Allopurinol

Allopurinol is a an Antigout Agent belonging to pharmacology class of Xanthine Oxidase Inhibitor

Allopurinol can be used in the treatment of gout treatment, Nephrolithiasis; prevention of recurrent calcium stones, Tumor Lysis syndrome. It is also used in treatment of Nephrolithiasis, prevention of recurrent uric acid stones

About 90% of the drug is absorbed from the digestive system. Peak plasma levels for allopurinol and oxipurinol typically occur 1.5 hours and 4.5 hours after the dose, respectively. Maximum plasma levels of approximately 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were determined after a single oral administration of 300 mg allopurinol. Allopurinol tissue concentrations in humans have not yet been recorded, however it is likely that the tissues described above would have the highest levels of both allopurinol and its metabolite, oxypurinol. The blood, liver, colon, and heart of animals have been reported to have the highest quantities of allopurinol, while the brain and lung tissues had the lowest values. Allopurinol rapidly transforms to oxipurinol (alloxanthine), a xanthine analog that likewise inhibits the xanthine oxidase enzyme. The actions of this enzyme are both inhibited by allopurinol and oxypurinol. The purine salvage mechanism also transforms allopurinol and oxypurinol into their respective ribonucleotides. To yet, the impact of these ribonucleotides on the hypouricemic action of allopurinol in humans has not been well understood. The enzyme amidophosphoribosyltransferase may be inhibited by these metabolites, which would prevent de novo purine production. It has not been discovered that the ribonucleotides are integrated into DNA. Allopurinol should be taken at smaller doses because patients with renal dysfunction or failure can accumulate the drug because allopurinol and its metabolites are mostly removed through the kidney. Allopurinol should be taken daily in doses of 200 mg with a creatinine clearance of 10 to 20 mL/min or above. The daily dosage shouldn't be more than 100 mg when the creatinine clearance is less than 10 mL/min. A longer time between doses may be recommended if there is severe renal impairment (creatinine clearance estimated at less than 3 mL/min).

The common side effects associated with Allopurinol include Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, loss of taste, gastritis.

Allopurinol is available in the form of Cream, Lotion, spra, Dermatitis, pruritus, erythema, eczema, rash.

The Allopurinol is available in India, USA, Japan, Germany.

Allopurinol belonging to the Xanthine Oxidase Inhibitor acts a Antigout Agent.

The pharmacologically active metabolite of allopurinol, oxypurinol, is produced during allopurinol's metabolism in the liver. Allopurinol has a half-life of one to two hours, whereas oxypurinol's is closer to fifteen hours. Allopurinol and oxypurinol are both eliminated by the kidneys. Both allopurinol and oxypurinol prevent the enzyme xanthine oxidase from converting hypoxanthine to xanthine and uric acid in the purine catabolism pathway.

Allopurinol is available in Solution, Tablet.

Allopurinol can be used in the treatment of gout treatment, Nephrolithiasis; prevention of recurrent calcium stones, Tumor Lysis syndrome. It is also used in treatment of Nephrolithiasis, prevention of recurrent uric acid stones.

Allopurinol and the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid, the byproduct of purine metabolism in people, are known as xanthine oxidase inhibitors. Oxypurinol is an intermediate of allopurinol. The biosynthesis of purines is unaffected by allopurinol.

Allopurinol is approved for use in the following clinical indications

Gout, treatment:

Management of primary or secondary gout (acute attack, tophi, joint destruction, uric acid lithiasis, and/or nephropathy)

Urate-lowering therapy (ULT) (eg, allopurinol) is indicated in all patients with recurrent flares, tophi, urate arthropathy, and/or renal stones. ULT initiation is recommended close in time to first diagnosis in patients presenting at a young age (<40 years of age) or with very high serum uric acid levels (>8 mg/dL) and/or comorbidities (eg, renal impairment, hypertension, ischemic heart disease, heart failure)

Nephrolithiasis, prevention of recurrent calcium stones: Management in patients with hyperuricosuria (uric acid excretion >800 mg/day in men and >750 mg/day in women)

Tumor lysis syndrome, prevention: Management of hyperuricemia associated with cancer treatment for leukemia, lymphoma, and other malignancies

Although not approved there have been certain off labelled uses indicated for Allopurinol which includes:

Nephrolithiasis, prevention of recurrent uric acid stones.

