Xozid

Each film-coated tablet contains: Febuxostat 40 mg.
A white colour round shaped film coated tablet plain on both sides.
Febuxostat is a xanthine oxidase inhibitor. The active ingredient in febuxostat tablet is 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C₁₆H₁₆N₂O₃S.
Febuxostat is a non-hygroscopic, white to off white powder that is freely soluble in N, N-dimethylformamide; soluble in dimethyl sulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 201°C to 208°C.
Febuxostat tablets for oral use contain the active ingredient, febuxostat, and is available in 40 mg dosage strength.

Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production. ATC code: M04AA03.
Pharmacology: Mechanism of action: Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Both steps in the previously mentioned transformations are catalysed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has been shown to potently inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
Pharmacodynamics: Febuxostat inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. By blocking uric acid production, febuxostat decreases serum concentrations of uric acid. Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.
Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, febuxostat resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. There was also a decrease in the total daily urinary uric acid excretion and an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40 to 55% at the exposure levels of 40 mg and 80 mg daily doses.
Effect on Cardiac Repolarization: The effect of febuxostat tablets on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout. Febuxostat tablets in doses up to 300 mg daily (3.75 times the maximum recommended daily dosage), at steady-state, did not demonstrate an effect.
Pharmacokinetic: In healthy subjects, maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours.
Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy patients.
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 of febuxostat occurred between 1- and 1.5-hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax 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.
Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs 51% fasting). Thus, febuxostat may be taken without regard to food.
Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of Febuxostat has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, Febuxostat may be taken without regard to antacid use.
Distribution: The mean apparent steady state volume of distribution (Vss/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 including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 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 formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-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 half-life (t1/2) of febuxostat was approximately 5 to 8 hours.
Renal Impairment: Following multiple doses of 80 mg of febuxostat in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min), or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change, relative to subjects with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to two and four-fold, respectively. However, the percent decrease in serum uric acid concentration for patients 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).
Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of ULORIC, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.
Febuxostat has not been studied in end stage renal impairment patients who are on dialysis.
Hepatic impairment: Following multiple doses of 80 mg of febuxostat in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to patients 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 patients with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients.
Age: There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of febuxostat in elderly as compared to younger healthy subjects.
Gender: Following multiple oral doses of febuxostat, the Cmax and AUC24 were 24 % and 12 % higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender.

XOZID is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult patients with gout in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).
XOZID is not recommended for the treatment of asymptomatic hyperuricemia.

40 mg or 80 mg once daily.
Recommended dose: 40 mg once daily.
The recommended starting dosage of XOZID is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks, the recommended XOZID dosage is 80 mg once daily.
XOZID can be taken without regard to food or antacid use.
Dosage Recommendations in Patients with Renal Impairment: No dose adjustment is necessary when administering XOZID in patients with mild or moderate renal impairment. The recommended dosage of XOZID is limited to 40 mg once daily in patients with severe renal impairment.
Dosage Recommendations in Patients with Hepatic Impairment: 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 less than 6 mg/dL may be performed as early as two weeks after initiating XOZID therapy.
Recommended Prophylaxis for Gout Flares: Gout flares may occur after initiation of XOZID due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of XOZID. Prophylactic therapy may be beneficial for up to six months.
If a gout flare occurs during XOZID treatment, XOZID need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.
Children (<18 years old): The safety and efficacy of XOZID have not been established in pediatric patients.
Male and Female Patients: No dose adjustment is necessary based on gender.
Method of administration: Oral use.
XOZID should be taken by mouth and can be taken with or without food.

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

XOZID is contraindicated in patients being treated with azathioprine or mercaptopurine.

