Date of approval.
Date of revision.
Febuxostat Tablets Instruction (Pharmacological Part)
[Drug Name].
Generic name: Febuxostat Tablets
English name：Febuxostat Tablets
Hanyu Pinyin: Feibusita Pian
Ingredients
The active ingredient of this product is febuxostat.
Chemical name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid
Chemical structure formula.
Molecular formula: C16H16N2O3S
Molecular weight: 316.37
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
For the long-term treatment of hyperuricemia in patients with gout.
Not recommended for hyperuricemia without clinical symptoms.
Specification
40 mg
Dosage and Administration
The initial dose is recommended to be 20 mg once daily, and the dosage can be gradually increased by 20 mg each time to a maximum of 80 mg daily after 4 weeks from the beginning of the drug administration, after the blood uric acid value reaches the standard (<6 mg/dL or <360µmol/L), the minimum dose is maintained. The effective dose is maintained after the blood uric acid value reaches the standard (<6 mg/dL or <360µ/L).
The effects of food and antacids need not be considered when administering the drug.
Special Populations
Patients with hepatic insufficiency: no dose adjustment is required for patients with mild or moderate hepatic insufficiency (Child-Pugh class A and B). Efficacy and safety studies of febuxostat in patients with severe hepatic insufficiency (Child-Pugh Class C) have not been conducted and febuxostat should therefore be used with caution in these patients.
Renal insufficiency: No dose adjustment is required in patients with mild to moderate renal insufficiency (Clcr 30-89 ml/min). There are no adequate study data in patients with severe renal insufficiency (Clcr < 30 ml/min), so febuxostat should be used with caution in these patients.
Gout attacks
Since febuxostat is a uric acid-lowering drug, its use during an attack of gouty arthritis (gout attack) may lower the blood uric acid value and aggravate gouty arthritis (gout attack), so it should not be used in patients with gouty arthritis before its use until the symptoms are stabilized. In addition, when gouty arthritis (gout attack) is found during the use of this product, the dosage of this product can be continued without changing, and colchicine, non-steroidal anti-inflammatory drugs, adrenal corticosteroids and other drugs can be used in combination according to the specific symptoms.
Adverse reactions
The following information is reported in foreign literature.
1. Clinical trial experience
Since clinical trials are conducted under a wide variety of conditions, the incidence of adverse reactions observed in clinical trials for a drug cannot be directly compared with another drug in a clinical trial, nor does it reflect the incidence in clinical practice.
In the clinical study, 2757 hyperuricemic patients with gout were treated with either 40 mg or 80 mg of febuxostat once daily. 559 patients in the 40 mg dose group were treated for ≥6 months. 1377 patients in the 80 mg dose group were treated for ≥6 months, 674 patients for ≥1 year, and 515 patients for ≥2 years.
Common adverse reactions
Physician-determined adverse reactions related to the trial drug in three randomized controlled clinical trials during treatment periods lasting 6 to 12 months were as follows.
Table 1 Common adverse reactions to febuxostat#
Adverse reactions placebo febuxostat allopurinol* (N = 134) 40 mg/d
(N = 757) 80 mg/d
(N = 1279) (N = 1277) Abnormal liver function
nausea
Joint pain
Skin rash 0.7%
0.7%
0%
0.7% 6.6%
1.1%
1.1%
0.5%4.6%
1.3%
0.7%
1.6%4.2%
0.8%
0.7%
1.6%# Common adverse reactions: the incidence was at least 1% in the febuxostat-treated group and was higher than that of at least 0.5% in the placebo group.
* Different doses of allopurinol were given according to renal insufficiency, including 10 cases of 100 mg, 145 cases of 200 mg and 1122 cases of 300 mg.
The most common adverse reaction leading to discontinuation of treatment was abnormal liver function, with the incidence of discontinuation being 1.8% in the febuxostat 40 mg group, 1.2% in the 80 mg group, and 0.9% in the allopurinol group.
