英文药名：Adenuric（Febuxostat、TMX-67、TEI-6720）

中文名称：非布司他(非布索坦)

生产厂家：Ipsen公司
药品介绍
2008年5月欧盟批准Ipsen公司的febuxostat(Adenuric)上市，用于治疗痛风的慢性高尿酸血症，是40多年来治疗严重退行性疾病新途径的第1个，规格：80mg和120mg。
2009年2月FDA批准TAKEDA公司的febuxostat(ULORIC)在美国上市，规格40mg、80mg
适应症:
用于已出现尿酸沉积(包括痛风石、痛风性关节炎)的慢性高尿酸血症的治疗。
用法及用量
非布司他口服推荐剂量为40毫克，每日一次。服药2周后如果血清尿酸含量大于6毫克/分升，则可考虑服用80毫克，每日一次。本品预防痛风发作建议至少服药6个月，服用本品时无需考虑食物或抗酸剂的影响。

Adenuric 80 mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/22830)
Adenuric 120 mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/30332)
Adenuric film-coated tablets
1. Name of the medicinal product
ADENURIC 80 mg film-coated tablets
ADENURIC 120 mg film-coated tablets
2. Qualitative and quantitative composition
ADENURIC 80 mg tablet: Each tablet contains 80 mg of febuxostat.
Excipient(s) with known effects:
Each tablet contains 76.50 mg of lactose (as monohydrate)
ADENURIC 120 mg tablet: Each tablet contains 120 mg of febuxostat.
Excipient(s) with known effects:
Each tablet contains 114.75mg of lactose monohydrate
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
ADENURIC 80 mg tablet: Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “80” on one side.
ADENURIC 120 mg tablet: Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “120” on one side.
4. Clinical particulars
4.1 Therapeutic indications
Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).
ADENURIC is indicated in adults.
4.2 Posology and method of administration
Posology
The recommended oral dose of ADENURIC is 80 mg once daily without regard to food. If serum uric acid is > 6 mg/dL (357 µmol/L) after 2-4 weeks, ADENURIC 120 mg once daily may be considered.
ADENURIC works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dL (357μmol/L).
Gout flare prophylaxis of at least 6 months is recommended (see section 4.4).
Older people
No dose adjustment is required in the elderly (see section 5.2).
Renal impairment
The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance <30 mL/min, see section 5.2).
No dose adjustment is necessary in patients with mild or moderate renal impairment.
Hepatic impairment
The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).
The recommended dose in patients with mild hepatic impairment is 80 mg. Limited information is available in patients with moderate hepatic impairment.
Paediatric population
The safety and the efficacy of ADENURIC in children aged below the age of 18 years have not been established. No data are available.
Method of administration
Oral use
ADENURIC should be taken by mouth and can be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.8).
4.4 Special warnings and precautions for use
Cardio-vascular disorders
Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended.
A numerical greater incidence of investigator-reported cardiovascular APTC events (defined endpoints from the Anti-Platelet Trialists' Collaboration (APTC) including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was observed in the febuxostat total group compared to the allopurinol group in the APEX and FACT studies (1.3 vs. 0.3 events per 100 Patient Years (PYs)), but not in the CONFIRMS study (see section 5.1 for detailed characteristics of the studies). The incidence of investigator-reported cardiovascular APTC events in the combined Phase 3 studies (APEX, FACT and CONFIRMS studies) was 0.7 vs. 0.6 events per 100 PYs. In the long-term extension studies the incidences of investigator-reported APTC events were 1.2 and 0.6 events per 100 PYs for febuxostat and allopurinol, respectively. No statistically significant differences were found and no causal relationship with febuxostat was established. Identified risk factors among these patients were a medical history of atherosclerotic disease and/or myocardial infarction, or of congestive heart failure.
Medicinal product allergy / hypersensitivity
Rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson Syndrome, Toxic epidermal necrolysis and acute anaphylactic reaction/shock, have been collected in the post-marketing experience. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. Severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were associated with fever, haematological, renal or hepatic involvement in some cases.
Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see section 4.8). Febuxostat treatment should be immediately stopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson Syndrome, occur since early withdrawal is associated with a better prognosis. If patient has developed allergic/hypersensitivity reactions including Stevens-Johnson Syndrome and acute anaphylactic reaction/shock, febuxostat must not be re-started in this patient at any time.
