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FEBUXOSTAT

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Febuxostat is a non-purine selective xanthine oxidase inhibitor which acts by decreasing serum uric acid.

Specific Substances

    1) 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid
    2) TMX-67
    3) Molecular formula: C16H16N2O3S
    4) CAS 144060-53-7
    1.2.1) MOLECULAR FORMULA
    1) C16-H16-N2-O3-S (Prod Info ULORIC(R) oral tablets, 2009)

Available Forms Sources

    A) FORMS
    1) Febuxostat is available as 40 mg and 80 mg tablets (Prod Info ULORIC(R) oral tablets, 2013).
    B) USES
    1) Febuxostat is FDA approved for the chronic management of hyperuricemia in patients with gout. It is not recommended in patients with asymptomatic hyperuricemia (Prod Info ULORIC(R) oral tablets, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Non-purine selective xanthine oxidase inhibitor used for chronic management of hyperuricemia in patients with gout.
    B) PHARMACOLOGY: Decreases serum uric acid.
    C) EPIDEMIOLOGY: At the time of this review, there were no reports of human overdose.
    D) WITH THERAPEUTIC USE
    1) COMMON: Liver enzyme elevations, headaches, flushing, dizziness, nausea, arthralgia, and rash. An increase in gout flares has been reported following initiation of febuxostat therapy.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: At the time of this review, there was no overdose information available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Febuxostat is classified as FDA pregnancy category C. There was no teratogenicity reported in animal studies; however, an increased incidence in neonatal mortality and a reduction in neonatal weight gain were reported following febuxostat administration to pregnant rats.

Laboratory Monitoring

    A) Monitor hepatic enzymes in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) In case of febuxostat overdose, treatment is symptomatic and supportive.
    B) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or airway is protected.
    C) ANTIDOTE
    1) None
    D) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding.