• Gout, treatment (chronic urate-lowering therapy): Oral: Note: Urate-lowering therapy may be initiated during a gout flare or after the flare subsides; concomitant pharmacologic prophylaxis with colchicine, NSAIDS, or a glucocorticoid is recommended for at least the first 3 to 6 months to decrease flare activity.

Initial: 100 mg once daily.

Dosage adjustments: Titrate in 100 mg increments every 2 to 4 weeks to achieve the desired serum uric acid level.

Maintenance: Doses ≥300 mg/day are usually needed to reach the desired uric acid target; doses up to 800 mg/day may be required.

Maximum: 800 mg/day

Frequency of administration: Once daily in a single dose or in 2 or 3 divided doses. Note: The manufacturer's labeling recommends doses >300 mg be given in divided doses; however, most experts prescribe a single daily dose, regardless of total dose administered, except during a brief period (eg, when initiating or titrating therapy) when divided doses may help improve GI tolerability.

• • Solution: 500mg/vial

  • Tablet: 100 mg, 200 mg, 300 mg

  Nephrolithiasis, prevention of recurrent calcium or uric acid stones:

Due to calcium oxalate stones: Patients with hyperuricosuria (who continue to have active disease despite attempted dietary modification): Oral: 300 mg/day, usually given in a single daily dose but may be given in 2 or 3 divided doses, if needed, to improve GI tolerability.

Due to uric acid stones (off-label use): Oral: 300 mg/day, usually given in a single daily dose but may be given in 2 or 3 divided doses, if needed, to improve GI tolerability; use is reserved for patients who continue to have active disease despite urinary alkalinization therapy and increased hydration .

Tumor lysis syndrome, prevention: Patients at intermediate risk for tumor lysis syndrome (TLS) and without preexisting hyperuricemia (serum uric acid ≥8 mg/dL [476 micromol/L]):

Note: Aggressive IV hydration should always be initiated prior to cytotoxic therapy in patients at elevated risk for TLS.

Oral: 300 mg/m²/day or 10 mg/kg/day, given in 3 divided doses every 8 hours (maximum: 800 mg/day). Begin therapy 1 to 2 days before the start of induction chemotherapy and may continue for up to 3 to 7 days after chemotherapy until normalization of laboratory evidence of TLS (eg, serum uric acid, serum LDH).

IV: 200 to 400 mg/m²/day, given in a single daily dose or in 2 or 3 divided doses (maximum: 600 mg/day). Begin therapy 1 to 2 days before the start of induction chemotherapy and may continue for 3 to 7 days after chemotherapy until normalization of laboratory evidence of TLS (eg, serum uric acid, serum LDH).

• Solution: 500mg/vial
• Tablet: 100 mg, 200 mg, 300 mg

Solution, Tablet

• Dose Adjustment in Kidney impairment patient:

Gout, treatment (chronic urate-lowering therapy): Oral:

Altered kidney function:

eGFR >60 mL/minute: No dosage adjustment necessary.

eGFR ≤60 mL/minute:

Initial: <100 mg daily ; to lower the risk of AHS, some experts recommend not exceeding an initial dose of ~1.5 mg of allopurinol per mL/minute of eGFR (eg, for an eGFR of 50 mL/minute/1.73 m², the initial dose should not exceed 75 mg daily; see table for suggested initial doses).

• Dose Adjustment in Pediatric patient:

Hyperuricemia associated with chemotherapy management: Maintain adequate hydration; begin allopurinol 1 to 2 days before initiation of induction chemotherapy; may continue for 3 to 7 days after chemotherapy; daily doses >300 mg should be administered in divided doses:

Oral:

Children <6 years: 150 mg daily.

Children 6 to 10 years: 300 mg daily.

Children >10 years and Adolescents: 600 to 800 mg daily for 2 to 3 days in 2 to 3 divided doses.

Alternate dosing: Tumor lysis syndrome; intermediate-risk: Limited data available (Ref): Infants, Children, and Adolescents:

Weight-directed dosing: 10 mg/kg/day divided every 8 hours; maximum daily dose: 800 mg/day.