Acute gouty attacks (gout flare)
Febuxostat treatment should not be started until an acute attack of gout has completely subsided. Gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits (see sections 4.8 and 5.1). At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (see section 4.2).
If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with febuxostat decreases frequency and intensity of gout flares.
Xanthine deposition
In patients in whom the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. As there has been no experience with febuxostat, its use in these populations is not recommended.
Mercaptopurine/azathioprine
Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine. Where the combination cannot be avoided patients should be closely monitored. A reduction of dosage of mercaptopurine or azathioprine is recommended in order to avoid possible haematological effects (see section 4.5).
Organ transplant recipients
As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended (see section 5.1).
Theophylline
Co-administration of febuxostat 80 mg and theophylline 400mg single dose in healthy subjects showed absence of any pharmacokinetic interaction (see section 4.5). Febuxostat 80 mg can be used in patients concomitantly treated with theophylline without risk of increasing theophylline plasma levels. No data is available for febuxostat 120 mg.
Liver disorders
During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgment (see section 5.1).
Thyroid disorders
Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with febuxostat (5.5%) in the long term open label extension studies. Caution is required when febuxostat is used in patients with alteration of thyroid function (see section 5.1).
Lactose
Febuxostat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Mercaptopurine/azathioprine
On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity (see section 4.4). Drug interaction studies of febuxostat with drugs that are metabolized by XO have not been performed.
Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data is available regarding the safety of febuxostat during cytotoxic therapy.
Rosiglitazone/CYP2C8 substrates
Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, coadministration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.
Theophylline
An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline. Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg.
Naproxen and other inhibitors of glucuronidation
Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250mg twice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/2 26%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.
Inducers of glucuronidation
Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.
Colchicine/indometacin/hydrochlorothiazide/warfarin
Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine/CYP2D6 substrates
Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg ADENURIC QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.
Antacids
Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.
4.6 Fertility, pregnancy and lactation
Pregnancy
Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development or parturition (see section 5.3). The potential risk for human is unknown. Febuxostat should not be used during pregnancy.
Breastfeeding
It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breastfeeding.
Fertility
In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects on fertility (see section 5.3). The effect of ADENURIC on human fertility is unknown.
4.7 Effects on ability to drive and use machines
Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of Febuxostat. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that ADENURIC does not adversely affect performance.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300 mg) and post-marketing experience are gout flares, liver function abnormalities, diarrhoea, nausea, headache, rash and oedema. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, have occurred in the post-marketing experience.
Tabulated list of adverse reactions
Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000) adverse reactions occurring in patients treated with febuxostat are listed below.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions in combined phase 3, long-term extension studies and post-marketing experience

Blood and lymphatic system disorders	Rare Pancytopenia, thrombocytopenia
Immune system disorders	Rare Anaphylactic reaction*, drug hypersensitivity*
Endocrine disorders	Uncommon Blood thyroid stimulating hormone increased
Eye disorders	Rare Blurred vision
Metabolism and nutrition disorders	Common*** Gout flares Uncommon Diabetes mellitus, hyperlipidemia, decrease appetite, weight increase Rare Weight decrease, increase appetite, anorexia
Psychiatric disorders	Uncommon Libido decreased, insomnia Rare Nervousness
Nervous system disorders	Common Headache Uncommon Dizziness, paraesthesia, hemiparesis, somnolence, altered taste, hypoaesthesia, hyposmia
Ear and labyrinth disorders	Rare Tinnitus
Cardiac disorders	Uncommon Atrial fibrillation, palpitations, ECG abnormal
Vascular disorders	Uncommon Hypertension, flushing, hot flush
Respiratory system disorders	Uncommon Dyspnoea, bronchitis, upper respiratory tract infection, cough
Gastrointestinal disorders	Common Diarrhoea**, nausea Uncommon Abdominal pain, abdominal distension, gastro-oesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent stools, flatulence, gastrointestinal discomfort Rare Pancreatitis, mouth ulceration
