.
Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child (see also Teratogenicity under Actions).
Use in lactation: Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of allopurinol 1.4 mg/L and oxipurinol 53.7 mg/L have been demonstrated in breast milk from a woman taking Zyloprim 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breastfed baby.
Adverse Reactions
For Zyloprim, there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The frequency categories assigned to the adverse drug reactions as follows are estimates. For most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency: Very common: ≥1/10 (≥10%); common: ≥1/100 and <1/10 (≥1% and <10%); uncommon: ≥1/1000 and <1/100 (≥0.1% and <1%); rare: ≥1/10,000 and <1/1000 (≥0.01% and <0.1%); very rare: <1/10,000 (<0.01%).
Adverse reactions in association with allopurinol are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.
Infections and Infestations: Very Rare: Furunculosis.
Blood and Lymphatic System Disorders: Very Rare: Agranulocytosis, aplastic anemia, thrombocytopenia.
Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
Immune System Disorders: Uncommon: Hypersensitivity reactions. Very Rare: Angioimmunoblastic lymphadenopathy.
Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson syndrome and toxic epidermal necrolysis, occur rarely (see Skin and Subcutaneous Tissue Disorders as follows). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment. Zyloprim should be withdrawn immediately and permanently.
Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalized hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalized lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
Metabolism and Nutrition Disorders: Very Rare: Diabetes mellitus, hyperlipidemia.
Psychiatric Disorders: Very Rare: Depression.
Nervous System Disorders: Very Rare: Coma, paralysis, ataxia, neuropathy, paresthesia, somnolence, headache, taste perversion.
Eye Disorders: Very Rare: Cataract, visual disorder, macular changes.
Ear and Labyrinth Disorders: Very Rare: Vertigo.
Cardiac Disorders: Very Rare: Angina, bradycardia.
Vascular Disorders: Very Rare: Hypertension.
Gastrointestinal Disorders: Uncommon: Vomiting, nausea. Very Rare: Recurrent hematemesis, steatorrhea, stomatitis, changed bowel habit.
In early clinical studies, nausea and vomiting were reported. Further reports suggest that this reaction is not a significant problem and can be avoided by taking allopurinol after meals.
Hepatobiliary Disorders: Uncommon: Asymptomatic increases in liver function tests. Rare: Hepatitis (including hepatic necrosis and granulomatous hepatitis).
Hepatic dysfunction has been reported without overt evidence of more generalized hypersensitivity.
Skin and Subcutaneous Tissue Disorders: Common: Rash. Rare: Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Very Rare: Angioedema, fixed drug eruption, alopecia, discolored hair.
Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative eg, SJS/TEN.
Zyloprim should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Zyloprim may, if desired, be re-introduced at a small dose (eg, 50 mg/day) and gradually increased. If the rash recurs, Zyloprim should be permanently withdrawn as more severe hypersensitivity reactions may occur (see Immune System Disorders mentioned previously).
The HLA-B*5801 allele has been has been identified as a genetic risk factor for Zyloprim associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers. However, the use of genotyping as a screening tool to make decisions about treatment with Zyloprim has not been established.
The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, Zyloprim should be withdrawn immediately and permanently.
Angioedema has been reported to occur with and without signs and symptoms of a more generalized allopurinol hypersensitivity reaction.
Renal and Urinary Disorders: Very Rare: Hematuria, uremia.
Reproductive System and Breast Disorders: Very Rare: Male infertility, erectile dysfunction, gynecomastia.
General Disorders and Administration Site Conditions: Very Rare: Edema, general malaise, asthenia, fever.
Fever has been reported to occur with and without signs and symptoms of a more generalized allopurinol hypersensitivity reaction (see Immune System Disorders mentioned previously).
The frequency categories assigned to the adverse drug reactions as follows are estimates. For most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency: Very common: ≥1/10 (≥10%); common: ≥1/100 and <1/10 (≥1% and <10%); uncommon: ≥1/1000 and <1/100 (≥0.1% and <1%); rare: ≥1/10,000 and <1/1000 (≥0.01% and <0.1%); very rare: <1/10,000 (<0.01%).
Adverse reactions in association with allopurinol are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.
Infections and Infestations: Very Rare: Furunculosis.
Blood and Lymphatic System Disorders: Very Rare: Agranulocytosis, aplastic anemia, thrombocytopenia.
Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
Immune System Disorders: Uncommon: Hypersensitivity reactions. Very Rare: Angioimmunoblastic lymphadenopathy.
Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson syndrome and toxic epidermal necrolysis, occur rarely (see Skin and Subcutaneous Tissue Disorders as follows). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment. Zyloprim should be withdrawn immediately and permanently.
Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalized hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalized lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
Metabolism and Nutrition Disorders: Very Rare: Diabetes mellitus, hyperlipidemia.
Psychiatric Disorders: Very Rare: Depression.