In addition to the adverse reactions in Table 1, the incidence of dizziness was higher in the febuxostat-treated group than in the placebo group, although it was more than 1%, compared with less than 0.5% in the placebo group.
Occasional Adverse Reactions
In Phase II and Phase III clinical studies, the following adverse reactions occurred in less than 1% of subjects in the dose range of 40 to 240 mg administered.
Hematologic and lymphatic: anemia, idiopathic thrombocytopenic purpura, leukocytosis/reduction, neutropenia, allogeneic cytopenia, splenomegaly, thrombocytopenia.
Heart: angina pectoris, atrial fibrillation/atrial flutter, heart murmur, abnormal ECG, palpitations, sinus bradycardia, tachycardia.
Ear and vagus: deafness, tinnitus, vertigo.
Eyes: blurred vision.
Gastrointestinal tract: bloating, abdominal pain, constipation, dry mouth, indigestion, flatulence, frequent stools, gastrointestinal discomfort, gastritis, gastroesophageal reflux disease, gum pain, hemoptysis, hyperacidity, blood in stool, mouth ulcers, pancreatitis, peptic ulcers, vomiting.
Systemic and administration site: weakness, chest pain/chest discomfort, edema, fatigue, abnormal sensation, abnormal gait, influenza-like symptoms, lumps, pain, thirst.
Hepatobiliary system: gallstones/cholangitis, hepatic steatosis, hepatitis, hepatomegaly.
Immune system: allergic reactions.
Infections: herpes zoster.
Complications: contusions.
Metabolic and nutritional: anorexia, decreased/increased appetite, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight loss/gain.
Musculoskeletal and connective tissue: arthritis, joint stiffness, joint swelling, muscle spasms/twitches/tension/weakness, skeletal pain/stiffness, myalgia.
Neurological: taste abnormalities, balance abnormalities, cerebrovascular accidents, Guillain-Barré syndrome, headache, mild hemiparesis, sensory dullness, hyposmia, lacunar cerebral infarction, lethargy, psychosis, migraine, sensory abnormalities, drowsiness, transient ischemic attack, tremor.
Mental disorders: irritability, anxiety, depression, insomnia, irritability, hypersexuality, hypersensitivity, acute anxiety disorder, personality changes.
Urinary system: hematuria, kidney stones, frequent urination, proteinuria, renal failure, renal insufficiency, urinary urgency, urinary incontinence.
Reproductive system and breast: breast pain, erectile dysfunction, gynecomastia.
Respiratory, thoracic and mediastinal: bronchitis, cough, dyspnea, epistaxis, nasal dryness, excessive sinus secretion, pharyngeal edema, respiratory congestion, sneezing, inflammation of the throat, upper respiratory tract infection.
Skin and subcutaneous tissues: alopecia, angioedema, dermatitis, cutaneous scratchiness, petechiae, eczema, hair color change, abnormal hair growth, hyperhidrosis, peeling, petechiae, photosensitivity, pruritus, purpura, skin discoloration/pigmentation, skin lesions, abnormal skin odor, urticaria.
Vascular: flushing, hot flushes, hypertension, hypotension.
Laboratory indicators: prolonged activated partial thromboplastin time, elevated creatine, decreased bicarbonate, increased sodium, abnormal EEG, elevated glucose, elevated cholesterol, elevated triglycerides, elevated amylase, increased potassium, elevated thyroid stimulating hormone, decreased platelet count, decreased erythrocyte specific volume, decreased hemoglobin, increased mean erythrocyte volume, decreased red blood cells, elevated creatinine, elevated blood urea, blood urea nitrogen/creatinine ratio, increased creatine phosphokinase, increased alkaline phosphatase, increased lactate dehydrogenase, increased prostate-specific antigen, increased/decreased urine volume, decreased lymphocyte count, decreased neutrophil count, increased/decreased white blood cells, abnormal coagulation test, increased LDL, prolonged prothrombin time, tubular urine, positive urine leukocytes, positive urine protein, increased C-reactive Protein is elevated.
