Febuxostat

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

Febuxostat can be used in the treatment Nephrolithiasis; prevention of recurrent calcium stones, Tumor Lysis syndrome. It is also used in treatment of Tumor lysis syndrome.

About 85% of febuxostat is quickly absorbed after oral treatment. Tmax lasts between one and one and a half hours. Following once-daily oral treatment, Cmax was around 1.6 ±0.6 mcg/mL at a dose of 40 mg febuxostat and 2.6 ±1.7 mcg/mL at a dose of 80 mg febuxostat. There were no clinically significant changes in the ability of febuxostat to lower blood uric acid concentrations, however a high-fat meal reduced Cmax by 49% and AUC by 18%.A low to medium volume of distribution is indicated by the apparent steady-state volume of distribution (Vss/F) of febuxostat, which ranges from 29 to 75 L. The relative role of each enzyme isoform in the metabolism of febuxostat has not yet been fully defined. Febuxostat is metabolized in the liver by UDP-glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) enzymes. The conjugation of febuxostat, which produces the acyl-glucuronide metabolite, is mediated by the enzymes UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and it accounts for roughly 22-44% of the whole dose's metabolism. The oxidation reaction, which is responsible for 2-8% of the dose's metabolism, is carried out by non-P450 enzymes, CYP1A2, CYP2C8, and CYP2C9. The pharmacologically active metabolites 67M-1, 67M-2, and 67M-4 are created during the oxidation process. Additional glucuronidation and sulfation processes are possible for 67M-1, 67M-2, and 67M-4.8 Human plasma contains hydroxy metabolites, albeit at considerably lower levels than the parent medication. Febuxostat is eliminated via both hepatic and renal pathways. Following oral administration of 80 mg radiolabeled febuxostat, approximately 49% of the dose was recovered in the urine. In urine, about 3% of the recovered dose accounted for unchanged febuxostat, 30% accounted for the acyl glucuronide metabolite, 13% accounted for oxidative metabolites and their conjugates, and 3% accounted for unidentified metabolites.

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

Febuxostat is available in the form of Tablets

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

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

Febuxostat is a novel, selective xanthine oxidase/dehydrogenase inhibitor that works by decreasing serum uric acid in a dose-dependent manner. In healthy subjects, febuxostat decreased the mean serum uric acid and serum xanthine concentrations, as well as the total urinary uric acid excretion. Febuxostat at daily doses of 40-80 mg reduced the 24-hour mean serum uric acid concentrations by 40 to 55%.Closely related to the drug-induced reduction of serum uric acid levels and mobilization of urate crystals in tissue deposits, febuxostat is associated with gout flares.

Febuxostat is available in Tablet.

Febuxostat 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 Tumor lysis syndrome.

Reduces uric acid by selectively inhibiting the enzyme known as xanthine oxidase, which is in charge of converting hypoxanthine to xanthine and uric acid. does not block other enzymes involved in pyrimidine and purine production when used at therapeutic concentrations.

Febuxostat is approved for use in the following clinical indications

Hyperuricemia: Chronic management of hyperuricemia in patients with gout who have an inadequate response to a maximally titrated dose of Febuxostat, who are intolerant to Febuxostat, or for whom treatment with Febuxostat is not advisable

Although not approved there have been certain off labelled uses documented for Febuxostat which includes:

Tumor lysis syndrome, prevention (alternative therapy).

Hyperuricemia: Oral: Initial: 40 mg once daily; may increase to 80 mg once daily in patients who do not achieve a serum uric acid level <6 mg/dL after 2 weeks. The dose may be increased further to 120 mg once daily if clinically indicated.

Tumor lysis syndrome, prevention (alternative therapy) (off-label use): Patients at intermediate or high risk for tumor lysis syndrome (TLS):

Note: Aggressive IV hydration should always be initiated prior to cytotoxic therapy in patients at elevated risk for TLS. The optimal dose of febuxostat for the prevention of TLS is not yet established.

Oral: 40 to 60 mg once daily or 120 mg once daily. Begin 1 to 2 days before the start of chemotherapy and continue for up to 14 days until normalization of laboratory evidence of TLS (eg, serum uric acid, serum lactate dehydrogenase).