Nervous System Disorders: Very Rare: Coma, paralysis, ataxia, neuropathy, paresthesia, somnolence, headache, taste perversion.
Eye Disorders: Very Rare: Cataract, visual disorder, macular changes.
Ear and Labyrinth Disorders: Very Rare: Vertigo.
Cardiac Disorders: Very Rare: Angina, bradycardia.
Vascular Disorders: Very Rare: Hypertension.
Gastrointestinal Disorders: Uncommon: Vomiting, nausea. Very Rare: Recurrent hematemesis, steatorrhea, stomatitis, changed bowel habit.
In early clinical studies, nausea and vomiting were reported. Further reports suggest that this reaction is not a significant problem and can be avoided by taking allopurinol after meals.
Hepatobiliary Disorders: Uncommon: Asymptomatic increases in liver function tests. Rare: Hepatitis (including hepatic necrosis and granulomatous hepatitis).
Hepatic dysfunction has been reported without overt evidence of more generalized hypersensitivity.
Skin and Subcutaneous Tissue Disorders: Common: Rash. Rare: Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Very Rare: Angioedema, fixed drug eruption, alopecia, discolored hair.
Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative eg, SJS/TEN.
Zyloprim should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Zyloprim may, if desired, be re-introduced at a small dose (eg, 50 mg/day) and gradually increased. If the rash recurs, Zyloprim should be permanently withdrawn as more severe hypersensitivity reactions may occur (see Immune System Disorders mentioned previously).
The HLA-B*5801 allele has been has been identified as a genetic risk factor for Zyloprim associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers. However, the use of genotyping as a screening tool to make decisions about treatment with Zyloprim has not been established.
The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, Zyloprim should be withdrawn immediately and permanently.
Angioedema has been reported to occur with and without signs and symptoms of a more generalized allopurinol hypersensitivity reaction.
Renal and Urinary Disorders: Very Rare: Hematuria, uremia.
Reproductive System and Breast Disorders: Very Rare: Male infertility, erectile dysfunction, gynecomastia.
General Disorders and Administration Site Conditions: Very Rare: Edema, general malaise, asthenia, fever.
Fever has been reported to occur with and without signs and symptoms of a more generalized allopurinol hypersensitivity reaction (see Immune System Disorders mentioned previously).
Drug Interactions
6-Mercaptopurine (6-MP) and Azathioprine: Azathioprine is metabolized to 6-MP which is inactivated by the action of xanthine oxidase. When 6-MP or azathioprine is given concurrently with Zyloprim, only ¼ of the usual dose of 6-MP or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.
Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma t½ of vidarabine is increased in the presence of allopurinol. When the 2 products are used concomitantly, extra vigilance is necessary to recognize enhanced toxic effects.
Salicylates and Uricosuric Agents: Oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity eg, probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of allopurinol, but the significance needs to be assessed in each case.
Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.
Coumarin Anticoagulants: There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with allopurinol, however, all patients receiving anticoagulants must be carefully monitored.
Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
Theophylline: Inhibition of the metabolism of theophylline has been reported. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man.
Theophylline levels should be monitored in patients starting or increasing allopurinol therapy.
Ampicillin/Amoxicillin: An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol, an alternative to ampicillin or amoxicillin is used where available.
Cyclophosphamide, Doxorubicin, Bleomycin, Procarbazine, Mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukemia) in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (mustine HCl), allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
Cyclosporin: Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced cyclosporin toxicity should be considered if the drugs are co-administered.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal t½. Therefore, dose reductions of didanosine may be required when used concomitantly with allopurinol.
Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma t½ of vidarabine is increased in the presence of allopurinol. When the 2 products are used concomitantly, extra vigilance is necessary to recognize enhanced toxic effects.
Salicylates and Uricosuric Agents: Oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity eg, probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of allopurinol, but the significance needs to be assessed in each case.
Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.
Coumarin Anticoagulants: There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with allopurinol, however, all patients receiving anticoagulants must be carefully monitored.
Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
Theophylline: Inhibition of the metabolism of theophylline has been reported. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man.
Theophylline levels should be monitored in patients starting or increasing allopurinol therapy.
Ampicillin/Amoxicillin: An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol, an alternative to ampicillin or amoxicillin is used where available.
Cyclophosphamide, Doxorubicin, Bleomycin, Procarbazine, Mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukemia) in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (mustine HCl), allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
Cyclosporin: Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced cyclosporin toxicity should be considered if the drugs are co-administered.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal t½. Therefore, dose reductions of didanosine may be required when used concomitantly with allopurinol.
Storage
Store at temperatures not exceeding 30°C. Keep dry.
Action
Pharmacology: Pharmacodynamics: Allopurinol is a xanthine-oxidase inhibitor and its main metabolite oxipurinol, lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid.
In addition to the inhibition of purine catabolism, in some but not all hyperuricemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase.
Pharmacokinetics: Absorption: Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 min after dosing. Estimates of bioavailability vary from 67-90%.