Cardiovascular risk
In randomized controlled and long-term extension studies, cardiovascular events and death were among the pre-defined endpoints (including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the APTC (Anti-Platelet Trialists’ Collaborations). In the randomized, controlled phase III trial, the incidence of APTC events per 100 patient-years was 0 (95% CI 0.00 to 6.16) in the placebo group, 0 (95% CI 0.00 to 1.08) in the febuxostat 40 mg group, 1.09 (95% CI 0.44 to 2.24) in the febuxostat 80 mg group, and 0.60 (95% CI 0.16 to 1.53) in the allopurinol group.
In the long-term extension study, the incidence of APTC events was 0.97 (95% CI 0.57 to 1.56) in the febuxostat 80 mg group and 0.58 (95% CI 0.02 to 3.24) in the allopurinol group, respectively.
In conclusion, the febuxostat-treated group had a higher incidence of APTC events compared with the allopurinol group, but the causal relationship with febuxostat has not been established. Signs and symptoms of myocardial infarction and stroke should be monitored while taking the drug.
A post-marketing cardiovascular outcomes study (double-blind non-inferiority clinical trial) [CARES] was conducted to assess the cardiovascular (CV) risk of febuxostat in patients with gout associated with cardiovascular disease. The median follow-up time of the study was 2.6 years with 3098 patients enrolled in the febuxostat-treated group and 3092 patients in the allopurinol-treated group. The results showed that the primary endpoint (a composite endpoint consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with emergency coronary revascularization) was noninferior to the allopurinol group. However, the incidence of cardiovascular death, one of the secondary endpoints, was 4.3% (134/3,098) and 3.2% (100/3,092) in the febuxostat and allopurinol groups, respectively, with a higher risk in the febuxostat group (HR 1.34, 95% CI 1.03-1.73). Among cardiovascular deaths, the most common cause was sudden cardiac death in both groups (2.7% (83/3,098) in the febuxostat group and 1.8% (56/3,092) in the allopurinol group. In addition, the incidence of all-cause mortality was 7.8% (243/3,098) and 6.4% (199/3,092) in the febuxostat and allopurinol groups, respectively, and the risk was also higher in the febuxostat group (HR 1.22, 95% CI 1.01-1.47).
2. Post-marketing experience with the product
Post-marketing use of febuxostat was screened for adverse reactions. As these adverse reactions were spontaneously reported from an unknown number of patients, it was not possible to accurately assess their frequency or to determine their causal relationship with the drug.
Blood and lymphatic system disorders: granulocyte deficiency, eosinophilia.
Hepatobiliary abnormalities: liver failure (some fatal), jaundice, grossly abnormal liver function test results, liver disease.
Immune system: allergic reactions.
Musculoskeletal and connective tissues: rhabdomyolysis.
Psychiatric abnormalities: psychotic behavior including aggressive tendencies.
Urinary system: tubulointerstitial nephritis.
Skin and subcutaneous tissues: systemic rash, Stevens Johnson syndrome, allergic skin reactions, erythema multiforme, eosinophilia and systemic symptoms of drug reactions, toxic epidermal necrolysis loosening disease.
Contraindications
(1) Patients with a history of hypersensitivity to the components of this product
(2) This product is contraindicated in patients receiving azathioprine or mercaptopurine therapy.
Precautions
(1) The safety of this product in patients with severe renal impairment has not been established due to the little experience in its use and should be used with caution.
(2) Post-marketing reports of lethal and non-lethal liver failure have been reported in patients taking febuxostat, but the information in these reports is not sufficient to establish a causal relationship with this product. In randomized controlled studies, aminotransferases were observed to be elevated to more than three times the upper limit of normal range value (ULN) (aspartate aminotransferase (AST) elevation in the febuxostat and allopurinol groups: 2%, 2%; alanine aminotransferase (ALT) elevation: 3%, 2%). There was no dose-effect relationship for these aminotransferase elevations.
Patients should have a liver function test (serum ALT, AST, alkaline phosphatase, and total bilirubin) prior to the first dose of febuxostat and use this result as the baseline level.
