Febuxostat is an inhibitor of the enzyme xanthine oxidase and is FDA-approved for the chronic management of hyperuricemia in patients diagnosed with gout.[1][2] Due to the finding of an increased risk of death with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol.[3]

Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase, which is involved in purine catabolism.[4] The xanthine oxidase enzyme catalyzes two reactions that ultimately generate uric acid from hypoxanthine. Febuxostat is a potent, selective inhibitor of xanthine oxidase, forming a stable complex with both the reduced and oxidized form of the enzyme, thereby inhibiting its function. Treatment with febuxostat leads to lower serum uric acid levels in animals and humans.[5] The therapeutic effect of febuxostat has as its basis the ability to lower serum uric acid levels in patients with hyperuricemia, defined by the uric acid serum concentration that exceeds the solubility of uric acid (approximately 7 mg/dL).[6][7] The chemical structure of febuxostat does not resemble either purines or pyrimidine structures, and it does not appear to inhibit other enzymes in the nucleotide catabolic pathways.[8]

Febuxostat is administered orally with an initial dose of 40 mg per day.[9]  Its administration can be without regard to food or antacid use.  The clinician can increase the dose of febuxostat 80 mg per day in patients that do not achieve a serum uric acid level of less than 6 mg/dL after two weeks of treatment with 40 mg so long as the patient does not have severe renal impairment (defined as a clearance of 15 to 29 mL/min).   Febuxostat is available in both 40 mg and 80 mg tablet formulations, and estimates are that greater than 49% of the dose is absorbed when taken orally.[9] Upon initiating treatment with febuxostat, gout flares may occur.[10]  Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months.[11][12]

Common adverse drug effects (greater than 1% of the febuxostat-treated group based on multiple randomized, controlled clinical studies ranging in length from 6 to 12 months) [10]:

• Liver function abnormalities, dizziness, arthralgia, nausea, and rash.

Less common adverse effects listed by organ system (less than 1% of the febuxostat-treated group based on multiple randomized, controlled clinical studies) [13][14]:

• Blood and Lymphatic System: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia
• Cardiac: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia
• Ear and Eye:  deafness, tinnitus, vertigo, blurred vision
• Gastrointestinal: 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
• Hepatobiliary: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly
• Immune: hypersensitivity, drug reaction with eosinophilia
• Infections: herpes zoster
• Metabolism-related: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased
• Musculoskeletal: arthritis, joint stiffness, joint swelling, muscle spasms, twitching, weakness, musculoskeletal pain/stiffness, myalgia
• Nervous System: altered taste, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor
• Psychiatric: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.
• Renal: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence
• Reproductive: breast pain, erectile dysfunction, gynecomastia
• Respiratory: 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: alopecia, angioedema, 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: flushing, hot flush, hypertension, hypotension
• Altered 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

Warnings and Precautions

Gout Flares

An increase in gout flares frequently occurs after the initiation of febuxostat.[10] This increase is likely due to the reduction of serum uric acid levels, which mobilizes the urate crystals in tissue deposits. Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months.  Febuxostat should not be used to treat secondary hyperuricemia or asymptomatic hyperuricemia. 

Cardiovascular Events

In randomized controlled studies, there was a higher rate of cardiovascular deaths as well as non-fatal myocardial infarctions and strokes in the febuxostat-treated group compared with the allopurinol-treated group.[3] Based on this new information, the FDA is limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol, and there is now a boxed warning of cardiovascular death.  

Hepatic Effects

In randomized controlled studies, liver function abnormalities were reported, including transaminase elevations greater than three times the upper limit of normal.[15][10] Although this effect has not demonstrated that it is clinically significant, recommendations include a liver test panel, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and total bilirubin, prior to initiating febuxostat treatment as a baseline measurement as well as periodically during treatment and in patients experiencing any signs of hepatic injury. 

Febuxostat contraindications include patients that are treated with azathioprine or mercaptopurine since xanthine oxidase inhibition enhances serious toxicity such as myelosuppression.[9]