• Tablet: 40mg, 80 mg.

Tablet

Dose Adjustment in Kidney impairment patient:

• CrCl ≥30 mL/minute: No dosage adjustment necessary.
• CrCl <30 mL/minute: Initial: 20 to 40 mg once daily. Note: Observational studies in patients with hyperuricemia have reported safety and tolerability of 60 and 80 mg/day; a careful titration may be considered in patients unresponsive to standard doses
• Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): Initial: 20 to 40 mg once daily; no supplemental dose necessary. Note: A small, retrospective, observational study in patients with hyperuricemia reported safety and tolerability of doses up to 80 mg/day; a careful titration may be considered in patient unresponsive to standard doses.
• Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): Initial: 20 to 40 mg once daily. Note: A small, retrospective, observational study in patients with hyperuricemia reported safety and tolerability of doses up to 80 mg/day; a careful titration may be considered in patients unresponsive to standard doses.
• CRRT: Dose as for CrCl <30 mL/minute.
• PIRRT (eg, sustained, low-efficiency diafiltration ): Dose as for CrCl <30 mL/minute

Dose Adjustment in Hepatic Patients:

• Preexisting hepatic impairment:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use caution.

• Hepatotoxicity during treatment:

ALT or AST >3 times ULN (in the clinical context of potential liver injury [eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice]): Interrupt febuxostat therapy and evaluate. Do not reinitiate febuxostat if liver injury is confirmed or no alternate etiology for liver test abnormalities is identified.

ALT or AST >3 times ULN and serum total bilirubin >2 times ULN without alternative etiology: Permanently discontinue.

The dietary restriction should be individualized as per patient requirements.

Febuxostat may be contraindicated in the following conditions:

Concomitant use with azathioprine, mercaptopurine.

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

Concerns related to adverse effects:

• Hepatic failure:

Postmarketing cases of hepatic failure (both fatal and nonfatal) have been reported (causal relationship has not been established). In controlled studies, significant hepatic transaminase elevations (>3 × ULN) have occurred (causal relationship not established). Evaluate liver function tests promptly in patients experiencing signs and symptoms of hepatic injury (eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice).

• Hypersensitivity: Hypersensitivity and serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS) have been reported, particularly in patients with prior skin reactions to Febuxostat; use with caution if a patient has a history of hypersensitivity reaction to Febuxostat.

Disease-related concerns:

• Cardiovascular disease: Consider prophylactic low-dose aspirin in patients with a history of CV disease.

• Secondary hyperuricemia: Use in secondary hyperuricemia has not been studied; avoid use in patients at increased risk of urate formation (eg, malignancy and its treatment; Lesch-Nyhan syndrome).

There is no sufficient scientific evidence traceable regarding use and safety of Febuxostat in concurrent use with alcohol.

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

The adverse reactions related to Febuxostat 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, paresthesia, neuritis, peripheral neuropathy.

The clinically relevant drug interactions of Febuxostat is briefly summarized here

• Xanthine Oxidase Substrate Drugs Febuxostat is an XO inhibitor. Based on a drug interaction study in healthy patients, Febuxostat altered the metabolism of theophylline (a substrate of XO) in humans ). Therefore, use with caution when co-administering Febuxostat with theophylline. Drug interaction studies of Febuxostat with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by Febuxostat may cause increased plasma concentrations of these drugs leading to toxicity/ Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine.
• Cytotoxic Chemotherapy Drugs Drug interaction studies of Febuxostat with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of Febuxostat during cytotoxic chemotherapy.
• In Vivo Drug Interaction Studies Based on drug interaction studies in healthy patients, Febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, Febuxostat may be used concomitantly with these medications.

The common side of Febuxostat include the following

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

Pregnancy

Risk Summary

Limited available data with Febuxostat use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. No adverse developmental effects were observed in embryo-fetal development studies with oral administration of Febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in a pre- and postnatal development study with administration of Febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US 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.

