Continuing Education Activity

Febuxostat is a medication used to manage and treat hyperuricemia and gout. It is in a class of drugs known as xanthine oxidase inhibitors. Due to an increased risk of cardiovascular mortality with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for whom allopurinol is not efficacious or who experience severe adverse effects with allopurinol. This activity will describe the indications, mechanism of action, administration, adverse event profile, contraindications, and monitoring of febuxostat. It also highlights other key factors of dosing, pharmacokinetics, toxicity, and relevant interactions pertinent for members of the interprofessional team in the management of patients with gout and related conditions.

Objectives:

• Identify the mechanism of action of febuxostat.
• Describe the adverse effects of febuxostat.
• Outline the appropriate monitoring for patients taking febuxostat.
• Summarize interprofessional team strategies for improving care coordination and communication to advance febuxostat and improve outcomes.

Indications

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 an increased risk of cardiovascular mortality with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for whom allopurinol is not efficacious or who experience severe adverse effects with allopurinol. It is important to recognize that febuxostat is not approved for treating asymptomatic hyperuricemia.[3]

Mechanism of Action

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]

Pharmacokinetics

• Absorption: Febuxostat is rapidly absorbed with peak plasma concentrations(Cmax) attained after 1 to 1.5 hours of oral administration. Approximately 49% of the orally administered dose of febuxostat is absorbed orally.[9] 

• Distribution: The steady-state volume of distribution of febuxostat is approximately 50 liters. Febuxostat has high plasma protein binding(PPB) and binds primarily to albumin. The PPB of febuxostat is approximately 99%.[10]

• Metabolism: Febuxostat is extensively metabolized by conjugation via UGT( uridine diphosphate glucuronosyltransferase) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7. Febuxostat is metabolized by CYPs1A2, CYP2C8, CYP2C9, and non-CYP enzymes. Febuxostat also inhibits breast cancer resistance protein (BCRP) activity.[11]

• Elimination: The apparent mean elimination half-life (t1/2) of febuxostat is approximately 5 to 8 hours. Metabolites of febuxostat are eliminated by both hepatic and renal routes. The percentage of febuxostat excreted unchanged in the urine is less than 5%.[12]

Administration

 Febuxostat is available in both 40 mg and 80 mg tablet formulations. Febuxostat is administered orally with an initial dose of 40 mg per day.[9] Its administration can be without regard to food. The clinician can increase the dose of febuxostat to 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. Upon initiating treatment with febuxostat, gout flares may occur.[13] 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.[14][15] The safety and efficacy of febuxostat in the pediatric age group have not been demonstrated. American College of Rheumatology 2020 guidelines state that urate-lowering therapy (with febuxostat/allopurinol) is conditionally suggested for patients with moderate-to-severe CKD (stage ≥3), urolithiasis or serum uric acid concentration >9 mg/dl.[16]

Use in Specific Patient Populations

• Patients with Hepatic Impairment: No dose adjustment is necessary for mild (Child-Pugh Class A) or moderate hepatic impairment(Child-Pugh Class B) in patients receiving febuxostat therapy. No clinical studies have been performed in patients with severe hepatic impairment (Child-Pugh Class C), hence use with extreme caution.

• Patients with Renal Impairment: No dosage adjustment of febuxostat is necessary for mild or moderate renal impairment (CrCl 30 to 89 mL/min). In patients with severe renal impairment (CrCl< 30 mL/min), the dose of febuxostat tablets is reduced to 40 mg once daily. American College of Rheumatology guidelines recommends febuxostat for patients with moderate to severe CKD.[16]

• Pregnancy Considerations: Gout is rare in reproductive-age females due to the uricosuric effects of estrogen. In pregnant women, gout is quite uncommon. In preclinical studies, neonatal mortality has been observed at approximately 40 times the MRHD(maximum recommended human dose). Use with caution. Pharmacological management should be based on risk-benefit assessments.[17]

• Breastfeeding Considerations: No clinical information is available on using febuxostat during lactation. Hypothetically, febuxostat is more than 99% bound to plasma proteins; consequently, the concentration of febuxostat in maternal milk is likely to be low. Additionally, the oral bioavailability of febuxostat is only about 50%, so the amount an infant receives systemically is expected to be very small. However, febuxostat is present in rat milk. Hence the risk-benefit analysis is crucial before febuxostat is administered to a nursing mother. An alternative agent, allopurinol, should be considered during lactation.[18]

Adverse Effects

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)[13]:

• 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 trials.)[19][20] These include the following:

• Blood and Lymphatic System: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia
• Cardiac: angina pectoris, atrial fibrillation/flutter, cardiac murmur, EKG 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
• Immune: hypersensitivity reactions
• 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, decreased libido, 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 & hemoglobin decreased, MCV increased, RBC decreased, creatinine & blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, LDH increased, PSA increased, lymphocyte count decreased, neutrophil count decreased, low-density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein

Boxed Warning

• Cardiovascular Events: In randomized controlled studies, there was a higher rate of cardiovascular deaths and non-fatal myocardial infarctions and strokes in the febuxostat-treated group compared with the allopurinol-treated group. 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 adverse effects with allopurinol, and there is now a boxed warning of cardiovascular death.[3]

Warnings and Precautions

• Gout Flares: An increase in gout flares frequently occurs after the initiation of febuxostat.[13] This increase is likely due to reduced serum uric acid levels, which mobilize 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.

