Xanthine Oxidase Substrate Drugs-

Co-administration of Febuxostat with Xanthine Oxidase Substrate ( azathioprine, Mercaptopurine, or theophylline ) could increase plasma concentrations of these drugs, resulting in severe toxicity .

Concomittant use is contraindicated. In vitro- In vitro studies have shown that Febuxostat does not inhibit P450 enzymes CYP1A2, CYO2C9, CyP2C19 or CYP3A4 and it does not induce CYp1A2, 2B6, 2C9, 2c19 or 3A4 at clinically relevant concentrtions. As such, pharmacokinetic interactions between the drugs metabolised by the CYP enzymes are unlikely.

When Febuxostat was administered with desipramine ( CYP2D6 substrate ) a slight increase in total exposure to desiopramine was observed. However this effect did not appear clinically important, therfore dose adjustments do not appear necessary when CYP2D6 substrates are coadministered with Febuxostat.

Febuxostat had no effect on the pharmcokinetics or pharmacodynamics of warfarin.

Hydrochlorthiazide had no effect on the pharmacokinetics of Febuxostat.

Febuxostat did not alter the pharmacokinetics of indomethicin nor did indomethicin alter the pharmacokinetics of Febuxostat.

Coadministration with Naproxen resulted in a 28% increase in Februxostat peak concentrations and a 40% increase in Febuxostat AUC. Dosage adjustments are not necessary with Indomethicn or Naproxen No dose adjustment is necesary for either

Febuxostat or colchicine when the two drugs are coadministered. Administration of Febuxostat ( 40mg daily ) with Colchicine ( 0.6mg twice daily ) resulted in a increase of 12% in Cmax and 7% AUC24 of Febuxostat. In addition, adninistration of Colchicine ( 0.6mg twice daily ) with Febuxostat ( 120mg daily ) resulted in less than 11% change in Cmax or AUC of Colchicine for both AM and PM doses. These changes were not considered significant.

Drug interaction studies of Febuoxstat with cytotoxic chemotherapy have not been conducted. nO dat available regarding the safety of Februxostat during cytotoxic therapy.

Chronic Management of Hyperurecemia and Gout

Adverse reactions

at least of 1% of Febuxostat treated patients, and at least 0.5% greater than placebo, are liver function abnormalitis , nausea, arthalgia, and rash.

Other adverse reactions reported during Febuxostat therapy included diarrhea, headache, musculoskeletal stiffness, constipation, gastrointestinal reflu, flushing, dizziness, and gout flares.

Febuxostat

Febuxostat is contraindicated in patients being treated with the xanthine oxidase substrates azathioprine, mercaptopurine, or theophylline

Warning and Precautions-

Gout flares-

An increase in gout flares idfrequently observed during initiation of Febuxostat. if a gout flare occcurs during treatment, Febuxostat need not be discontinued. Oncurrent prophylactic treatment with NSAID or Colchicine is recommended for up to six months.

Liver enzyme elevation-

Transaminase elevation ( up to > 3 times the upeer limit of normal ) have been observed in Febuxostat treated patients. Periodic liver function tests are advised. Cardiovascular Events- A higher rate of cardiovascular thromboembolic events was observed in patients treated with Febuxostat than Allopurinol in clinical trials. Althoug a causal relationship has not been established, it is recommended that patients patients be monitored for signs and symptoms of myocardial infraction and stroke. Severe Renal/Hepatic impairment- Caution advised with the use of Febuoxstat in patients with severe renal impairment ( CrCl , 30ml/min) and in patients with severe hepatic impairment ( Child-Pugh Class C)

Indication-

Chronic Management of Hyperurecemia and Gout

Recommended Dose-

40mg or 80mg once daily Recommended stating dose is 40mg once daily. For patients who do acheive a serum uric acid (sUA) ,6mg/dL after 2 weeks with 40mg Febuxostat 80 is recommended.

Febuxostat can be administerd without regard to food or antacid use.

Pharmacolgy-

Mechanism of Action. Febxostat is a 2-arylthiazole derivative that acheives theapeutic effect of decreasing serum uric acid by selectively inhibiting xanthine oxidase ( XO). Febixostat isa potent non purine selective inhibitor of XO Febuxostat has beenshown to potently inhibit the oxidised reduced forms of XO Pharmacokinetics-

Absorption -

Febuxostat is rapidly and well absorbed and metabolised in the liver by glucuronidation to produce the acyl-glucuronide metabolite and to a lesser extent to produce oxidative metabolites. Less than 4% of orally administered Febuxostat is eliminated in the urine in patients with Gout.

 Febuxostat can be administerd without regard to food or antacid use.

Pregnancy-

Febuxostat is category C drug- Tetrogenecity wass not seen in animal models. As there are no adequate and well-controlled studies in pregnant women, Febuxostat should be used during pregnancy only if the potential benefit justifies the potentaial risk to the fetus.

Nursing mothers-

Febuxostat is excreted in te milk of rats. It is not known whether this drug is excreted in human milk. Caution is advised if Febuxostat is administered to women who are breast feeding.

Pediatric Use-

Safety and effectiveness in pediatric patients undrer 18 years of age have not been established. Geriatric Use- No dose adjustments is necessary in elderly patients. In clinical trials the Cmax and CAUC 24 of Febuxostat in geriatric subjects ( >/= 65years ) wre similar to those in younger subjects( 18- 40 years) In patients with secondary hyperuricemia- Febuxostat is not recommended in patients with secondary hyperuricemia., including patients being treated for Lesch-Nyhan Syndrome or malignant disease, or in transplant receipient due to lack of data.