Continuing Education Activity

An educational discussion of managing hyperuricemia conditions, including gout, is essential for healthcare providers. This session addresses the indications, mechanism of action, administration guidelines, adverse event profile, contraindications, and monitoring strategies for febuxostat, a xanthine oxidase inhibitor. Given recent FDA recommendations regarding cardiovascular risks associated with febuxostat compared to allopurinol, understanding when to opt for febuxostat over allopurinol is crucial. Furthermore, understanding febuxostat's pharmacology empowers healthcare professionals to tailor treatment plans to individual patient needs, optimizing therapeutic efficacy while minimizing potential adverse effects. By integrating dosing considerations, pharmacokinetic insights, toxicity profiles, and pertinent drug interactions, healthcare providers can make informed decisions to enhance patient care outcomes in managing gout and related conditions.

This activity facilitates an in-depth exploration of febuxostat's role within the therapeutic landscape, fostering a holistic understanding of its clinical utility and challenges. This session enhances a clinician's ability to navigate febuxostat therapy effectively by equipping healthcare professionals with the requisite knowledge and skills. Through proactive monitoring and thoughtful consideration of patient-specific factors, healthcare providers can mitigate risks and maximize benefits associated with febuxostat treatment, ultimately improving outcomes for individuals with gout or hyperuricemia.

Objectives:

• Identify the mechanism of action of febuxostat.

• Evaluate the adverse effects of febuxostat.

• Determine the appropriate monitoring strategies for patients taking febuxostat.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from febuxostat therapy.

Indications

Febuxostat received approval from the Food and Drug Administration (FDA) in 2009.[1]

FDA-Approved Indications

Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase and is FDA-approved for the chronic management of hyperuricemia in patients diagnosed with gout.[2][3] 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 effective or who experience severe adverse effects with allopurinol. Febuxostat is not approved for treating asymptomatic hyperuricemia.[4] 

Off-Label Uses

Febuxostat demonstrates efficacy in hyperuricemia as part of tumor lysis syndrome, especially when allopurinol is contraindicated.[5][6]

Mechanism of Action

Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase, which is involved in purine catabolism.[7] The xanthine oxidase enzyme catalyzes 2 reactions that ultimately generate uric acid from hypoxanthine. Febuxostat forms a stable complex with both the reduced and oxidized form of the enzyme, inhibiting its function. Treatment with febuxostat lowers serum uric acid levels in animals and humans.[8] The therapeutic effect of febuxostat involves lowering 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).[9][10] 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.[11]

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.[12] 

Distribution: The steady-state volume of distribution of febuxostat is approximately 50 L. Febuxostat has high plasma protein binding (PPB) and binds primarily to albumin. The PPB of febuxostat is approximately 99%.[13]

Metabolism: Febuxostat is 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.[14]

Excretion: Febuxostat's apparent mean elimination half-life (t_1/2) 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%.[15]

Administration

Available Dosage Forms and Strengths 

Febuxostat is available in both 40 mg and 80 mg tablet formulations. 

Adult Dosage

Febuxostat is administered orally with an initial dose of 40 mg/d.[12] This drug can be administered without regard to food. The clinician can increase the dose of febuxostat to 80 mg daily in patients who do not achieve a serum uric acid level of less than 6 mg/dL after 2 weeks of treatment with 40 mg. Upon initiating treatment with febuxostat, gout flares may occur.[16] 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 6 months.[17][18] The safety and efficacy of febuxostat in the pediatric age group have not been demonstrated. The 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.[19]

Specific Patient Populations

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). Use with extreme caution.

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 recommend febuxostat for patients with moderate to severe CKD.[19]

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.[20]

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 administering a febuxostat to a nursing mother. An alternative agent, allopurinol, should be considered during lactation.[21]

Pediatric patients: Febuxostat's safety and efficacy have not been confirmed in the pediatric population.

Older patients: No dose adjustment is required in older patients. While there were no considerable variations in safety or efficacy across different age groups, some older individuals might exhibit increased sensitivity to the febuxostat.

Secondary hyperuricemia: Febuxostat is not FDA-approved for individuals with markedly increased urate formation rates, such as those with malignant disease or undergoing treatment and those with Lesch-Nyhan syndrome. In rare instances, increased urine xanthine levels may lead to urinary tract deposition.

