Febustin

Febuxostat.

An off-yellow to yellow, capsule shaped film-coated tablet, engraved with "980" on one surface and "S D" on the other side having a splitting line between S and D.
Each film coated tablet contains: Febuxostat 80 mg.

Pharmacology: Pharmacodynamics: Febuxostat is a non-purine-selective inhibitor of xanthine oxidase. It works by non-competitively blocking the molybdenum pterin center which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat inhibits both oxidized as well as reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site.
Pharmacokinetics: Febuxostat has an apparent mean terminal elimination half-life (t½) of approximately 5 to 8 hours. Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours post-dose. 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. Febuxostat is eliminated by both hepatic and renal pathways.

Treatment of hyperuricemia in patients with gout, not recommended for treatment of asymptomatic hyperuricemia.

The recommended oral dose of Febuxostat is 40 mg or 80 mg once daily without regard to food. The recommended starting dose of Febuxostat is 40 mg once daily. If serum uric acid is > 6 mg/dL (357 μmol/L) after 2-4 weeks, Febuxostat 80 mg once daily is recommended. Febuxostat works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to decrease and maintain serum uric acid below 6.0 mg/dL (357 μmol/L). Gout flare prophylaxis of at least 6 months is recommended. No dose adjustment is required in the elderly.
Renal & Hepatic Impairment: The efficacy and safety have not been fully evaluated in patients with severe renal impairment and severe hepatic impairment. No dose adjustment is necessary in patients with mild or moderate renal impairment and mild hepatic impairment. Limited information is available in patients with moderate hepatic impairment.
Pediatric population: Safety and the efficacy of Febuxostat in children aged below the age of 18 years have not been established. No data are available.

Febuxostat was studied in healthy subjects 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.

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

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 colchicine studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with Febuxostat (0.74 per 100 P-Y [95% Confidence Interval (CI) 0.36-1.37]) than allopurinol (0.60 per 100 P-Y [95% CI 0.16-1.53]). A causal relationship with Febuxostat has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.
Hepatic Effects: There have been post marketing reports of fatal and non-fatal hepatic failure in patients taking Febuxostat, although the reports contain insufficient information necessary to establish the probable cause. 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. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Febuxostat can be used with caution.
Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with Febuxostat, including over-the-counter medications.
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.

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Febuxostat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Breastfeeding: It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breastfeeding.

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of Febuxostat 40 mg, 1.2% of Febuxostat 80 mg. Nausea, arthralgia and rash were also reported. Dizziness was reported in more than 1% of Febuxostat-treated subjects.
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, abnormal ECG, 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, haematemesis, 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, abnormal skin odor, urticaria.
Vascular Disorders: Flushing, hot flush, hypertension, hypotension.
Laboratory Parameters: 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.
Hepatobiliary Disorders: Hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.
Immune System Disorders: Anaphylaxis, anaphylactic reaction.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.
Psychiatric Disorders: Psychotic behavior including aggressive thoughts.
Renal and Urinary Disorders: Tubulointerstitial nephritis.
Skin and Subcutaneous Tissue Disorders: Generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions.

Theophylline: Febuxostat altered the metabolism of theophylline (a substrate of XO) in humans. Therefore, use with caution when coadministering Febuxostat with theophylline.
Azathioprine or Mercaptopurine: 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.
Other Drug Interaction: Febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, Febuxostat may be used concomitantly with these medications.

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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