Liver function tests should be promptly performed in patients reporting symptoms that may indicate liver damage such as fatigue, loss of appetite, right upper abdominal discomfort, soy sauce-colored urine, or jaundice. On the clinical side, if a patient is found to have abnormal liver function (ALT more than 3 times the upper limit of the reference range), the drug should be discontinued and investigated to determine a causal relationship with the drug. Febuxostat should not be reintroduced in these patients with abnormal liver function tests for which there is no other reasonable explanation.
If a patient’s serum ALT is more than 3 times the reference range and his or her total serum bilirubin is more than 2 times the reference range, and other etiologies are excluded, the patient is at risk for severe drug-induced liver damage and febuxostat should not be reintroduced in these patients. Treatment with febuxostat needs to be used with caution in patients with small increases in serum ALT or bilirubin that have other plausible explanations.
(3) In randomized controlled studies, the probability of cardiovascular thrombotic events (including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was higher in patients treated with febuxostat compared with allopurinol, with 0.74/100 patient-years (95% CI: 0.36 to 1.37) for febuxostat and 0.60/100 patient-years (95% CI: 0.16 to 1.53). A causal relationship between febuxostat and cardiovascular thrombotic events has not been established. Monitor for signs and symptoms of myocardial infarction and stroke at the time of drug administration.
In the CARES study, which targeted patients with gout with cardiovascular disease, the incidence of cardiovascular death was higher in the febuxostat group compared with the allopurinol group. Therefore, this product should be used with caution in patients with gout associated with cardiovascular disease. If the clinician assesses that the benefit of using this product outweighs the risk, the deterioration of existing cardiovascular disease and new cardiovascular disease should be closely monitored during the use of this product, and prompt medical treatment should be provided in the event of these conditions.
(4) Since this product is a uric acid-lowering drug, its use during an attack of gouty arthritis (gout attack) may lower the blood uric acid value and aggravate gouty arthritis (gout attack), so patients with gouty arthritis before the use of this product should not use this product until the symptoms are stabilized. In addition, if gouty arthritis (gout attack) is found during the use of this product, the dosage of this product can be continued without changing, and colchicine, non-steroidal anti-inflammatory drugs, adrenal corticosteroids and other drugs can be used in combination according to the specific symptoms.
(5) Serious skin reactions and allergic reactions have been reported in patients taking febuxostat, including Stevens-Johnson syndrome, drug reactions with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis relaxation (TEN). If a severe skin reaction is suspected, febuxostat should be discontinued. Many such patients have reported similar skin reactions with allopurinol. Febuxostat should be used with caution in these patients.
(6) There are no studies of this product in patients with secondary hyperuricemia (including organ transplant recipients) and therefore it is not recommended for use in patients with massive elevations of urates (e.g., malignant disease, Lesch-Nyhan syndrome). A small number of cases have shown that urinary tract deposits can occur following markedly elevated urinary xanthine concentrations.
7) Observe for thyroid-related symptoms during the use of this product, and perform thyroid function-related tests if abnormalities are found.
Pregnant women and nursing mothers
(1) Pregnant women or women who may become pregnant should be administered only if the therapeutic benefit is confirmed to be greater than the risk [safety of use during pregnancy has not been established].
(2) Lactating women should stop breastfeeding during the administration of this product.
Pediatric use]
The safety and efficacy of this product in the treatment of patients under 18 years of age have not been established.
Geriatric use]
No dose adjustment is required for elderly patients. According to foreign literature, in clinical studies of febuxostat, 16% of the subjects were 65 years of age and older, and 4% were 75 years of age and older. There were no clinically significant differences in efficacy and safety when comparing subjects in different age groups, but it cannot be excluded that some elderly patients are more sensitive to this product. The Cmax and AUC0-24hr after multiple oral doses of febuxostat in elderly subjects (65 years and older) were similar to those in younger subjects (18-40 years).
[Drug Interactions].