Range Of Toxicity

    A) A specific toxic dose has not been established. During clinical trials, there was no evidence of dose-limiting toxicities in healthy subjects following febuxostat administration at doses up to 300 mg/day for seven days.
    B) THERAPEUTIC DOSE: 40 to 80 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Non-purine selective xanthine oxidase inhibitor used for chronic management of hyperuricemia in patients with gout.
    B) PHARMACOLOGY: Decreases serum uric acid.
    C) EPIDEMIOLOGY: At the time of this review, there were no reports of human overdose.
    D) WITH THERAPEUTIC USE
    1) COMMON: Liver enzyme elevations, headaches, flushing, dizziness, nausea, arthralgia, and rash. An increase in gout flares has been reported following initiation of febuxostat therapy.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: At the time of this review, there was no overdose information available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Using pre-defined cardiovascular event and death endpoints from the Anti-Platelet Trialists' Collaborations (APTC) (cardiovascular deaths, non-fatal MI, and non-fatal strokes), more patients who received febuxostat (combined, 0.74 per 100 patient years of exposure (PY) (95% CI, 0.36-1.37); 40 mg/day, zero per 100 PY (95% CI, 0.0-1.08); 80 mg/day, 1.09 per 100 PY (95% CI, 0.44-2.24)) experienced cardiovascular thromboembolic events compared with patients who received allopurinol (0.6 per 100 PY; 95% CI, 0.16-1.53) or placebo (zero per 100 PY; 95% CI, 0.0-6.16) in randomized, phase 3 trials. Additionally, the incidence of cardiovascular thromboembolic events was higher in patients who received febuxostat 80 mg/day (0.97 per 100 PY; 95% CI, 0.57 to 1.56) compared with allopurinol (0.58 per 100 PY; 95% CI, 0.02 to 3.24) in long-term extension studies (Prod Info ULORIC(R) oral tablets, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of 3 randomized, double-blind trials in patients with hyperuricemia and gout, dizziness occurred in more than 1% of patients who received febuxostat 40 mg/day or 80 mg/day. Additionally, all patients in these studies received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis (Prod Info ULORIC(R) oral tablets, 2009).
    b) During a phase I placebo-controlled dose-escalation trial, dizziness was reported in 10 patients who received febuxostat at doses ranging from 40 to 160 mg daily (n=80) (Becker et al, 2004).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a phase I placebo-controlled dose escalation study, headaches were reported in 39 patients receiving febuxostat at doses ranging from 10 to 180 mg daily (32.5%, n=120) as compared with the 7 patients in the placebo group (26.9%, n=26) (Becker et al, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of 3 randomized, double-blind trials in patients with hyperuricemia and gout, nausea was reported in 1.1% and 1.3% of patients who received febuxostat 40 mg/day (n=757) and 80 mg/day (n=1279), respectively, compared with 0.7% and 0.8% of patients who received placebo (n=134) and allopurinol 100 to 300 mg/day (n=1277), respectively. Additionally, all patients in these studies received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis (Prod Info ULORIC(R) oral tablets, 2009).
    b) During a phase I placebo-controlled dose-escalation study, nausea was reported frequently, occurring in 22 patients in the febuxostat group (n=130), following administration of doses ranging from 10 to 240 mg daily, as compared with 1 patient in the placebo group (n=26). Nausea appeared to occur more frequently at the higher dosage amounts, with 5 patients and 4 patients experiencing nausea at 180 mg and 240 mg daily, respectively (Becker et al, 2004).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) During a phase II placebo-controlled randomized trial, diarrhea was reported in 10% (n=40) and 8% (n=38) of patients who received febuxostat at doses of 80 mg/day and 120 mg/day, respectively, as compared with 8% of patients in the placebo group (n=38) (Becker et al, 2005).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of 3 randomized, double-blind trials in patients with hyperuricemia and gout, liver function abnormalities were reported in 6.6% and 4.6% of patients who received febuxostat 40 mg/day (n=757) and 80 mg/day (n=1279), respectively, compared with 0.7% and 4.2% of patients who received placebo (n=134) and allopurinol 100 to 300 mg/day (n=1277), respectively. Additionally, all patients in these studies received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis (Prod Info ULORIC(R) oral tablets, 2009).
    b) During randomized, controlled trials in patients with hyperuricemia and gout, transaminase elevations greater than 3 times the upper limit of normal were observed with febuxostat (AST 2%; ALT 3%) and allopurinol (AST 2%; ALT 2%). No dose-effect relationship was noted (Prod Info ULORIC(R) oral tablets, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of 3 randomized, double-blind trials in patients with hyperuricemia and gout, rash was reported in 0.5% and 1.6% of patients who received febuxostat 40 mg/day (n=757) and 80 mg/day (n=1279), respectively, compared with 0.7% and 1.6% of patients who received placebo (n=134) and allopurinol 100 to 300 mg/day (n=1277), respectively. Additionally, all patients in these studies received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis (Prod Info ULORIC(R) oral tablets, 2009).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) During a phase I placebo-controlled dose escalation study, flushing or a feeling of warmth was reported in 15 patients who received febuxostat at doses ranging from 40 to 240 mg daily (n=100) as compared with 2 patients in the placebo group (n=26) (Becker et al, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of 3 randomized, double-blind trials in patients with hyperuricemia and gout, arthralgia was reported in 1.1% and 0.7% of patients who received febuxostat 40 mg/day (n=757) and 80 mg/day (n=1279), respectively, compared with 0% and 0.7% of patients who received placebo (n=134) and allopurinol 100 to 300 mg/day (n=1277), respectively. Additionally, all patients in these studies received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis (Prod Info ULORIC(R) oral tablets, 2009).
    B) ACUTE GOUT
    1) WITH THERAPEUTIC USE
    a) Gout flares have frequently been reported after initiation of febuxostat. A reduction in serum uric acid levels may result in urate mobilization from tissue deposits. Gout flare prophylaxis with a NSAID or colchicine for up to 6 months may be beneficial (Prod Info ULORIC(R) oral tablets, 2009).
    b) During a phase II placebo-controlled, randomized, double-blind trial, the overall incidence of gout flares appeared to be similar between the febuxostat group at a dose of 40 mg/day (35%; n=37) and the placebo group (37%; n=38); however, the incidence in the febuxostat group increased with increasing doses (43% (n=40) and 55% (n=38) in the 80 mg/day and 120 mg/day doses, respectively) (Becker et al, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Febuxostat is classified as FDA pregnancy category C. There was no teratogenicity reported in animal studies; however, an increased incidence in neonatal mortality and a reduction in neonatal weight gain were reported following febuxostat administration to pregnant rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - There was no evidence of teratogenicity when rats and rabbits were given oral febuxostat doses up to 48 mg/kg (40 and 51 times the human plasma exposure at 80 mg/day based on body surface area, respectively) during organogenesis (Prod Info ULORIC(R) oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Febuxostat is classified by the manufacturer as FDA pregnancy category C (Prod Info ULORIC(R) oral tablets, 2009).
    B) ANIMAL STUDIES
    1) RATS - There was an increase in neonatal mortality and reduction in neonatal body weight gain when pregnant rats were given oral febuxostat at doses up to 48 mg/kg (40 times the human plasma exposure at 80 mg/day) during organogenesis and through lactation (Prod Info ULORIC(R) oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether febuxostat is excreted in human milk (Prod Info ULORIC(R) oral tablets, 2009).
    B) ANIMAL STUDIES
    1) Febuxostat is excreted in the milk of rats (Prod Info ULORIC(R) oral tablets, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - Febuxostat did not appear to have an effect on fertility and reproductive performance of male and female rats following febuxostat oral administration at doses up to 48 mg/kg/day (approximately 35 times the human plasma exposure at 80 mg/day) (Prod Info ULORIC(R) oral tablets, 2009).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS144060-53-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) An increased incidence of transitional cell papilloma and urinary bladder carcinoma have occurred following febuxostat administration at doses of 24 mg/kg (25 times the maximum recommended human dose (MRHD)) and 18.75 mg/kg (12.5 times the MRHD) in male rats and female mice, respectively. The development of urinary bladder carcinoma appears to occur secondary to calculus formation in the kidney and urinary bladder (Prod Info ULORIC(R) oral tablets, 2009).

