AALLOPURINOLLLOPURINOL
Y09PHD0103V/VI Pharm.D
Dept. Of Pharmacy Practice Run By: Chalapathi Institute Of Pharmaceutical
Sciences GGH, Guntur
Chemical Structure
Allopurinol is known chemically as 1,5 Dihydro-4H-pyrazolo[3,4-d ]pyrimidin-4-one.
Category: Uricosuric agent(Antigout, Xanthine Oxidase Inhibitor)
History:Allopurinol was first synthesized and reported in 1956 by
Roland K. Robins (1926-1992), in a search for antineoplasitic agents. Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name of Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome.
Brands & Prices In IndiaTrade Name
&Mnfu. Company Name
Dosage Form & strength
PRICE (Rps)
ALLGORIC TABKAMRON LAB
100mg300 mg
10 - 19.7010- 40.00
APLLINOL TABSYNTONIC LIFE SCIENCES
100 mg300mg
10 - 27.3010 - 49.00
CIPLORIC, TABCIPLA
100 mg300mg
10- 25.8510- 49.80
LODIRIC TAB , CAP-SRNOVARTIS
100mg250mg
10- 20.0010- 65.00
UREKA TABCHEMO BIOLOGICAL
100mg300mg
10-18.5010-48.00
ZYLORIC TABGLAXO SMITHKLINE
100mg300mg
10-34.2510-81.75
Mechanism Of Action
Allopurinol and its metabolite, oxypurinol (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.
Allopurinol also increases reutilization of hypoxanthine
and xanthine for nucleotide and nucleic acid synthesis;
the resultant increase in nucleotide concentration leads to
feedback inhibition of de novo purine synthesis.
Allopurinol thereby decreases uric acid
concentrations in both serum and
urine by inhibiting uric acid
formation.
Schematic diagram of the purine degradation pathway
uric acid
allopurinol inhibits
xanthine oxidase
oxypurinol
IndicationsFDA-Labeled Indications
Calcium renal calculus, recurrent Cancer - Hyperuricemia Gout Hyperuricemia - Tumor lysis syndrome
Non-FDA Labeled IndicationsDisorder of hematopoietic structure - Hyperuricemia Hyperuricemia, thiazide-induced Leishmaniasis Malaria
Dosage &Route Of Administration
ADULT DOSING
Calcium renal calculus, recurrent: 200 to 300 mg
Orally as a single or divided dose (2-3 times
daily); maximum dose: 800 mg/day
Gout: (mild) 100-300 mg/day Orally as a single
or divided dose (2-3 times daily)
Gout: (moderate to severe) 400-600 mg/day Orally as a single or divided dose (2-3 times daily); maximum dose 800 mg/day
Hyperuricemia - Tumor lysis syndrome: 600 to 800 mg/day Orally for 2 or 3 days; MAX daily dose, 800 mg , 12 hours to 3 days prior to initiation of chemotherapy
Pediatric Dosing
Cancer - Hyperuricemia: (under 6 y) 150 mg PO daily, evaluate response after 48 hour and dose adjust accordinglyCancer - Hyperuricemia: (6 to 10 y) 300 mg PO daily, evaluate response after 48 hour and dose adjust accordingly Hyperuricemia - Tumor lysis syndrome: (under 6 years) 150 mg Orally once daily for 2 to 3 daysHyperuricemia - Tumor lysis syndrome: (6 to 10 years) 300 mg Orally once daily for 2 to 3 days
Dose Adjustments
Maintenance dose should be based on serum uric
acid determinations performed 48 hours after initial
dose
Renal impairment: CrCL 10 to 20 mL/min, 200 mg
daily
Renal impairment: CrCL 3 to 10 mL/min, 100 mg
daily
Renal impairment: CrCL less than 3 mL/min, 100 mg
at extended intervals greater than every 24 hours
PharmacokineticsAbsorption
Tmax, Oral: 1.5 hours (allopurinol), 4.5 hours (oxipurinol) Bioavailability, Oral: 80% to 90% Onset: Initial effect: 2-3 d, peak effect: 7-14 days
DistributionVd: 1.6 L/kg (allopurinol) Protein Bound: <1%
MetabolismLiver: 70% Oxypurinol: active
ExcretionRenal clearance: approx GFR (allopurinol) ; 16.5 mL/minute (oxipurinol) Renal: approximately 80%, Feces: 20% Total body clearance: 15.7 mL/min/kg .