Hepato-biliary disorders	Common Liver function abnormalities** Uncommon Cholelithiasis Rare Hepatitis, jaundice*, liver injury*
Skin and subcutaneous tissue disorders	Common Rash (including various types of rash reported with lower frequencies, see below) Uncommon Dermatitis, urticaria, pruritus, skin discolouration, skin lesion, petechiae, rash macular, rash maculopapular, rash papular Rare Toxic epidermal necrolysis*, Stevens-Johnson Syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms*, generalized rash (serious)*, erythema, exfoliative rash, rash follicular, rash vesicular, rash pustular, rash pruritic*, rash erythematous, rash morbillifom, alopecia, hyperhidrosis
Musculoskeletal and connective tissue disorders	Uncommon Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tightness, bursitis Rare Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness
Renal and urinary disorders	Uncommon Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria Rare Tubulointerstitial nephritis*, micturition urgency
Reproductive system and breast disorder	Uncommon Erectile dysfunction
General disorders and administration site conditions	Common Oedema Uncommon Fatigue, chest pain, chest discomfort Rare Thirst
Investigations	Uncommon Blood amylase increase, platelet count decrease, WBC decrease, lymphocyte count decrease, blood creatine increase, blood creatinine increase, haemoglobin decrease, blood urea increase, blood triglycerides increase, blood cholesterol increase, haematocritic decrease, blood lactate dehydrogenase increased, blood potassium increase Rare Blood glucose increase, activated partial thromboplastin time prolonged, red blood cell count decrease, blood alkaline phosphatase increase

* Adverse reactions coming from post-marketing experience
** Treatment-emergent non-infective diarrhoea and abnormal liver function tests in the combined Phase 3 studies are more frequent in patients concomitantly treated with colchicine.
*** See section 5.1 for incidences of gout flares in the individual Phase 3 randomized controlled studies.
Description of selected adverse reactions
Rare serious hypersensitivity reactions to febuxostat, including Stevens-Johnson Syndrome, Toxic epidermal necrolysis and anaphylactic reaction/shock, have occurred in the post-marketing experience. Stevens-Johnson Syndrome and Toxic epidermal necrolysis are characterised by progressive skin rashes associated with blisters or mucosal lesions and eye irritation. Hypersensitivity reactions to febuxostat can be associated to the following symptoms: skin reactions characterised by infiltrated maculopapular eruption, generalised or exfoliative rashes, but also skin lesions, facial oedema, fever, haematologic abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis) (see section 4.4).
Gout flares were commonly observed soon after the start of treatment and during the first months. Thereafter, the frequency of gout flare decreases in a time-dependent manner. Gout flare prophylaxis is recommended (see section 4.2 and 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Patients with an overdose should be managed by symptomatic and supportive care.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, ATC code: M04AA03
Mechanism of action
Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has been shown to potently inhibit both the oxidized and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
Clinical efficacy and safety
The efficacy of ADENURIC was demonstrated in three Phase 3 pivotal studies (the two pivotal APEX and FACT studies, and the additional CONFIRMS study described below) that were conducted in 4101 patients with hyperuricaemia and gout. In each phase 3 pivotal study, ADENURIC demonstrated superior ability to lower and maintain serum uric acid levels compared to allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthly serum uric acid levels were < 6.0 mg/dL (357 µmol/L). In the additional phase 3 CONFIRMS study, for which results became available after the marketing authorisation for ADENURIC was first issued, the primary efficacy endpoint was the proportion of patients whose serum urate level was < 6.0 mg/dL at the final visit. No patients with organ transplant have been included in these studies (see section 4.2).
APEX Study: The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a Phase 3, randomized, double-blind, multicenter, 28-week study. One thousand and seventy-two (1072) patients were randomized: placebo (n=134), ADENURIC 80 mg QD (n=267), ADENURIC 120 mg QD (n=269), ADENURIC 240 mg QD (n=134) or allopurinol (300 mg QD [n=258] for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg QD [n=10] for patients with a baseline serum creatinine >1.5 mg/dL and ≤2.0 mg/dL). Two hundred and forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation dose.
The APEX study showed statistically significant superiority of both the ADENURIC 80 mg QD and the ADENURIC 120 mg QD treatment arms versus the conventionally used doses of allopurinol 300 mg (n = 258) /100 mg (n = 10) treatment arm in reducing the sUA below 6 mg/dL (357 µmol/L) (see Table 2 and Figure 1).
FACT Study: The Febuxostat Allopurinol Controlled Trial (FACT) Study was a Phase 3, randomized, double-blind, multicenter, 52-week study. Seven hundred sixty (760) patients were randomized: ADENURIC 80 mg QD (n=256), ADENURIC 120 mg QD (n=251), or allopurinol 300 mg QD (n=253).