Azathioprine, mercaptopurine
Because febuxostat’s analog (allopurinol) inhibits xanthine oxidase, co-administration of febuxostat with azathioprine or mercaptopurine may increase the blood concentration of mercaptopurine, resulting in enhanced adverse effects such as myelosuppression. Therefore, febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine.
Theophylline
The febuxostat analog (allopurinol) inhibits xanthine oxidase. According to a drug interaction study in healthy subjects, febuxostat alters the metabolism of theophylline (a substrate of xanthine oxidase) in humans. Therefore, caution should be exercised when febuxostat is used in combination with theophylline.
Algocytidine
Because febuxostat’s analog (allopurinol) inhibits xanthine oxidase, febuxostat may cause enhanced adverse effects of cytarabine such as hallucinations, tremors, and neurological deficits when taken with cytarabine (a substrate of xanthine oxidase). Therefore, caution should be exercised when febuxostat is used in combination with cytarabine.
Dehydroinosine
Since febuxostat’s analog (allopurinol) inhibits xanthine oxidase. According to a drug-drug interaction study in healthy subjects and HIV patients, febuxostat increased the Cmax and AUC of dehydroxylinosine (a xanthine oxidase substrate). Therefore, when combined with this product, care should be taken in the administration of dehydroxylated inosine.
Cytotoxic chemotherapeutic agents
Interaction studies between febuxostat and cytotoxic chemotherapeutic agents have not been performed. Safety data on the use of febuxostat during chemotherapy with cytotoxic agents are unknown.
In vivo Drug Interaction Studies
Based on in vivo drug interaction studies in healthy subjects, there were no significant interactions when febuxostat was combined with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin, and desipramine. Therefore, febuxostat can be used in combination with these drugs.
Drug overdose]
Studies in healthy subjects have shown no dose-limiting toxicity with febuxostat at 300 mg/d for 7 consecutive days. No overdose has been reported in clinical studies. Patients should receive symptomatic treatment and supportive therapy in case of overdose.
Pharmacology and Toxicology
Pharmacological effects
Febuxostat, a 2-arylthiazole derivative, is a xanthine oxidase inhibitor that reduces serum uric acid concentration by inhibiting uric acid synthesis. Febuxostat does not inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at conventional therapeutic concentrations.
Toxicological studies
Repeated dosing toxicity: In a 12-month Beagle dog toxicity test, xanthine crystalline precipitation and stones were observed in the kidney at a dose of 15 mg/kg (approximately 4 times the plasma exposure at a human dose of 80 mg/d). Similarly, in the rat 6-month test, xanthine crystals were observed at a dose of 48 mg/kg (approximately 35 times the plasma exposure at the human dose of 80 mg/d).
Genotoxicity: Febuxostat showed positive results in the chromosomal aberration test in CHL cells with and without metabolic activation. The results of febuxostat Ames test, human peripheral blood lymphocyte chromosomal aberration test, L5178Y mouse lymphoma cell chromosomal aberration test, mouse micronucleus test, rat extra-programmed DNA synthesis test, and rat bone marrow cell micronucleus test were all negative.
Reproductive toxicity: No significant effects on fertility and reproductive behavior were observed in male and female rats when febuxostat was administered orally at doses up to 48 mg/kg/d (approximately 35 times the plasma exposure at the human dose of 80 mg/d).
No teratogenic effects were observed in pregnant rats and rabbits given febuxostat orally at doses up to 48 mg/kg (approximately 40-51 times the plasma exposure at the human dose of 80 mg/d) during the organogenesis period. In pregnant rats, oral administration of febuxostat up to 48 mg/kg during the perinatal period (approximately 40-51 times the plasma exposure at the human dose of 80 mg/d) resulted in increased birth mortality and reduced body weight of the pups.
Carcinogenicity: In a two-year carcinogenicity study in F344 rats and B6C3F1 mice, migratory cell papilloma and bladder cancer were observed in male and female mice at 24 mg/kg (approximately 25 times the human plasma exposure at 80 mg/d) and 18.75 mg/kg (approximately 12.5 times the human plasma exposure at 80 mg/d), respectively. . Bladder cancer is secondary to kidney and bladder stones.