Peak plasma levels of allopurinol generally occur approximately 1.5 hrs after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 hrs. Peak plasma levels of oxipurinol generally occur after 3-5 hrs after oral administration of allopurinol and are much more sustained.
Distribution: Allopurinol is negligibly bound by plasma proteins and therefore, variations in protein-binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 L/kg which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.
Metabolism: The main metabolite of allopurinol is oxipurinol. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
Elimination: Approximately 20% of the ingested allopurinol is excreted in the feces. Allopurinol is mainly eliminated by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase with <10% of the unchanged drug excreted in the urine.
Allopurinol has a plasma t½ of about 0.5-1.5 hrs.
Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol but the plasma t½ of oxipurinol is far more prolonged. Estimates range from 13-30 hrs in man. Therefore, effective inhibition of xanthine oxidase is maintained over a 24-hr period with a single daily dose of allopurinol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking allopurinol 300 mg/day will generally have plasma oxipurinol concentrations of 5-10 mg/L.
Oxipurinol is eliminated unchanged in the urine but has a long elimination t½ because it undergoes tubular reabsorption. Reported values for the elimination t½ range from 13.6-29 hrs. The large discrepancies in these values may be accounted for by variations in study design and/or CrCl in the patients.
Special Populations: Renal Impairment: Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment (CrCl 10-20 mL/min), showed plasma oxipurinol concentrations of approximately 30 mg/L after prolonged treatment with allopurinol 300 mg/day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of allopurinol is therefore required in patients with renal impairment.
Elderly: The kinetics of allopurinol is not likely to be altered other than due to deterioration in renal function (see Renal Impairment as mentioned previously).
Toxicology: Preclinical Safety Data: Carcinogenesis/Mutagenesis: Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 mcg/mL and in vivo at doses up to 600 mg/day for a mean period of 40 months. Allopurinol does not produce nitroso compounds in vitro or affect lymphocyte transformation in vitro.
Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.
Teratogenicity: One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in fetal abnormalities however, in a similar study in rats at 120 mg/kg on day 12 of gestation, no abnormalities were observed.
Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8-16 of gestation produced no teratogenic effects.
An in vitro study using fetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.
In addition to the inhibition of purine catabolism, in some but not all hyperuricemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase.
Pharmacokinetics: Absorption: Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 min after dosing. Estimates of bioavailability vary from 67-90%.
Peak plasma levels of allopurinol generally occur approximately 1.5 hrs after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 hrs. Peak plasma levels of oxipurinol generally occur after 3-5 hrs after oral administration of allopurinol and are much more sustained.
Distribution: Allopurinol is negligibly bound by plasma proteins and therefore, variations in protein-binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 L/kg which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.
Metabolism: The main metabolite of allopurinol is oxipurinol. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
Elimination: Approximately 20% of the ingested allopurinol is excreted in the feces. Allopurinol is mainly eliminated by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase with <10% of the unchanged drug excreted in the urine.
Allopurinol has a plasma t½ of about 0.5-1.5 hrs.
Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol but the plasma t½ of oxipurinol is far more prolonged. Estimates range from 13-30 hrs in man. Therefore, effective inhibition of xanthine oxidase is maintained over a 24-hr period with a single daily dose of allopurinol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking allopurinol 300 mg/day will generally have plasma oxipurinol concentrations of 5-10 mg/L.
Oxipurinol is eliminated unchanged in the urine but has a long elimination t½ because it undergoes tubular reabsorption. Reported values for the elimination t½ range from 13.6-29 hrs. The large discrepancies in these values may be accounted for by variations in study design and/or CrCl in the patients.
Special Populations: Renal Impairment: Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment (CrCl 10-20 mL/min), showed plasma oxipurinol concentrations of approximately 30 mg/L after prolonged treatment with allopurinol 300 mg/day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of allopurinol is therefore required in patients with renal impairment.
Elderly: The kinetics of allopurinol is not likely to be altered other than due to deterioration in renal function (see Renal Impairment as mentioned previously).
Toxicology: Preclinical Safety Data: Carcinogenesis/Mutagenesis: Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 mcg/mL and in vivo at doses up to 600 mg/day for a mean period of 40 months. Allopurinol does not produce nitroso compounds in vitro or affect lymphocyte transformation in vitro.
Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.
Teratogenicity: One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in fetal abnormalities however, in a similar study in rats at 120 mg/kg on day 12 of gestation, no abnormalities were observed.
Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8-16 of gestation produced no teratogenic effects.
An in vitro study using fetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.
MedsGo Class
Hyperuricemia & Gout Preparations
Features
Brand
Zyloprim
Full Details
Dosage Strength
100mg
Drug Ingredients
- Allopurinol
Drug Packaging
Tablet 1's
Generic Name
Allopurinol
Dosage Form
Tablet
Registration Number
DR-273
Drug Classification
Prescription Drug (RX)
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