The FACT study showed the statistically significant superiority of both ADENURIC 80 mg and ADENURIC 120 mg QD treatment arms versus the conventionally used dose of allopurinol 300 mg treatment arm in reducing and maintaining sUA below 6 mg/dL (357 µmol/L).
Table 2 summarises the primary efficacy endpoint results:
Table 2
Proportion of Patients with Serum Uric Acid Levels <6.0 mg/dL (357µmol/L)
Last Three Monthly Visits

Study	ADENURIC 80 mg QD	ADENURIC 120 mg QD	Allopurinol 300 / 100 mg QD1
APEX (28 weeks)	48% * (n=262)	65% *, # (n=269)	22% (n=268)
FACT (52 weeks)	53%* (n=255)	62%* (n=250)	21% (n=251)
Combined Results	51%* (n=517)	63%*, # (n=519)	22% (n=519)
1 results from subjects receiving either 100 mg QD (n=10: patients with serum creatinine >1.5 and ≤2.0 mg/dL) or 300 mg QD (n=509) were pooled for analyses. * p < 0.001 vs allopurinol, # p < 0.001 vs 80 mg

The ability of ADENURIC to lower serum uric acid levels was prompt and persistent. Reduction in serum uric acid level to <6.0 mg/dL (357 µmol/L) was noted by the Week 2 visit and was maintained throughout treatment. The mean serum uric acid levels over time for each treatment group from the two pivotal Phase 3 studies are shown in Figure 1.
Figure 1 Mean Serum Uric Acid Levels in Combined Pivotal Phase 3 Studies

Note: 509 patients received allopurinol 300 mg QD; 10 patients with serum creatinine >1.5 and < 2.0 mg/dL were dosed with 100 mg QD. (10 patients out of 268 in APEX study).
240 mg febuxostat was used to evaluate the safety of febuxostat at twice the recommended highest dose.
CONFIRMS Study: The CONFIRMS study was a Phase 3, randomized, controlled, 26-week study to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg, in comparison with allopurinol 300 mg or 200 mg, in patients with gout and hyperuricaemia. Two thousand and two hundred-sixty nine (2269) patients were randomized: ADENURIC 40 mg QD (n=757), ADENURIC 80 mg QD (n=756), or allopurinol 300/200 mg QD (n=756). At least 65% of the patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min). Prophylaxis against gout flares was obligatory over the 26-week period.
The proportion of patients with serum urate levels of < 6.0 mg/dL (357 µmol/L) at the final visit, was 45% for 40 mg febuxostat, 67% for febuxostat 80 mg and 42% for allopurinol 300/200 mg, respectively.
Primary endpoint in the sub-group of patients with renal impairment
The APEX Study evaluated efficacy in 40 patients with renal impairment (i.e., baseline serum creatinine > 1.5 mg/dL and ≤2.0 mg/dL). For renally impaired subjects who were randomized to allopurinol, the dose was capped at 100 mg QD. ADENURIC achieved the primary efficacy endpoint in 44% (80 mg QD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared to 0% in the allopurinol 100 mg QD and placebo groups.
There were no clinically significant differences in the percent decrease in serum uric acid concentration in healthy subjects irrespective of their renal function (58% in the normal renal function group and 55% in the severe renal dysfunction group).
An analysis in patients with gout and renal impairment was prospectively defined in the CONFIRMS study, and showed that febuxostat was significantly more efficacious in lowering serum urate levels to < 6 mg/dL compared to allopurinol 300 mg/200 mg in patients who had gout with mild to moderate renal impairment (65% of patients studied).
Primary endpoint in the sub group of patients with sUA ≥ 10 mg/dL
Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 10 mg/dL. In this subgroup ADENURIC achieved the primary efficacy endpoint (sUA < 6.0 mg/dL at the last 3 visits) in 41% (80 mg QD), 48% (120 mg QD), and 66% (240 mg QD) of patients compared to 9% in the allopurinol 300 mg/100 mg QD and 0 % in the placebo groups.
In the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint (sUA < 6.0 mg/dL at the final visit) for patients with a baseline serum urate level of ≥ 10 mg/dL treated with febuxostat 40 mg QD was 27% (66/249), with febuxostat 80 mg QD 49% (125/254) and with allopurinol 300 mg/200 mg QD 31% (72/230), respectively.