• Hepatotoxicity: In randomized controlled studies, liver function abnormalities were reported, including transaminase elevations greater than three times the upper limit of normal.[21][13] 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, before initiating febuxostat treatment as a baseline measurement as well as periodically during treatment and in patients experiencing any signs of hepatic injury.[22]

• Severe cutaneous adverse reaction (SCAR): Severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia & systemic symptoms (DRESS) have been attributed to febuxostat. Discontinue febuxostat if severe skin reactions are suspected and initiate prompt treatment.[23][24]

Drug-Drug Interactions

• Antacids such as magnesium hydroxide and aluminum hydroxide delay absorption by approximately 1 hour, but the extent of absorption is not affected. Therefore, febuxostat may be administered without regard to antacid use.[10]

• Administration of febuxostat with theophylline increases the concentration and absorption of theophylline. These differences were not deemed statistically significant in the study. However, there was a 400-fold increase in 1-methylxanthine (a metabolite of theophylline) excreted in urine due to xanthine oxidase inhibition by febuxostat. The safety of chronic long-term exposure to 1-methylxanthine has not been assessed. Caution is advised when febuxostat is administered with theophylline.[25]

• Concurrent administration of repaglinide with febuxostat can cause severe hypoglycemia. Febuxostat inhibits CYP2C8, resulting in delayed elimination and increased concentration of repaglinide.[26]

• Febuxostat inhibits the breast cancer resistance protein (BCRP), and concomitant administration of febuxostat increases methotrexate-induced hepatotoxicity by inhibiting hepatic BCRP.[11]

• Rosuvastatin is a BCRP substrate; febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine.[27]

Contraindications

Febuxostat contraindications include patients treated with azathioprine or mercaptopurine. Xanthine oxidase inhibition increases concentrations of azathioprine and mercaptopurine, resulting in serious toxicity such as myelosuppression.[9] The formulation of febuxostat contains lactose as an excipient. Use with caution in lactose intolerant patients.[28]

Monitoring

Patient monitoring should include signs and symptoms of MI, stroke, and liver injury, as described above in the warnings and precautions section.[3] Patients with impaired renal function appear to tolerate febuxostat well, and no dose adjustments are necessary. Febuxostat may delay the progression of chronic kidney disease.[29][8][30]

A treat-to-target management strategy includes urate-lowering therapy (febuxostat/allopurinol) dosing directed by serial serum urate measurements to accomplish a target serum urate is recommended over a fixed-dose drug strategy. Consequently, monitor serum urate levels and adjust the dose of febuxostat to maintain the serum urate target of <6 mg/dl. (ACR 2020 guidelines).[16]

A lower serum urate target (<5 mg/dL) helps promote the rapid dissolution of crystals. It is suggested for patients with severe gout until total crystal dissolution and resolution of gout, according to EULAR (European Alliance of Associations for Rheumatology) guidelines.[7]

Toxicity

There is no known human toxicity with febuxostat treatment. Febuxostat was evaluated in healthy patients in doses of up to 300 mg daily for seven days without evidence of dose-limiting toxicities. Patients should be given symptomatic and supportive care in overdose.[4]

Enhancing Healthcare Team Outcomes

Gout is the most common form of inflammatory arthritis, characterized by painful episodes of arthritis; gout results in substantial morbidity and disability.[31] Interprofessional communication and teamwork are necessary for the administration and monitoring of febuxostat for effective management of gout. With the recent revisions of the FDA guidelines, physicians, nurses, and pharmacists must be particularly aware of current prescribing information.[3]

As of early 2019, febuxostat is now recommended only for patients with gout who cannot tolerate allopurinol or if allopurinol lacks efficacy; this is particularly pertinent in patients with cardiovascular disease. Pharmacists should familiarize themselves with the patient's gout medication history and verify that febuxostat is appropriate. They can also confirm dosing and perform medication reconciliation, alerting the patient's clinician to any concerns or potential interactions. Nursing will be able to assess treatment efficacy and patient compliance and look for medication side effects, reporting any concerns to the treating physician. All healthcare providers should educate patients regarding lifestyle modifications such as limiting alcohol, purine, and high fructose corn syrup intake. The interprofessional healthcare team, consisting of clinicians (MD, DO, NP, PA), specialists including rheumatologists, specialty-trained nursing, and pharmacy, must work together to ensure that proper dosing and dispensing protocols are in place and be aware of the possibility of adverse effects, which includes informing the patient of the increased risk of gout flares upon treatment with febuxostat and treating the flares appropriately.[13] 

Delivering an augmented protocol of urate-lowering therapy by a team of clinicians, pharmacists, and nursing-led interventions to improve the treat-to-target strategy that includes patient education and shared decision-making can optimize the patient outcomes related to febuxostat therapy.[16][31] [Level 5]