Adverse Effects

Liver function abnormalities, dizziness, arthralgia, nausea, and rash have been known to occur in more than 1% of patients, based on multiple randomized, controlled clinical studies ranging in length from 6 to 12 months.[16]

Less common adverse effects are listed below by organ system. Based on multiple randomized controlled clinical trials, these occur in less than 1% of the febuxostat-treated group.[22][23]

• 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 decrease/increase
• 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, abnormal hair growth, 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 include:
  • Prolonged activated partial thromboplastin and prothrombin time
  • Abnormal EEG
  • Elevated
    • Creatinine
    • Sodium
    • Glucose
    • Cholesterol
    • Triglycerides
    • Amylase
    • Potassium
    • TSH
    • MCV
    • BUN/Cr
    • Creatine phosphokinase (CPK)
    • LDH
    • PSA
    • Low-density lipoprotein (LDL)
  • Reduced
    • Bicarbonate
    • Platelet count
    • RBC
    • Hematocrit & hemoglobin
    • Lymphocyte count
    • Neutrophil count
  • Urinary casts
  • Urine positive for white blood cells and protein

Drug-Drug Interactions

Antacids: 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.[13]

Theophylline: The administration of febuxostat with theophylline increases its concentration and absorption. 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.[24]

Repaglinide: Concurrent administration of repaglinide with febuxostat can cause severe hypoglycemia. Febuxostat inhibits CYP2C8, resulting in delayed elimination and increased concentration of repaglinide.[25]

Methotrexate: Febuxostat inhibits the breast cancer resistance protein (BCRP), and concomitant administration of febuxostat increases methotrexate-induced hepatotoxicity by inhibiting hepatic BCRP.[14]

Rosuvastatin: Rosuvastatin is a BCRP substrate; febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine.[26]

Contraindications

Febuxostat contraindications include patients treated with azathioprine or mercaptopurine. Xanthine oxidase inhibition increases concentrations of azathioprine and mercaptopurine, resulting in serious toxicity that can cause myelosuppression.[12] Febuxostat's formulation contains lactose as an excipient. Use with caution for patients who are lactose-intolerant.[27]

Box 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.[4] In patients using febuxostat with a previous history of cardiovascular disease (CVD) or encountering a new cardiovascular event, the American College of Rheumatology (ACR) suggests considering a transition to another urate-lowering therapy (ULT) agent.[19]

Warnings and Precautions

Gout Flares: An increase in gout flares frequently occurs after initiating febuxostat.[16] 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 6 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 3 times the normal upper limit.[28][16] Although this effect has not been demonstrated to be clinically significant, recommendations include a baseline liver test panel (including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin) before initiating febuxostat treatment. A liver panel is also recommended periodically during treatment and in patients experiencing any signs of hepatic injury.[29] The case report highlights 2 instances of febuxostat-induced acute liver injury in patients who are hospitalized with heart failure. While rare, this form of drug-induced liver injury presents challenges for clinicians. Both patients had heart failure with reduced ejection fraction, prompting further investigation into whether heart failure may be a risk factor for febuxostat-related liver injury. This emphasizes the importance of regular liver function monitoring, especially in patients with heart failure, during febuxostat treatment.[30]

Severe cutaneous adverse reaction (SCAR): Severe hypersensitivity reactions, including 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.[31][32]

Monitoring

Patient monitoring should include signs and symptoms of MI, stroke, and liver injury, as described in the warnings and precautions section.[4] Patients with impaired renal function appear to tolerate febuxostat well, and dose adjustments are only required for severe renal impairment. Febuxostat may delay the progression of chronic kidney disease.[33][11][34]

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. Per ACR 2020 guidelines, serum urate levels should be monitored, and the dose of febuxostat should be adjusted to maintain the serum urate target of <6 mg/dL.[19]

A lower serum urate target (<5 mg/dL) helps promote the rapid dissolution of crystals. Recommendations for patients with severe gout include reducing serum urate level until total crystal dissolution and resolution of gout, according to EULAR (European Alliance of Associations for Rheumatology) guidelines.[10]

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 7 days without evidence of dose-limiting toxicities. Patients who overdose should be given symptomatic and supportive care.[7]

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.[35] 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.[4]

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.[36] 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. Nurses can assess treatment efficacy and patient compliance, look for adverse drug reactions to medication, and report 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, specialists including rheumatologists, specialty-trained nurses, and pharmacists, 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.[16] 

The relationship between febuxostat and cardiovascular disease remains controversial due to challenges in comparing trials and heterogeneous outcomes. A systematic review of 20 randomized controlled trials found reassuring cardiovascular safety outcomes in patients with gout who are treated with febuxostat compared to allopurinol. However, further research is needed to conclude patients with severe cardiovascular disease.[37]

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.[38][19][35]