[Pharmacokinetics].
According to domestic and international literature.
1. blood concentration
(1) Single dose
The changes in plasma febuxostat concentrations and pharmacokinetic parameters in 30 healthy adult males in Japan during single oral doses of 10, 20, 40 and 80 mg of febuxostat under fasting conditions are shown below.
Plasma febuxostat concentration (ng/ml) Time (hr) dosage pharmacokinetic parameters AUCinf
(ng-hr/ml) Cmax
(ng/ml) t1/2
(hr)tmax
(hr)10 mg (N=8)1537.0±430.9496.2±166.06.2±0.91.4±1.120 mg (N=8)3296.2±751.91088.3±178.96.2±1.11.3±0.540 mg (N=8)7085.2±1341.22270.3± 866.77.3±1.81.2±0.880 mg (N=6)13300.5±3032.33765.3±1008.36.9±1.81.9±1.0 (mean±standard deviation)
(2) Repeated dosing
In 6 healthy Japanese adult males, 40 mg of febuxostat was administered orally once daily after breakfast for 7 days, and plasma febuxostat concentrations reached steady state 3 days after the start of dosing, and no drug accumulation was observed with repeated dosing.
Dosing observation day Cmax (ng/ml) tmax (hr) AUC0-24hr
(ng-hr/ml) t1/2 (hr) 40mg/day
(N=6) Day 1 1019.1±343.21.8±0.83658.5±625.66.3±1.6 Day 7 1299.8±312.61.5±0.34442.1±729.58.8±2.2 (Mean±standard deviation)
(3) Repeated dosing (patients with hyperuricemia)
The pharmacokinetic parameters of 10 Japanese patients with hyperuricemia when febuxostat was administered orally as 10 mg/day once daily after breakfast for 2 weeks, followed by 20 mg/day for 4 weeks, 6 weeks after the start of dosing are shown below.
Administration group Cmax (ng/ml) tmax (hr) AUC0-24hr
(ng-hr/ml) t1/2 (hr) 20 mg/day
(N=10) 541.8±227.82.2±1.62092.3±463.28.2±2.4 (Mean±standard deviation)
(4) Effect of diet
In 16 healthy Japanese adults, Cmax and AUCinf were reduced by 28% and 18%, respectively, when a single oral dose of 40 mg as febuxostat was administered after diet compared with the dose administered on an empty stomach.
Cmax (ng/ml) tmax (hr) AUCinf in the administration group
(ng-hr/ml) t1/2 (hr) Administration in fasted state (N=16) 2049.1±782.31.2±0.86538.3±1263.06.8±1.7 Administration after diet
(N=16) 1456.0±514.81.8±1.05321.6±910.46.3±1.5 (Mean±standard deviation)
2. Pharmacokinetics in special populations
Patients with renal impairment
Among patients with renal impairment (defined as normal: Clcr>80 ml/min, mild: Clcr 50-80 ml/min/, moderate: Clcr 30-49 ml/min, severe: Clcr 10-29 ml/min/), Japanese patients with mild (5 cases) and moderate (7 cases) renal impairment were given 20 mg of febuxostat after breakfast The Cmax of febuxostat in the mild renal impairment group did not change from that of the normal renal function group (9 patients) at 7 days after administration, but the AUC0-24hr increased by 53% compared with that of the normal renal function group. In the moderate renal impairment group, Cmax and AUC0-24hr increased by 26% and 68%, respectively, compared with the normal renal function group.
In patients with mild (6 patients), moderate (7 patients) and severe (7 patients) renal impairment in the United States who took febuxostat 80 mg once daily before breakfast for 7 days, the Cmax and AUC0-24hr of febuxostat increased by 41% and 48%, 2% and 48%, 4% and 76%, respectively, compared with the normal renal function group (11 patients) at 7 days after dosing.
