Furic

Each film-coated tablet contains: Color: Yellow oxide of iron and titanium dioxide I.P.
Febuxostat is a xanthine oxidase inhibitor. The active ingredient is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38.

Pharmacology: Pharmacodynamics: Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, febuxostat resulted in a dose dependent decrease in 24-hr mean serum uric acid concentrations and an increase in 24-hr mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hr mean serum uric acid concentrations was between 40-55% at the exposure levels of 40 mg and 80 mg daily doses.
Effect on Cardiac Repolarization: The effect of febuxostat on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. Febuxostat in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.
Mechanism of Action: Febuxostat, a xanthine oxidase (XO) inhibitor achieves its therapeutic effect by decreasing serum uric acid. Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.
Pharmacokinetics: In healthy subjects, maximum plasma concentrations (C_max) and area under the concentration-time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10-120 mg. There is no accumulation when therapeutic doses are administered every 24 hrs. Febuxostat has an apparent mean terminal elimination half-life (t_½) of approximately 5-8 hrs. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analysis were similar to those estimated in healthy subjects.
Absorption: The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations (C_max) of febuxostat occured between 1-1.5 hrs post-dose. After multiple oral 40 mg and 80 mg once daily doses, C_max is approximately 1.6±0.6 mcg/mL (N=30), and 2.6±1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied.
Distribution: The mean apparent steady-state volume of distribution (V_ss/F) of febuxostat was approximately 50 L (CV-40%). The plasma protein-binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses.
Metabolism: Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes and oxidation via cytochrome P450 (CYP450) enzymes including CYP1A2, 2CB and 2C9, and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formulation of 4 pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%) and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%) and other unknown metabolites (7%). The apparent mean terminal elimination t_½ of febuxostat was approximately 5-8 hrs.
Special Populations: Pediatric Use: The pharmacokinetics of febuxostat in patients under the age of 18 years have not been studied.
Renal Impairment: Following multiple 80 mg doses of febuxostat in healthy subjects with mild [creatinine clearance (CrCl) 50-80 mL/min], moderate (CrCl 30-49 mL/min) or severe renal impairment (CrCl 10-29 mL/min), the C_max of febuxostat did not change relative to subjects with normal renal function (CrCl >80 mL/min). Area under the concentration-time curve (AUC) and t_½ of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among 3 renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean C_max and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).
No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a serum uric acid <6 mg/dL after 2 weeks with 40 mg. Febuxostat 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients. Febuxostat has not been studied in end-stage renal impairment patients who are on dialysis.
Hepatic Impairment: Following multiple doses of febuxostat 80 mg in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increased was observed for both C_max and AUC₂₄ (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients.

For the chronic management of hyperuricemia in patients with gout.

Recommended Dose: For treatment of hyperuricemia in patients with gout. Febuxostat is recommended at 40 or 80 mg once daily. The recommendation starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a serum uric acid <6 mg/dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended.
Febuxostat can be taken without regard to food or antacid use.
Special Populations: No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal impairment. The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a serum uric acid <6 mg/dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended.
No dose adjustment is necessary in patients with mild to moderate hepatic impairment.
Uric Acid Level: Testing for the target serum uric acid level of <6 mg/dL may be performed as early as 2 weeks after initiating febuxostat therapy.
Gout Flares: Gout flares may occur after initiation of febuxostat due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a nonsteroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of febuxostat. Prophylactic therapy may be beneficial for up to 6 months.
If a gout flare occurs during febuxostat treatment, febuxostat need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.

Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine or theophylline.

Gout Flare: After initiation of febuxostat, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits. In order to prevent gout flares when febuxostat is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended.
Cardiovascular Events: In the randomized, controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, nonfatal myocardial infarctions and nonfatal strokes) in patients treated with febuxostat [0.74/100 P-Y (95% Cl 0.36-1.37)] than allopurinol [0.60/100 P-Y (95% Cl 0.16 -1.53 ]. A casual relationship with febuxostat has not been established. Monitor for signs and symtoms of myocardial infarction and stroke.
Liver Enzyme Elevations: During randomized, controlled studies, transaminase elevations >3 times the upper limit of normal (ULN) were observed [aspartate aminotransferase (AST): 2%, 2% and alanine aminotransferase (ALT): 3%, 2% in febuxostat and allopurinol-treated patients, respectively]. No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at eg, 2 and 4 months following initiation of febuxostat and periodically thereafter.
Renal Impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment (CrCl 30-89 mL/min). The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a serum uric acid <6 mg/dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended. There are insufficient data in patients with severe renal impairment (CrCl <30 mL /min); therefore, caution should be exercised in these patients.
Hepatic Impairment: No dose adjustment is necessary in patients with Child-Pugh class A or B. No studies have been conducted in patients with Child-Pugh 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 (eg, 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.
Use in lactation: Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when febuxostat is administered to a nursing woman.
Use in children: Safety and effectiveness in pediatric patients <18 years of age have not been established.
Use in the elderly: No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of febuxostat, 16% were ≥65, while 4% were ≥75. Comparing subjects 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 C_max and AUC₂₄ of febuxostat following multiple oral doses of febuxostat in geriatric subjects (=65 years) were similar to those in younger subjects (18-40 years).

Use in lactation: Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when febuxostat is administered to a nursing woman.