Elimination Half Life
Allopurinol: 1 to 2 hours ; Oxipurinol: 15 h (range 12 to 30 h)
Administration Oral - better tolerated if administered
following meals
Contraindications & Precautions
ContraindicationsConcomitant use with didanosine Hypersensitivity to allopurinol
PrecautionsAllergic reaction may occur; discontinue at first sign Liver disease; monitoring recommendedRenal function, decreased; risk of worsening condition; monitoring and dosage adjustment recommended
Pregnancy Category & Breast Feeding
Pregnancy Category Category -C
Breast Feeding Compatible with breastfeeding
Adverse drug reactions (ADRS)Common
Dermatologic: Maculopapular eruption, Pruritus (less than 1% ) SeriousDermatologic: Rash (less than 1% ), Stevens-Johnson syndrome (less than 1% ), Toxic epidermal necrolysis (less than 1% )Hematologic: Agranulocytosis, Aplastic anemia, Eosinophilia, Myelosuppression, Thrombocytopenia (0.6% )
Hepatic: Granulomatous hepatitis (less
than 1% ), Hepatic necrosis (less than
1% ), Hepatotoxicity
Immunologic: Immune hypersensitivity
reaction
Renal: Renal failure (less than 1% )
Drug-Drug Interactions DRUGS SEVERIT
Y SUMMARY
ALLOPURINOL -- DIDANOSINE
Contraindicated
result in increased serum concentrations of didanosine.
(Decre M)
AZATHIOPRINE -- ALLOPURINOL
Major result in azathioprine toxicity by decre M (nausea, vomiting, leukopenia,
anemia).
MERCAPTOPURINE -- ALLOPURINOL
Major result in mercaptopurine toxicity by decre M (bone
marrow suppression, nausea, vomiting). Management: reduce dose to 25-35%
during concurrent admin.
ALUMINUM HYDROXIDE -- ALLOPURINOL
Moderate
may result in decreased allopurinol effectiveness(Separate
by 2 hours) decre A
CYCLOSPORINE -- ALLOPURINOL
Moderate result in an increased risk of cyclosporine toxicity
(renal dysfunction, cholestasis, paresthesias).
unknown mechanism
WARFARIN POTASSIUM -- ALLOPURINOL
Moderate result in an increased risk of bleeding. (Decre M)Management: consider
monitoring CT, aPTT, INR and administer vit-k
accordingly
MonitoringSerum uric acid levels; goal of serum uric acid level in adults is 6 mg/dL or less Hyperuricosuria: 24-hour urinary urate excretion to determine best dose and frequency for efficacyPain relief is indicative of efficacyLiver function tests; periodically with preexisting liver disease, or if anorexia, weight loss, or pruritus develop in any patient renal function tests; periodically if renal impairment is present or if concomitant conditions affecting renal function (eg, hypertension, diabetes mellitus) are present
Treatment In Allopurinol Toxicity
Support: Management Of Mild To Moderate Toxicity:
Treatment is symptomatic and supportive. Management Of Severe Toxicity: Treatment is
symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.Decontamination: Airway management: Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.Antidote: None.
Myelosuppression: (leukocytosis, leukopenia, eosinophilia, thrombocytopenia, granulocytopenia, and fatal bone marrow suppression); these effects may be the result of concomitant use of other myelosuppressive drugs.
Treat severe neutropenia with filgrastim 5 mcg/kg/day IV infused over 4 hours. Monitor serial CBC with differential.
Hypersensitivity reaction: Mild/Moderate: Antihistamines with or without inhaled
beta agonists, corticosteroids or epinephrine. Severe: Oxygen, aggressive airway management,
antihistamines, epinephrine (Adult: 0.3 to 0.5 mL of a 1:1000 solution subcutaneously;
Child: 0.01 mL/kg, 0.5 mL max; may repeat in 20 to 30 min), corticosteroids, ECG monitoring, and IV fluids.
Monitoring of patient: Monitor renal function and liver enzymes in symptomatic patients. Monitor CBC after significant overdose. Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
Enhanced elimination procedure: Allopurinol and oxypurinol are removed during hemodialysis.
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT
OF ASYMPTOMATIC HYPERURICEMIA
ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH
OR OTHER SIGNS OF AN ALLERGIC REACTION
Allopurinol – black box warning
Patient EducationWarn patient to immediately report a skin rash or signs/symptoms of an allergic reaction (painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth) as drug may cause severe, sometimes fatal, hypersensitivity reactions.Drug may cause diarrhea, nausea.Instruct patient to report signs/symptoms of hepatotoxicity (anorexia, weight loss, or pruritus). Advise patient that optimal benefit may be delayed for 2 to 6 weeks. Counsel patient to take drug after meals to reduce gastric irritation.Encourage patient to maintain adequate hydration during therapy to prevent renal stonesTake the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
REFFERENCES
http://reference.medscape.com/drug/zyloprim-aloprim-allopurinol-342811#91http://www.micromedexsolutions.com http://www.drugsupdate.com/generic/view/115http://www.drugs.com/allopurinol.htmlhttp://www.medlineindia.com/metabolism/allopurinol.htmhttp://www.drugsupdate.com/brand/showavailablebrands/115/2