febuxostat (Rx)

1-10%

Liver function abnormalities (4.6-6.6%)

Rash (0.5-1.6%)

Nausea (1.1-1.3%)

Arthralgia (0.7-1.1%)

>1%

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: Vision blurred

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 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 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 increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein

Postmarketing Reports

Immunologic: Anaphylaxis, anaphylactic reaction

Musculoskeletal: Rhabdomyolysis

Hepatobiliary: Hepatic failure (some fatal), jaundice, serious cases of abnormal LFT results, liver disorders

Psychiatric: Psychotic behavior, including aggressive thoughts

Renal and urinary: Tubulointerstitial nephritis

Dermatologic: Generalized rash, Stevens-Johnson syndrome, hypersensitivity skin reactions, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN)

Blood and lymphatic system disorders: Agranulocytosis, eosinophilia

Contraindications

Coadministration with azathioprine or mercaptopurine

Cautions

After initiation, an increase in gout flares is frequently observed; increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits

Not tested for secondary hyperuricemia; not recommended in patients whose rate of urate formation is greatly increased (eg, malignant disease and its treatment, Lesch-Nyhan syndrome)

Postmarketing reports of serious skin and hypersensitivity reactions reported; discontinue if serious skin reactions are suspected; caution in patients who reported previous similar skin reactions to allopurinol

Postmarketing reports of fatal and nonfatal hepatic failure; may increase liver enzyme activity; obtain LFTs at baseline, and do not initiate if alanine aminotransferase is 3x ULN with total bilirubin >2x ULN

Serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) reported; discontinue therapy if serious skin reactions suspected; many patients reported previous similar skin reactions to allopurinol; use caution in these patients

Cardiovascular death

• A cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035) in patients with a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease showed that febuxostat had a significantly higher incidence of CV deaths compared with allopurinol
• Most common cause of adjudicated CV deaths in the febuxostat group was sudden cardiac death compared with the allopurinol group; similar results to allopurinol were observed for nonfatal MI, nonfatal stroke, and unstable angina with urgent coronary revascularization (see Black Box Warnings)
• Because of increased risk of CV death, drug 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

Drug interaction overview

• Xanthine oxidase substrates

  • Febuxostat inhibits xanthine oxidase (XO)
  • Based on a drug interaction study in healthy patients, febuxostat altered the metabolism of theophylline in humans; caution if coadministered
  • Other drugs that are metabolized by XO (eg, mercaptopurine and azathioprine) have not been conducted; XO inhibition may increase plasma concentrations of these drugs leading to toxicity (see Contraindications)

Pregnancy

Limited available data in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes

Animal data

• No adverse developmental effects 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 observed in a pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure ~11 times the MRHD

Lactation

There are no data on presence of febuxostat in human milk, effects on breastfed infant, or on milk production; drug is present in rat milk

Consider the developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Xanthine oxidase inhibitor; inhibits conversion of hypoxanthine to xanthine to uric acid; at therapeutic dosages, decreases production of uric acid without disrupting synthesis of vital purines and pyrimidines

Absorption

Absorption: 49%

Peak plasma concentration: ~1.6 mcg/mL (40-mg dose); 2.6 mcg/mL (80-mg dose)

Peak plasma time: 1-1.5 hr

Following multiple 80 mg qDay doses with a high fat meal, peak plasma concentration decreased by 49% and AUC decreased by 18%

Distribution

Protein bound: 99.2%

Vd: 50 L

Metabolism

Metabolized by UGT1A1, UGT1A3, UGT1A9, and UGT2B7; oxidized by CYP1A2, CYP2C8, and CYP2C9; also metabolized by non-CYP450 enzymes

Elimination

Half-life: 5-8 hr

Excretion: Feces (45%; 12% unchanged; 25% their conjugates; 7% other unknown metabolites), urine (49%; 3% unchanged)

Oral Administration

Take without regard to food or antacid use

Storage

Protect from light

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)