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