Genotoxicity

    A) Mutagenicity was positive following a chromosomal aberration assay performed in Chinese hamster lung fibroblast cell lines with and without in vitro metabolic activation; however, a negative result occurred following an in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes and in mouse lymphoma cell lines, and with in vivo tests performed in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells (Prod Info ULORIC(R) oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor hepatic enzymes in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor hepatic enzymes in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of febuxostat overdose, treatment is symptomatic and supportive. There is no antidote available.
    B) MONITORING OF PATIENT
    1) Monitor hepatic enzymes in symptomatic patients.
    2) No specific lab work (CBC, electrolyte, urinalysis) is needed is asymptomatic patients unless otherwise clinically indicated.

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective following overdose due to high protein binding of febuxostat (99.2%).

Range Of Toxicity

Summary

    A) A specific toxic dose has not been established. During clinical trials, there was no evidence of dose-limiting toxicities in healthy subjects following febuxostat administration at doses up to 300 mg/day for seven days.
    B) THERAPEUTIC DOSE: 40 to 80 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) TABLETS
    1) The recommended adult dose is 40 or 80 mg/day (Prod Info ULORIC(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) TABLETS
    1) Safety and efficacy in pediatric patients have not been established (Prod Info ULORIC(R) oral tablets, 2013).

Maximum Tolerated Exposure

    A) During clinical trials, there was no evidence of dose-limiting toxicities in healthy subjects following febuxostat administration at doses up to 300 mg/day for seven days (Prod Info ULORIC(R) oral tablets, 2009).

Workplace Standards

    A) ACGIH TLV Values for CAS144060-53-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS144060-53-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS144060-53-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS144060-53-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Febuxostat is a xanthine oxidase inhibitor which acts by decreasing serum uric acid (Prod Info ULORIC(R) oral tablets, 2013).

Physicochemical

Physical Characteristics

    A) Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide, sparingly soluble in ethanol, and practically insoluble in water (Prod Info ULORIC(R) oral tablets, 2009).

Molecular Weight

    A) 316.38 (Prod Info ULORIC(R) oral tablets, 2009)

References

General Bibliography

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