Allopurinol information from DrugsUpdate  

Pharmacodynamics

Pharmacokinetics

Absorption

About 90% absorbed from GI tract. T max is 1.5 h (allopurinol) and 4.5 h (oxipurinol). C max is 3 mcg/mL (allopurinol 300 mg) and 6.5 mcg/mL (oxipurinol).

Metabolism
Rapidly oxidized to oxipurinol.

Elimination
About 20% is excreted in the feces. Allopurinol is essentially cleared by glomerular filtration, whereas oxipurinol is reabsorbed in the kidney tubules. T 1/2 , plasma is about 1 to 2 h (allopurinol) and about 15 h (oxipurinol).

Onset
Uric acid decreases in about 2 to 3 days.

Peak
May require a week or more of treatment.

Duration
Xanthine oxidase inhibition is maintained over 24 h; however, uric acid levels may not return to pretreatment levels until 7 to 10 days following cessation of therapy.

Allopurinol Indications / Allopurinol Uses

Information Not Available

Allopurinol Adverse Reactions / Allopurinol Side Effects

Drowsiness, postural hypotension, syncope, asthenia, depression, headache, dry mouth, GI disturbances, edema, blurred vision, rhinitis, erectile disorders, tachycardia, palpitation, hypersensitivity reactions; flushes; chest pain; dizziness; lack of energy.

Precautions

An increase in acute attacks of gout has been reported during the early stages of Allopurinol administration, even when normal or subnormal serum uric acid levels have been attained. Accordingly, maintenance doses of colchicine generally should be given prophylactically when Allopurinol is begun. In addition, it is recommended that the patient start with a low dose of Allopurinol (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day). The use of colchicine or anti-inflammatory agents may be required to suppress gouty attacks in some cases. The attacks usually become shorter and less severe after several months of therapy. The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. Even with adequate Allopurinol therapy, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to avoid the theoretical possibility of formation of xanthine calculi under the influence of Allopurinol therapy and help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during Allopurinol administration. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of Allopurinol administration and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Renal failure in association with Allopurinol administration has been observed among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after Allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with Allopurinol. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.

Patients with decreased renal function require lower doses of Allopurinol than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of Allopurinol administration. In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels.

Bone marrow depression has been reported in patients receiving Allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as six weeks to as long as six years after the initiation of Allopurinol therapy. Rarely a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving Allopurinol alone.

Special Precautions

Elderly; hypertension; coronary insufficiency; angina (discontinue); renal or hepatic impairment. Monitor BP regularly. May affect ability to drive or operate machinery.

Other Drug Interactions

CYP3A4 inhibitors e.g. azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil may increase the levels of alfuzosin. Reduced serum levels when used with CYP3A4 inducers e.g. aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin and rifamycins.

Potentially Fatal: Concurrent use with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole or ritonavir) is contraindicated.

Other Interactions

Information Not Available

Dosage

Oral

Hyperuricaemia
Adult: Initially, 100 mg daily increased according to response until the plasma conc of urate is reduced to ≤6 mg/100 ml. Maintenance: 100-300 mg daily for mild to moderate gout; up to 600 mg daily for moderately severe tophaceous gout. Max: 800 mg daily. Up to 300 mg may be taken as a single dose; larger doses should be taken in divided doses to minimise gastric irritation.
Renal impairment: Max initial dose: 100 mg daily, increase only if the response is inadequate. Severe impairment: Doses should be <100 mg daily or 100 mg at intervals >1 day. Patients receiving dialysis 2-3 times/wk: 300-400 mg immediately after dialysis only. Adjust dose to maintain plasma-oxipurinol concentrations <15.2 mcg/ml.
Hepatic impairment: Dose reduction may be needed. Monitor liver function regularly.

Oral
Gout
Adult: Initially, 100 mg daily increased according to response until the plasma conc of urate is reduced to ≤6 mg/100 ml. Maintenance: 100-300 mg daily for mild to moderate gout; up to 600 mg daily for moderately severe tophaceous gout. Max: 800 mg daily. Up to 300 mg may be taken as a single dose; larger doses should be taken in divided doses to minimise gastric irritation.
Renal impairment: Max initial dose: 100 mg daily, increase only if the response is inadequate. Severe impairment: Doses should be <100 mg daily or 100 mg at intervals >1 day. Patients receiving dialysis 2-3 times/wk: 300-400 mg immediately after dialysis only. Adjust dose to maintain plasma-oxipurinol concentrations <15.2 mcg/ml.
Hepatic impairment: Dose reduction may be needed. Monitor liver function regularly.