BSA-directed dosing: 50 to 100 mg/m²/dose every 8 hours; maximum daily dose: 300 mg/m²/day.

IV: For patients unable to tolerate oral therapy (BSA-directed dosing):

Manufacturer's labeling: Children and Adolescents: Initial: 200 mg/m²/day administered once daily or in equally divided doses at 6-, 8-, or 12-hour intervals.

Alternate dosing: Tumor lysis syndrome; intermediate-risk: Limited data available: Infants, Children, and Adolescents: 200 to 400 mg/m²/day in 1 to 3 divided doses; maximum daily dose: 600 mg/day.

Hyperuricemia associated with inborn errors of purine metabolism (Lesch-Nyhan syndrome): Limited data available: Oral: Infants, Children, and Adolescents: Initial: 5 to 10 mg/kg/day; adjust dose to maintain a high-normal serum uric acid concentration and a urinary uric acid/creatinine ratio <1; reported range: 3.7 to 9.7 mg/kg/day; usual maximum daily dose: 600 mg/day.

Recurrent calcium oxalate renal stones (including glycogen storage disease): Limited data available: Oral: Children and Adolescents: 4 to 10 mg/kg/day in divided doses 3 to 4 times daily; maximum daily dose: 300 mg/day.

The dietary restriction should be individualized as per patient requirements

For tumor lysis syndrome prevention, administer aggressive fluids sufficient to maintain adequate hydration and urinary output. For other indications, fluid intake should be administered to yield neutral or slightly alkaline urine and an output of ~2 L (in adults).

Allopurinol may be contraindicated in the following conditions:

Allopurinol is contraindicated in patients with a history of severe reaction to any formulation of allopurinol.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• CNS effects: May occasionally cause drowsiness; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Renal impairment: Dose reductions are recommended in patients with renal impairment; monitor closely. Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN with allopurinol. Patients with renal impairment should be carefully monitored during the early stages of allopurinol treatment; reduce the dose or withdraw therapy if increased renal function abnormalities appear and persist. Renal failure associated with allopurinol has been observed in patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions including multiple myeloma and congestive myocardial disease were present among patients whose renal dysfunction increased after allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.

Other warnings/precautions:

• Hydration: For tumor lysis syndrome prevention, administer aggressive fluids sufficient to maintain adequate hydration and urinary output (Coiffier 2008). For other indications, fluid intake sufficient to yield a daily urinary output of at least 2 L and maintenance of a neutral or (preferably) a slightly alkaline urine are desirable in order to avoid possible formation of xanthine calculi due to allopurinol therapy and to help prevent renal urate precipitation in patients receiving concomitant uricosuric agents.

Increased blood uric acid levels and risk of gastrointestinal toxicity with alcohol.

Risk Summary

Allopurinol and oxypurinol can be detected in human milk. Based on data from one case report, allopurinol and its active metabolite, oxypurinol, were found in a mother's milk five weeks after giving birth, with an estimated relative infant dose of between 0.14 and 0.2 mg/kg of allopurinol and between 7.2 to 8 mg/kg of oxypurinol daily. There have been no reports of allopurinol's effects on breastfed infants or milk production. Women are advised not to breastfeed during treatments with Allopurinol and for one week following the last dosage due to the possibility of major negative effects in a breastfed child.

There is no sufficient scientific evidence traceable regarding use and safety of Allopurinol in concurrent use with any particular food.

The adverse reactions related to Allopurinol can be categorized as

Common Adverse effects: Nausea, vomiting, diarrhea, abdominal pain, dyspepsia, loss of taste, gastritis.

Less Common Adverse effects: Granulomatous hepatitis, hepatic necrosis, hepatomegaly, cholestatic jaundice, hyperbilirubinemia.

Rare Adverse effects: Headache, paraesthesia, neuritis, peripheral neuropathy.

The clinically relevant drug interactions of Allopurinol is briefly summarized here

Decreases the metabolism of azathioprine and mercaptopurine, raising the risk of serious bone marrow toxicity. may increase the half-life of vidarabine, chlorpropamide, and dicoumarol. may raise ciclosporin levels. In individuals on thiazide diuretics who have impaired renal function, it may raise the risk of hypersensitivity. Theophylline metabolism might be hampered. Uricosuric medications (such as probenecid) and high dosages of salicylate may cause oxipurinol to be excreted more quickly and impair the effectiveness of allopurinol. skin rash more frequently occurring when ampicillin or amoxicillin is also being used.