Cardiovascular Death: In a cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035), gout patients with established CV disease treated with febuxostat tablets had a higher rate of CV death compared to those treated with allopurinol. The CV outcomes study in patients with gout (CARES) was a randomized, double-blinded, allopurinol-controlled, non-inferiority study conducted to evaluate the risk of major adverse cardiovascular events (MACE) in patients with gout who were treated with febuxostat tablets. The study enrolled patients who had a history of major CV disease, cerebrovascular disease or diabetes mellitus with micro-and/or macrovascular disease. The primary endpoint was the time to first occurrence of MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. Results showed that febuxostat was non-inferior to allopurinol for the primary endpoint of MACE [Hazard Ratio: 1.03, 95% Confidence Interval (CI): 0.89, 1.21]. However, there was a significant increase in CV deaths in patients treated with febuxostat (134 [1.5 per 100 patient-years]) compared to patients treated with allopurinol (100 [1.1 per 100 patient-years]) [Hazard Ratio: 1.34, 95% CI: 1.03, 1.73]. Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat tablets group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). Febuxostat were similar to allopurinol for nonfatal MI, nonfatal stroke and unstable angina with urgent coronary revascularization. Because of the increased risk of CV death, XOZID should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. Consider the risks and benefits of XOZID when deciding to prescribe or continue patients on XOZID. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Physicians and patients should remain alert for the development of adverse CV event signs and symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

Gout Flares: 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 tablets are initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended.
Hepatic Failure: There have been post-marketing cases of fatal and nonfatal hepatic failure in patients taking febuxostat, although the reports contain insufficient information necessary to establish the probable cause. Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating febuxostat tablets.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), febuxostat tablets treatment should be interrupted and investigation done to establish the probable cause. Febuxostat tablets should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on febuxostat tablets. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with febuxostat tablets can be used with caution.
Serious Skin and Hypersensitivity Reactions: Post-marketing reports: Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported in patients taking febuxostat tablets. Discontinue febuxostat if serious skin reactions are suspected. Many of these patients had reported previous similar skin reactions to allopurinol. Febuxostat tablets should be used with caution in these patients.
Secondary Hyperuricemia: Febuxostat tablets are 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.
Effects on Ability to Drive and Use Machines: Somnolence, dizziness, paresthesia and blurred vision have been reported with the use of febuxostat. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that febuxostat does not adversely affect performance.

Pregnancy: Limited available data with febuxostat tablets 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.
Lactation: It is not known if febuxostat is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when administering febuxostat to breastfeeding women.

Most Common Adverse Reactions: The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities.
Dizziness and diarrhea are also common adverse reactions.
Less Common Adverse Reactions: Blood and Lymphatic System Disorders: Anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.
Cardiac Disorders: Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.
Ear and Labyrinth Disorders: Deafness, tinnitus, vertigo.
Eye Disorders: Blurred vision.
Gastrointestinal Disorders: Abdominal distention, abdominal 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: Asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.
Hepatobiliary Disorders: Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.
Immune System Disorder: Hypersensitivity.
Infections and Infestations: Herpes zoster.
Procedural Complications: Contusion.
Metabolism and Nutrition Disorders: Anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.
Musculoskeletal and Connective Tissue Disorders: Arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.
Nervous System Disorders: Altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.
Psychiatric Disorders: Agitation, anxiety, depression, insomnia, irritability, libido decreased, 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, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria.
Vascular Disorders: Flushing, hot flush, hypertension, hypotension.
Laboratory Tests: Activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.

Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine and Theophylline: Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity.
Febuxostat are contraindicated in patients being treated with azathioprine or mercaptopurine.
Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because febuxostat is a xanthine oxidase 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: No dose adjustment is necessary for theophylline when co-administered with febuxostat. The study demonstrated an approximately 400-fold increase in the amount of 1-¬methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by febuxostat. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to co-administer febuxostat tablets and theophylline.
P450 Substrate Drugs: In vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. Pharmacokinetic interactions between febuxostat and drugs metabolized by these CYP enzymes are unlikely.
Colchicine: No dose adjustment is necessary for either febuxostat or colchicine when the two drugs are co-administered.
Naproxen: No dose adjustment is necessary for febuxostat or naproxen when the two drugs are co-administered.
Indomethacin: No dose adjustment is necessary for either febuxostat or indomethacin when these two drugs are co-administered.
Hydrochlorothiazide: No dose adjustment is necessary for febuxostat when co-administered with hydrochlorothiazide.
Warfarin: No dose adjustment is necessary for warfarin when co-administered with febuxostat.
Desipramine: Co-administration of desipramine (CYP2D6 substrate) with febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo.

Store at temperatures not exceeding 30°C.
Protect from light.

Hyperuricemia & Gout Preparations

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

Rx