Patients with hepatic impairment
In patients with mild (8) and moderate (8) hepatic impairment (Child Pugh A and B) in the United States who were given febuxostat 80 mg once daily before breakfast for 7 days, the Cmax and AUC0-24hr of febuxostat in the mild hepatic impairment group increased by 24% and 30%, respectively, compared to the normal hepatic group (11 patients) at 7 days after dosing. The Cmax and AUC0-24hr in the moderate liver impairment group increased by 53% and 55%, respectively.
Effect of elderly and gender
In the United States, Cmax and AUC0-24hr were 1% lower and 12% higher in the elderly (65 years and older, 24 cases) and young adults (18-40 years, 24 cases), respectively, when febuxostat 80 mg once daily was administered before breakfast for 7 days, compared with young adults 7 days after the start of dosing. In addition, foreign literature reported that after multiple oral doses of febuxostat, Cmax and AUC0-24hr of febuxostat were 30% and 14% higher in women than in men, respectively. However, after performing weight correction, Cmax and AUC were similar in both genders. In addition, the rate of decrease in serum uric acid concentration was similar between the sexes. No drug dose adjustment according to gender was required.
3. Protein binding rate
The human plasma protein binding rate of febuxostat (when added at 0.4-10 mg/ml) was 97.8-99.0%, and the major bound protein was albumin (in vitro test).
4. Metabolism and excretion
(1) The main metabolic pathway of febuxostat is glucuronidation. In addition, there are various other oxidative metabolites that are further metabolized in the form of its sulfated conjugates and glucuronide conjugates. No inhibition of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5 by febuxostat was observed. In addition, the Ki values of febuxostat for CYP2C8 and CYP2D6 were 20 μmol/L and 40 μmol/L, respectively (in vitro assay with human liver microsomes).
Febuxostat did not induce CYP1A1/2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 (human primary hepatocytes in an in vitro assay).
(2) Urinary excretion rates of febuxostat in 24 healthy Japanese adult males given single oral doses of febuxostat 10 mg, 20 mg and 40 mg in the fasted state, 24 hours and 96 hours post-dose relative to the dose administered, were 2.1% to 3.8% and 2.2% to 3.9%, respectively. In addition, the urinary excretion rates of glucuronide conjugates of febuxostat ranged from 46.7% to 49.7% and 49.0% to 51.6% at 24 and 96 hours post-dose, respectively.
(3) The total plasma radioactivity of febuxostat and its glucuronide conjugate in 6 healthy adult males in the United States with a single oral dose of 14C febuxostat 80 mg liquid in the fasted state was 83.8% to 95.8% and 2.3% to 6.8%. The urinary excretion rate of febuxostat (relative to the dose administered, hereinafter) ranged from 1.1% to 3.5% within 48 hours after administration, and the fecal excretion rate ranged from 7.8% to 15.8% within 120 hours after administration. In addition, the excretion rates of total radioactivity including metabolites in urine and feces were 49.1% and 44.9%, respectively, within 216 hours after administration.
5. Drug interactions
(1)Theophylline
There is no need to adjust the dose when this product is taken together with theophylline. Coadministration of the product (80 mg once daily) with theophylline will result in an increase in the Cmax and AUC of theophylline by 6% and 6.5%, respectively. Changes in these two parameters for theophylline were considered to be statistically insignificant or non-significant. However, tests have shown that the inhibitory effect of this product on xanthine oxidase leads to an approximately 400-fold increase in urinary excretion of 1-methylxanthine, a major metabolite of theophylline. No experimental studies have been conducted on the safety of long-term exposure to 1-methylxanthine in humans. The accumulation of 1-methylxanthine in the body should be taken into account when deciding to take this product together with theophylline.
(2) Colchicine
When this product and colchicine are co-administered, no dose adjustment is required for either. Co-administration of this product (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in a 12% and 7% increase in febuxostat Cmax and AUC0-24hr, respectively. In addition, coadministration of colchicine (0.6 mg twice daily) with this product (120 mg daily) resulted in a change in Cmax or AUC of less than 11% after morning and afternoon administration. These changes were not clinically significant.