Clinical Outcomes: proportion of patients requiring treatment for a gout flare
APEX study: During the 8-week prophylaxis period, a greater proportion of subjects in the febuxostat 120 mg (36%) treatment group required treatment for gout flare compared to febuxostat 80 mg (28%), allopurinol 300 mg (23%) and placebo (20%). Flares increased following the prophylaxis period and gradually decreased over time. Between 46% and 55% of subjects received treatment for gout flares from Week 8 and Week 28. Gout flares during the last 4 weeks of the study (Weeks 24-28) were observed in 15% (febuxostat 80, 120 mg), 14% (allopurinol 300 mg) and 20% (placebo) of subjects.
FACT study: During the 8-week prophylaxis period, a greater proportion of subjects in the febuxostat 120 mg (36%) treatment group required treatment for a gout flare compared to both the febuxostat 80 mg (22%) and allopurinol 300 mg (21%) treatment groups. After the 8-week prophylaxis period, the incidences of flares increased and gradually decreased over time (64% and 70% of subjects received treatment for gout flares from Week 8-52). Gout flares during the last 4 weeks of the study (Weeks 49-52) were observed in 6-8% (febuxostat 80 mg, 120 mg) and 11% (allopurinol 300 mg) of subjects.
The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) was numerically lower in the groups that achieved an average post-baseline serum urate level <6.0 mg/dL, <5.0 mg/dL, or <4.0 mg/dL compared to the group that achieved an average post-baseline serum urate level ≥6.0 mg/dL during the last 32 weeks of the treatment period (Week 20-Week 24 to Week 49 - 52 intervals).
During the CONFIRMS study, the percentages of patients who required treatment for gout flares (Day 1 through Month 6) were 31% and 25% for the febuxostat 80 mg and allopurinol groups, respectively. No difference in the proportion of patients requiring treatment for gout flares was observed between the febuxostat 80 mg and 40 mg groups.
Long-term, open label extension Studies
EXCEL Study (C02-021): The Excel study was a three years Phase 3, open label, multicenter, randomised, allopurinol-controlled, safety extension study for patients who had completed the pivotal Phase 3 studies (APEX or FACT). A total of 1,086 patients were enrolled: ADENURIC 80 mg QD (n=649), Adenuric 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). About 69 % of patients required no treatment change to achieve a final stable treatment. Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn.
Serum urate levels were maintained over time (i.e. 91% and 93% of patients on initial treatment with febuxostat 80 mg and 120 mg, respectively, had sUA <6 mg/dL at Month 36).
Three years data showed a decrease in the incidence of gout flares with less than 4% of patients requiring treatment for a flare (i.e. more than 96 % of patients did not require treatment for a flare) at Month 16-24 and at Month 30-36.
46% and 38%, of patients on final stable treatment of febuxostat 80 or 120 mg QD, respectively, had complete resolution of the primary palpable tophus from baseline to the Final Visit.
FOCUS Study (TMX-01-005) was a 5 years Phase 2, open-label, multicenter, safety extension study for patients who had completed the febuxostat 4 weeks of double blind dosing in study TMX-00-004. 116 patients were enrolled and received initially febuxostat 80 mg QD. 62% of patients required no dose adjustment to maintain sUA <6 mg/dL and 38 % of patients required a dose adjustment to achieve a final stable dose.
The proportion of patients with serum urate levels of <6.0 mg/dL (357 µmol/L) at the final visit was greater than 80% (81-100%) at each febuxostat dose.
During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). These rates were similar to the rates reported on allopurinol (4.2%) (see section 4.4). Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with febuxostat (5.5%) and patients with allopurinol (5.8%) in the long term open label extension studies (see section 4.4).
5.2 Pharmacokinetic properties
In healthy subjects, maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours.
Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients with hyperuricaemia and gout, treated with ADENURIC 40-240 mg QD. In general, febuxostat pharmacokinetic parameters estimated by these analyses are consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for pharmacokinetic/pharmacodynamic assessment in the patient population with gout.
Absorption
Febuxostat is rapidly (tmax of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 and 120 mg once daily doses, Cmax is approximately 2.8-3.2 µg/mL, and 5.0-5.3 µg/mL, respectively. Absolute bioavailability of the febuxostat tablet formulation has not been studied.
Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in Cmax and a 18% and 16% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). Thus, ADENURIC may be taken without regard to food.
Distribution
The apparent steady state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L after oral doses of 10-300 mg. The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 91%.
Biotransformation
Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9.
Elimination
Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as the unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).
Renal impairment
Following multiple doses of 80 mg of ADENURIC in patients with mild, moderate or severe renal impairment, the Cmax of febuxostat did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 μgh/mL in the normal renal function group to 13.2 μg.h/mL in the severe renal dysfunction group. The Cmax and AUC of active metabolites increased up to 2- and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment.
Hepatic impairment
Following multiple doses of 80 mg of ADENURIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the Cmax and AUC of febuxostat and its metabolites did not change significantly compared to subjects with normal hepatic function. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).
Age
There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of ADENURIC in elderly as compared to younger healthy subjects.
Gender
Following multiple oral doses of ADENURIC, the Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. No dose adjustment is needed based on gender.
5.3 Preclinical safety data
Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.
Carcinogenesis, mutagenesis, impairment of fertility
In male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 11 times human exposure. There was no significant increase in any other tumour type in either male or female mice or rats. These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use.
A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat.
Febuxostat at oral doses up to 48 mg/kg/day was found to have no effect on fertility and reproductive performance of male and female rats.
There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due to febuxostat. There was high dose maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring in rats at approximately 4.3 times human exposure. Teratology studies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately 13 times human exposure did not reveal any teratogenic effects.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Magnesium stearate
Hydroxypropylcellulose
Croscarmellose sodium
Silica, colloidal hydrated
Tablet coating
Opadry II, Yellow, 85F42129 containing:
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogols 3350
Talc
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Clear (Aclar/PVC/Aluminium) blister of 14 tablets.