The common side of Allopurinol include the following

Nausea, vomiting, diarrhea, abdominal pain, dyspepsia, loss of taste, gastritis.

Pregnancy

Risk Summary

Based on findings in animals, Allopurinol may cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been described in exposed animals . Allopurinol and its metabolite oxypurinol have been shown to cross the placenta following administration of maternal allopurinol. Available limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in published literature, 2 infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to a fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

Risk Summary

Allopurinol and oxypurinol are present in human milk. Based on information from a single case report, allopurinol and its active metabolite, oxypurinol, were detected in the milk of a mother at five weeks postpartum at an estimated relative infant dose of 0.14 and 0.2 mg/kg of allopurinol and between 7.2 to 8 mg/kg of oxypurinol daily. There was no report of effects of allopurinol on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatments with Allopurinol and for one week after the last dose.

Pediatric Use

The safety and effectiveness of Allopurinol have been established in approximately 200 pediatric patients. The efficacy and safety profile observed in this patient population were similar to that observed in adults.

Geriatric Use

Clinical studies of Allopurinol did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients.

Renal Impairment

Allopurinol and its primary active metabolite, oxypurinol, are eliminated by the kidneys.Therefore, changes in renal function will likely increase allopurinal and oxypurinol exposure. In patients with decreased renal function, or who have concurrent illnesses that can affect renal function such as hypertension and diabetes mellitus, perform periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed. In patients with severely impaired renal function or decreased urate clearance, the half-life of oxypurinol in the plasma is greatly prolonged. Reduce the dose of Allopurinol in patients with creatinine clearance ≤ 20 mL/min. Patients should be treated with the lowest effective dose, in order to minimize possible side effects.

Symptoms: Nausea, vomiting, diarrhea, dizziness.

Management: General supportive treatment. Maintain optimum diuresis through adequate hydration to facilitate excretion of the drug.

• Pharmacodynamic:

Allopurinol inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. Allopurinol is metabolized to oxypurinol which is also an inhibitor of xanthine oxidase; allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines.

• Pharmacokinetics:

Absorption: About 90% of the drug is absorbed from the digestive system. Peak plasma levels for allopurinol and oxipurinol typically occur 1.5 hours and 4.5 hours after the dose, respectively. Maximum plasma levels of approximately 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were determined after a single oral administration of 300 mg allopurinol.

Distribution: Allopurinol tissue concentrations in humans have not yet been recorded, however it is likely that the tissues described above would have the highest levels of both allopurinol and its metabolite, oxypurinol. The blood, liver, colon, and heart of animals have been reported to have the highest quantities of allopurinol, while the brain and lung tissues had the lowest values.

Metabolsim:

Allopurinol rapidly transforms to oxipurinol (alloxanthine), a xanthine analog that likewise inhibits the xanthine oxidase enzyme. The actions of this enzyme are both inhibited by allopurinol and oxypurinol. The purine salvage mechanism also transforms allopurinol and oxypurinol into their respective ribonucleotides. To yet, the impact of these ribonucleotides on the hypouricemic action of allopurinol in humans has not been well understood. The enzyme amidophosphoribosyltransferase may be inhibited by these metabolites, which would prevent de novo purine production. It has not been discovered that the ribonucleotides are integrated into DNA.

Excretion: Allopurinol should be taken at smaller doses because patients with renal dysfunction or failure can accumulate the drug because allopurinol and its metabolites are mostly removed through the kidney. Allopurinol should be taken daily in doses of 200 mg with a creatinine clearance of 10 to 20 mL/min or above. The daily dosage shouldn't be more than 100 mg when the creatinine clearance is less than 10 mL/min. A longer time between doses may be recommended if there is severe renal impairment (creatinine clearance estimated at less than 3 mL/min).

1. https://www.uptodate.com/contents/Allopurinol -drug-information?search=Allopurinol &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Allopurinol _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Allopurinol ?type=full&mtype=generic#mechanism-of-action