Febuxostat is generally well-tolerated, the most common adverse reaction associated with use of febuxostat are as follows:
Blood and Lymphatic System Disorders: Anemia, idiopathic thrombocytoperic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.
Cardiac Disorders: Angina pectoris, atrial fibrillation/flutter, cardiac murmur, abnormal electrocardiogram, palpitations, sinus bradycardia, tachycardia.
Ear and Labyrinth Disorders: Deafness, tinnitus, vertigo.
Eye Disorders: Blurred vision.
Gastrointestinal Disorders: Abdominal distention and pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, hematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting.
General Disorders and Administration Site Conditions: Asthma, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass pain, thirst.
Hepatobilliary Disorders: Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.
Immune System Disorder: Hypersensitivity.
Infections and Infestations: Herpes zoster.
Procedural Complications: Contusion.
Metabolism and Nutrition Disorders: Anorexia, decreased/increased appetite, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.
Nervous System Disorders: Altered taste, balance disorder, cerebrovascular accident, Guillian-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infraction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.
Psychiatric Disorders: Agitation, anxiety, depression, insomia, irritability, decreased libido, nervousness, panic attack, personality change.
Renal and Urinary Disorders: Hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.
Reproductive System and Breast Changes: Breast pain, erectile dysfunction, gynecomastia.
Respiratory, Thoracic and Mediastinal Disorders: Bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.
Skin and Subcutaneous Tissue Disorders: Alopecia, angioedema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, abnormal hair growth, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, abnormal skin odor, uriticaria.
Vascular Disorders: Flushing, hot flush, hypertension, hypotension.
Laboratory Parameters: Prolonged activated partial thromboplastin and prothrombin time; increased sodium, potassium glucose, amylase, thyroid-stimulating hormone (TSH), mean corpuscular volume (MCV), creatine, creatinine, blood urea, blood urea nitrogen (BUN)/creatinine ratio, creatinine phosphokinase (CPK), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate-specific antigen (PSA), cholesterol, triglycerides and low density lipoprotein (LDL); decreased platelet, neutrophil and lymphocyte count, hematocrit, hemoglobin, red blood cells (RBC), and bicarbonate; abnormal electroencephalogram (EEG) and coagulation test; increased/decreased white blood cells (WBC) and urine output; urinary casts, and urine positive for white blood cells and protein.
Cardiovascular Safety: The incidences of cardiovascular events per 100 patient-years of exposure were: Placebo 0 (95% CI 0-6.16), febuxostat 40 mg 0 (95% CI 0-1.08), febuxostat 80 mg 1.09 (95% CI 0.44-2.24) and allopurinol 0.60 (95% CI 0.16-1.53). In the long-term extension studies, the incidences of adjudicated APTC events were: Febuxostat 80 mg 0.97 (95% CI 0.57-1.56) and allopurinol 0.58 (95% CI 0.02-3.24).

Xanthine Oxidase Substrate Drugs: Febuxostat is an XO inhibitor. Drug interaction studies of febuxostat with drugs that are metabolized by XO (eg, theophylline, mercaptopurine, 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, mercaptopurine or theophylline.
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 subjects, febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, febuxostat may be used concomitantly with these medications.
Effect of Febuxostat on Other Drugs: Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine and Theophylline: Febuxostat is an XO inhibitor. Drug interaction studies that febuxostat with drugs that are metabolizer by XO (eg, theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibitor of XO by febuxostat may cause increased plasma concentrations of these drug leading to toxicity. Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine and theophylline.
Azathioprine and mercaptopurine undergo metabolism via 3 major metabolic pathways, 1 of which is mediated by XO. Although febuxostat drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol (a XO inhibitor) with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because febuxostat is a XO inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity.
Theophylline is a CYP1A2 and XO substrate. Although no febuxostat drug interaction study with theophylline has been conducted, concomitant administration of theophylline with allopurinol, a xanthine oxidase inhibitor at doses=600 mg/day, has been reported to increase theophylline plasma concentrations. Because febuxostat is a xanthine oxidase inhibitor and theophylline is a low therapeutic index drug, febuxostat could inhibit the XO-mediated metabolism of theophylline leading to increased plasma concentrations of theophylline that could induce severe theophylline toxicity.
P450 Substrate Drugs: In vitro studies have shown that febuxostat does not inhibit P450 enzymes CPY1A2, 2C9, 2C19, 2D6 or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between febuxostat and drugs metabolized by these CYP enzymes are unlikely.
Effect of Other Drugs on Febuxostat: Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between febuxostat and a drug that inhibits or induces 1 particular enzyme isoform in general is not expected.
In Vivo Drug Interaction Studies: Colchicine: No dose adjustment is necessary for either febuxostat or colchicine when the 2 drugs are co-administered. Administration of febuxostat (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in C_max and 7% in AUC₂₄ of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with febuxostat (120 mg daily) resulted in <11% change in C_max or AUC of colchicine for both am and pm doses. These changes were not considered clinically significant.
Naproxen: No dose adjustment is necessary for febuxostat or naproxen when the two drugs are co-adminstered. Administration of febuxostat (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in C_max and a 40% increase in AUC of febuxostat. The increase were not considered clinically significant. In addition, there were no significant changes in the C_max or AUC of naproxen (<2%).
Indomethacin: No dose adjustment is necessary for either febuxostat or indomethacin when these 2 drugs are co-administered. Administration of febuxostat (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in C_max or AUC of febuxostat or indomethacin (<7%).
Hydrochlorothiazide: No dose adjustment is necessary for febuxostat when co-administered with hydrochlorothiazide. Administration of febuxostat (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in C_max or AUC of febuxostat (<4%) and serum uric acid concentrations were not substantially affected.
Warfarin: No dose adjustment is necessary for warfarin when co-administered with febuxostat. Administration of febuxostat (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. International normalized ratio (INR) and factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine: Co-administration of drugs that are CYP2D6 substrates (eg, desipramine) with febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in C_max (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).

Store at temperatures not exceeding 30°C.

Hyperuricemia & Gout Preparations

M04AA03 - febuxostat ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.

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