ADENURIC 80 mg is available in pack sizes of 14, 28, 42, 56, 84 and 98 film-coated tablets.
ADENURIC 120 mg is available in pack sizes of 14, 28, 42, 56, 84 and 98 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
8. Marketing authorisation number(s)
EU/1/08/447/001
EU/1/08/447/002
EU/1/08/447/003
EU/1/08/447/004
EU/1/08/447/005
EU/1/08/447/006
EU/1/08/447/007
EU/1/08/447/008
EU/1/08/447/009
EU/1/08/447/010
EU/1/08/447/011
EU/1/08/447/012
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 21 April 2008
Date of latest renewal: 20 December 2012
10. Date of revision of the text
20 February 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
美国FDA批准了近40年来的第一个用于治疗高尿酸症的痛风药物

武田制药的非布索坦（febuxostat；ULORIC）。非布索坦通过降低患者血液中的尿酸水平改善来痛风患者的症状。此外，武田制药北美公司还是该产品在美国市场中的独立开发商与销售商。 　　
根据武田公司的一项声明：该产品的结构与40年前开发的黄嘌呤氧化酶抑制剂药物完全不同，它是一种全新的高效的非嘌呤类黄嘌呤氧化酶选择性抑制剂。黄嘌呤氧化酶则是促进尿酸生成的关键酶。
非布索坦可以降低高尿酸血症痛风患者血液中的尿酸水平，在临床研究中已经证明了非布索坦的安全性和有效性，而且在中、重度肝肾功能不全的患者中也不需要进行剂量调整。该产品的服用剂量为每日一次，一次40 毫克或者80毫克，但是该产品不推荐用于无高尿酸血症的痛风患者。 　　
非布索坦的原研厂家为日本的另一家公司，日本帝人制药（TeijinPharma）。在帝人制药公司总裁最近的一份声明中，我们可以了解到该公司对该产品采取的全球战略。他说，在本品获得FDA的许可之前，Ipsen公司的产品也获得了欧盟的上市许可。Ipsen公司是帝人制药关于该产品在欧盟的许可公司，而武田北美制药是本品在美国的许可公司。所以公司在全球已经取得了里程碑式的战略意义。同时他还指出，在亚洲市场，帝人制药将采取自主开发或联合开发的形式。 　　
据专家介绍，痛风是一组异质性疾病，是遗传性和（或）获得性引起的尿酸排泄减少和（或）嘌呤代谢障碍。临床特点：高尿酸血症，以及尿酸盐结晶，沉积所致的特征性急性关节炎、痛风石、间质性肾炎、严重者呈关节畸形及功能障碍；常伴尿酸性尿路结石。假性痛风常常与痛风混淆，因为其症状非常相似，假性痛风是由磷酸钙的代谢障碍引起，而不是尿酸代谢障碍引起。 　　　
根据美国国家关节肌肉骨骼疾病与皮肤病研究所（NIAMS）的研究数据表明，在美国有600万20岁及其以上的人生平有患痛风的经历。通常40~50岁的男性患者较为常见，而绝经前的女性患者少见。经历过器官移植的患者也容易患痛风。
药理作用特点　　
痛风的发生是由于体内产生尿酸过多及肾脏清除能力下降，尿酸体内蓄积，导致尿酸盐结晶在关节及各脏器沉积。因此，痛风的治疗通常采取的手段是：促进尿酸排泄和抑制尿酸生成，并采用适当措施改善相关症状。 　　
体内尿酸的生成与嘌呤代谢有关，在嘌呤代谢的最后步骤中，次黄嘌呤在黄嘌呤氧化还原酶（XOR）的作用下生成黄嘌呤，再进一步生成尿酸，抑制该酶的活性可以有效的减少尿酸的生成。非布索坦为目前世界上最新研制的XOR抑制剂，其通过高度选择性地作用于该氧化酶，减少体内尿酸合成，降低尿酸浓度，从而有效治疗通风疾病。 　　
30年来，别嘌呤醇是临床上唯一一个用于抑制尿酸生成的药物，并作为痛风的黄金治疗药物广泛用于临床，在抗痛风的治疗中取得了不俗的成绩。 　　
与别嘌呤相比，非布索坦具有明显优势： 　　
（1）别嘌呤醇只对还原型的XOR有抑制作用，而非布索坦对氧化型和还原型的XOR均有显著的抑制作用，因而其降低尿酸的作用更强大、持久； 　　
（2）由于别嘌呤醇为嘌呤类似物，不可避免的造成涉及嘌呤及吡啶代谢其他酶活性的影响。因此别嘌呤醇治疗中，需要重复大剂量给药来维持较高的药物水平。由此也带来由于药物蓄积所致的严重甚至致命的不良反应。而非布索坦为非嘌呤类XOR抑制剂，因此具有更好的安全性。
临床评价　　
一项多中心、双盲、随机Ⅱ期临床研究评价了非布索坦的安全性和对痛风的疗效。总共有136名男性和17名女性痛风病人随机接受安慰剂或本品(40、80或120mg/d),4周后检测发现,本品各剂量组病人血清尿酸浓度较治疗前均显著降低,按剂量由低至高各组分别平均降低37%、44%和59%,而安慰剂组病人仅降低了2%；绝大多数病人坚持完成了试验,本品和安慰剂组不良反应发生率相近，并且这些不良反应大多轻微,具有自限性,常见的有腹泻、疼痛、背痛、头痛和关节痛。 　　
一项Ⅲ期临床试验平行比较了本品(80和120mg/d)和别嘌醇(300mg/d)的疗效。对760名病人进行的为期1年的研究显示,与别嘌醇组相比,本品组中有更多的病人达到主要试验疗效指标－最后3个月均测得sUA浓度低于60mg/L(所有受试者均为痛风病人,且试验前sUA浓度均在80mg/L以上)；在治疗52周后,本品未能显著减少痛风石面积(痛风石是痛风特有的尿酸盐结晶的聚集体),但在试验早期的高剂量组,该作用较明显；各治疗组中,sUA浓度达标(<60mg/L)的病人较少再突发痛风，且其痛风石面积有更明显的减少；各治疗组的不良反应及其发生率相似,不良反应包括肝功能异常、腹泻、头痛、关节相关征和症状及肌骨骼/结缔组织症状。

フェブリク錠１０ｍｇ／フェブリク錠２０ｍｇ／フェブリク錠４０ｍｇ
商標名
Feburic Tablet
一般名
フェブキソスタット(Febuxostat)
包装f规格
フェブリク錠10mg
PTP：140錠(14錠×10)
**フェブリク錠20mg
PTP：70錠(14錠×5)、500錠(10錠×50)、700錠(14錠×50)
瓶：500錠(プラスチック製瓶入り)
フェブリク錠40mg
PTP：140錠(14錠×10)
製造販売元
帝人ファーマ株式会社