Oral
Prophylaxis of uric acid nephropathy associated with cancer therapy
Adult: 600-800 mg/day in 2-3 divided doses for 2-3 days before starting cancer treatment. Ensure adequate fluid intake. Maintenance for patients with hyperuricaemia secondary to cancer or cancer therapy: 100-300 mg daily for mild to moderate gout; up to 600 mg daily for moderately severe tophaceous gout. Max: 800 mg daily. Dose is titrated based on response. Up to 300 mg may be taken as a single dose; larger doses should be taken in divided doses to minimise gastric irritation.
Child: <15 yr: 10-20 mg/kg daily. Max: 400 mg daily.
Renal impairment: Max initial dose: 100 mg daily, increase only if the response is inadequate. Severe impairment: Doses should be <100 mg daily or 100 mg at intervals >1 day. Patients receiving dialysis 2-3 times/wk: 300-400 mg immediately after dialysis only. Adjust dose to maintain plasma-oxipurinol concentrations <15.2 mcg/ml.
Hepatic impairment: Dose reduction may be needed. Monitor liver function regularly.

Oral
Recurrent calcium oxalate stones
Adult: 200-300 mg daily, may be given as a single dose or in divided doses. Dose is adjusted based on subsequent 24-hr urinary urate excretion.
Renal impairment: Max initial dose: 100 mg daily, increase only if the response is inadequate. Severe impairment: Doses should be <100 mg daily or 100 mg at intervals >1 day. Patients receiving dialysis 2-3 times/wk: 300-400 mg immediately after dialysis only. Adjust dose to maintain plasma-oxipurinol concentrations <15.2 mcg/ml.
Hepatic impairment: Dose reduction may be needed. Monitor liver function regularly.

Intravenous
Cancer therapy-induced hyperuricaemia
Adult: 200-400 mg/m2 daily given as a single dose or equally divided doses at 6-, 8- or 12-hr intervals; given as an infusion over 15-60 minutes. Max: 600 mg daily. Therapy should be started 24-48 hr before initiating the treatment. Ensure sufficient fluid intake to produce a daily urinary output of at least 2 L and maintenance of a neutral, or slightly alkaline urine.
Child: ≤10 yr: Start with 200 mg/m2 daily; >10 yr: 200-400 mg/m2 daily (max: 600 mg/day). Dose can be given as a single dose or equally divided doses at 6-, 8- or 12-hr intervals; infuse over 15-60 minutes. Therapy should be started 24-48 hr before initiating the chemotherapy treatment.
Renal impairment: Haemodialysis: Administer dose after session or administer 50% supplemental dose.
CrCl (ml/min)    Dosage Recommendation
10-20    200 mg daily.
<3    100 mg daily at extended intervals.
3-10    100 mg daily.
Hepatic impairment: Dose reduction may be needed. Monitor liver function regularly.

Reconstitution
Recommended to further dilute the reconstituted solution to ≤ 6 mg/ml with normal saline or 5% dextrose solution.

Incompatibility
Y-site incompatibility: Amikacin sulfate, amphotericin B, carmustine, cefotaxime sodium, chlormethine hydrochloride, chlorpromazine hydrochloride, cimetidine hydrochloride, clindamycin phosphate, cytarabine, dacarbazine, daunorubicin hydrochloride, diphenhydramine hydrochloride, doxorubicin hydrochloride, doxycycline hyclate, droperidol, floxuridine, gentamicin sulfate, haloperidol lactate, hydroxyzine hydrochloride, idarubicin hydrochloride, imipenem with cilastatin sodium, methylprednisolone sodium succinate, metoclopramide hydrochloride, minocycline hydrochloride, nalbuphine hydrochloride, netilmicin sulfate, ondansetron hydrochloride, pethidine hydrochloride, prochlorperazine edisilate, promethazine hydrochloride, sodium bicarbonate, streptozocin, tobramycin sulfate and vinorelbine tartrate.

Food(before/after)

Should be taken with food

Allopurinol and Pregnancy

Caution when used during pregnancy

Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg/day), and it was concluded that there was no impaired fertility or harm to the fetus due to Allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg Allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg Allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of Allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary to maternal toxicity. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Experience with Allopurinol during human pregnancy has been limited partly because women of reproductive age rarely require treatment with Allopurinol. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving Allopurinol during pregnancy.

Allopurinol and Lactation

Contraindicated in lactation

Allopurinol and oxipurinol have been found in the milk of a mother who was receiving Allopurinol. Since the effect of Allopurinol on the nursing infant is unknown, caution should be exercised when Allopurinol is administered to a nursing woman.

Allopurinol and Children

Allopurinol is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism

Allopurinol and Geriatic

Information Not Available

Allopurinol and Other Contraindications

Severe hepatic impairment; history of postural hypotension and micturition syncope; intestinal occlusion; severe renal insufficiency; lactation.

Storage

Intravenous

Powder for inj: Store at 15-30°C. After reconstitution: Store at 20-25°C. Solution should be used within 10 hr of preparation.

Oral

Store below 25°C.

Lab interference

Intravenous

Powder for inj: Store at 15-30°C. After reconstitution: Store at 20-25°C. Solution should be used within 10 hr of preparation.

Oral

Store below 25°C.