(3) Naproxen
This product was co-administered with naproxen, neither of which required dose adjustment. Co-administration of this product (80 mg once daily) with naproxen (500 mg twice daily) resulted in increases in febuxostat Cmax and AUC of 28% and 40%, respectively. This increase was not clinically significant. Moreover, there was no significant change in Cmax or AUC for naproxen (<2%).
(4) Indomethacin
When this product is co-administered with indomethacin, no dose adjustment is required for either. Co-administration of this product (80 mg once daily) and indomethacin (50 mg twice daily) did not produce any significant changes in Cmax or AUC of febuxostat or indomethacin (<7%).
(5) Hydrochlorothiazide
No dose adjustment is required when this product is co-administered with hydrochlorothiazide. Co-administration of this product (80 mg) with hydrochlorothiazide (50 mg) did not produce any clinically meaningful changes in Cmax or AUC of febuxostat (<4%) and serum uric acid concentrations were not significantly affected.
(6) Warfarin
No dose adjustment is required for coadministration of warfarin with this product. Co-administration of this product (80 mg once daily) with warfarin had no effect on warfarin pharmacokinetics in healthy subjects. Administration of this product also had no effect on the international normalized ratio (INR) or coagulation factor VII activity.
(7) Desipramine
CYP2D6 substrates (e.g., desipramine) are administered in combination with this product without dose adjustment. In vitro and in vivo tests have shown febuxostat to be a weak inhibitor of CYP2D6. Co-administration of febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the metabolic ratio of 2-hydroxydesipramine to desipramine (based on AUC).
6. Pharmacokinetic trials in China
In an open clinical pharmacokinetic trial in healthy Chinese volunteers with single and multiple doses, it was determined that there was no difference between single and multiple doses in each dose group and that there was no accumulation of febuxostat tablets in the body after multiple doses. The pharmacokinetic parameters obtained in this study are shown below.
Main parameters
Group Cmax
(ng/ml)AUCinf
(ng-h/ml)Tmax
(h)t1/2
(h)20mg
(n=10)Single (day 1)1169.5±210.04136.0±558.11.8±1.26.9±2.6Multiple (day 11)1013.1±307.63476.3 ± 676.61.4±1.07.4±5.840mg
(n=10) Single (day 1) 2203.9 ± 868.37362.9 ± 2521.61.2 ± 1.16.0 ± 1.9 Multiple (day 11)* 1569.1 ± 388.35631.2 ± 1253.91.8 ± 1.15.7 ± 2.160mg
(n=10)Single (day 1)3569.8±1360.111824.9 ±3341.31.0±0.56.8±2.0Multiple (day 11)2793.8±796.310018.1±3302.91.7±0.68.0±3.680mg
(n=10) Single (day 1) 5165.9±1989.116756.6±6564.61.6±1.46.9±1.8 Multiple (day 11) 4358.2±1368.316240.9±6414.51.5±1.07.6±1.7 (mean±standard deviation)*: 10 subjects in the 40 mg group completed Single dose test, 9 subjects completed multiple dose test.
Storage】Kept in airtight storage.
Package】Packaged in aluminum-plastic blister, plus composite film bag.
12 tablets/plate× 1 plate/bag, 1 bag/box; 12 tablets/plate× 2 plates/bag, 1 bag/box.
12 tablets/plate x 3 plates/bag, 1 bag/box; 7 tablets/plate x 1 plate/bag, 1 bag/box.
7 tablets/plate x 2 plates/bag, 1 bag/box; 14 tablets/plate x 2 plates/bag, 1 bag/box.
Expiration date】 12 months
【Execution standard
【Approval number】
[Drug Marketing License Holder
Company name: Hangzhou Zhu Yangxin Pharmaceutical Co.
Registered Address: No. 10, No. 11 Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province
Manufacturer
Company Name: Hangzhou Zhu Yangxin Pharmaceutical Co.
Production Address: Hangzhou Economic and Technological Development Zone, Baiyang Street, No. 11 Street 10
Postal code: 310018
Telephone number: 0571-88845384
Fax number: 0571-88847119
Web address: www.zuyaxi.com