Data

Animal Data In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7 – 17, Febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 6 – 18, Febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed orally from gestation Day 7 through lactation Day 20, Febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD (on an AUC basis at a maternal oral dose of 12 mg/kg/day). However, increased neonatal mortality and a reduction in neonatal body weight gain were observed in the presence of maternal toxicity at a dose approximately 40 times the MRHD (on an AUC basis at a maternal oral dose of 48 mg/kg/day). Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.

Lactation

Risk Summary

There are no data on the presence of Febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Febuxostat and any potential adverse effects on the breastfed child from Febuxostat or from the underlying maternal condition.

Data

Animal Data Orally administered Febuxostat was detected in the milk of lactating rats at up to approximately 7 times the plasma concentration.

Pediatric Use

Safety and effectiveness in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use No dose adjustment is necessary in elderly patients. Of the total number of patients in clinical studies of Febuxostat, 16% were 65 and over, while 4% were 75 and over. Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of Febuxostat following multiple oral doses of Febuxostat in geriatric patients (≥65 years) were similar to those in younger patients (18 to 40 years).

Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of Febuxostat is 40 mg once daily. For patient who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, Febuxostat 80 mg is recommended. For patients with severe renal impairment (Clcr 15 to 29 mL/min), the dose of Febuxostat is limited to 40 mg once daily

Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (ChildPugh Class C); therefore, caution should be exercised in these patients

Secondary Hyperuricemia

No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); Febuxostat is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

Febuxostat was studied in healthy patients in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of Febuxostat was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose.

Pharmacodynamic:

Febuxostat is a potent, non-purine, selective inhibitor of xanthine oxidase, the enzyme that catalyses the conversion of hypoxanthine to xanthine to uric acid. The inhibition of xanthine oxidase decreases the serum concentrations of uric acid.

Pharmacokinetics:

Absorption: About 85% of Febuxostat is quickly absorbed after oral treatment.5 Tmax lasts between one and one and a half hours. Following once-daily oral treatment, Cmax was around 1.6± 0.6 mcg/mL at a dose of 40 mg Febuxostat and 2.6± 1.7 mcg/mL at a dose of 80 mg Febuxostat .

There were no clinically significant changes in the ability of Febuxostat to lower blood uric acid concentrations, however a high-fat meal reduced Cmax by 49% and AUC by 18%.

Distribution: A low to medium volume of distribution is indicated by the apparent steady-state volume of distribution (Vss/F) of Febuxostat , which ranges from 29 to 75 L.

Metabolism:

The relative role of each enzyme isoform in the metabolism of Febuxostat has not yet been fully defined. Febuxostat is metabolized in the liver by UDP-glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) enzymes. The conjugation of Febuxostat , which produces the acyl-glucuronide metabolite, is mediated by the enzymes UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and it accounts for roughly 22-44% of the whole dose's metabolism. The oxidation reaction, which is responsible for 2-8% of the dose's metabolism, is carried out by non-P450 enzymes, CYP1A2, CYP2C8, and CYP2C9. The pharmacologically active metabolites 67M-1, 67M-2, and 67M-4 are created during the oxidation process. Additional glucuronidation and sulfation processes are possible for 67M-1, 67M-2, and 67M-4.8 Human plasma contains hydroxy metabolites, albeit at considerably lower levels than the parent medication.

Excretion:

Febuxostat is eliminated via both hepatic and renal pathways. Following oral administration of 80 mg radiolabeled Febuxostat , approximately 49% of the dose was recovered in the urine. In urine, about 3% of the recovered dose accounted for unchanged Febuxostat , 30% accounted for the acyl glucuronide metabolite, 13% accounted for oxidative metabolites and their conjugates, and 3% accounted for unidentified metabolites.

Approximately 45% of the total dose was recovered in the feces, where 12% of the dose accounted for the unchanged parent drug. About 1% accounted for the acyl glucuronide metabolite, 25% accounted for oxidative metabolites and their conjugates, and 7% accounted for unidentified metabolites.

1. https://www.uptodate.com/contents/Febuxostat -drug-information?search=Febuxostat &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/Febuxostat _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Febuxostat ?type=full&mtype=generic#mechanism-of-action