We searched the MEDLINE and … Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds. There was no significant increase in any other tumour type in either male or female mice or rats. In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects on fertility (see section 5.3). Following multiple doses of 80 mg of febuxostat in patients with mild, moderate or severe renal impairment, the Cmax of febuxostat did not change, relative to subjects with normal renal function. According to Hira et al, 10. Febuxostat. Mild to moderate (CrCl 30-89 mL/min): No dosage adjustment necessary ; Severe (CrCl ; 30 mL/min): Not to exceed 40 mg/day Hepatic impairment. However, weight-corrected Cmax and AUC were similar between the genders. 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. … Rare serious hypersensitivity reactions to febuxostat, including Stevens-Johnson-Syndrome, Toxic epidermal necrolysis and anaphylactic reaction/shock, have occurred in the post-marketing experience. It allows continued monitoring of the benefit/risk balance of the medicinal product. Febuxostat has been shown to potently inhibit both the oxidized and reduced forms of XO. For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Serious side effects include an increased risk of death as compared with allopurinol Hira D. Chisaki Y. Noda S. et al. One thousand and seventy-two (1072) patients were randomized: placebo (n=134), febuxostat 80 mg QD (n=267), febuxostat 120 mg QD (n=269), Febuxostat 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 studies compared the efficacy and safety of febuxostat with allopurinol and 1 study compared with benzbromarone. Febuxostat should not be used while breastfeeding. At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (see section 4.2). 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. In trials, febuxostat 80 mg/day was shown to reduce and maintain serum uric acid levels below the guideline target of 0.36 mmol/L in most patients (about 70%). Back to top. No dose adjustment is necessary in patients with mild or moderate renal impairment. These adverse reactions were mostly mild or moderate in severity. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is unknown whether febuxostat is excreted in human breast milk. Primary endpoint in the sub-group of patients with renal impairment. A total of 1,086 patients were enrolled: Febuxostat 80 mg QD (n=649), febuxostat 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). Crude rates of incident renal disease per 1000 person-years were lower with higher daily dose: allopurinol <200, 200–299 and ≥300 mg/day with 238, 176 and 155; and febuxostat 40 and 80 mg/day with 341 and 326, respectively. as inhibition of xanthine oxidase by febuxostat may cause increased plasma concentrations of mercaptopurine/azathioprine that could result in severe toxicity. The recommended dose is 40 or 80 mg daily. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. Es kann Arzneimittel geben, mit denen Wechselwirkungen auftreten. Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Naomi Schlesinger MD, in Gout, 2019. 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. As there has been no experience with febuxostat, its use in these populations is not recommended. Febuxostat 80 mg is available in pack sizes of 14, 28, 56 and 98 film-coated tablets. To bookmark a medicine you must sign up and log in. In the additional phase 3 CONFIRMS study, for which results became available after the marketing authorisation for febuxostat 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. Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn. Date of first authorisation/renewal of the authorisation. Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. The apparent steady state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L after oral doses of 10-300 mg. 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. Table 2 summarises the primary efficacy endpoint results: Table 2: Proportion of Patients with Serum Acid Levels < 6.0 mg/dL (357 µmol/L) Last Three Monthly Visits, 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. Co-administration of febuxostat 80 mg and theophylline 400mg single dose in healthy subjects showed absence of any pharmacokinetic interaction (see section 4.5). The safety and the efficacy of Febuxostat in children aged below the age of 18 years have not been established. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis). Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. The FACT study showed the statistically significant superiority of both febuxostat 80 mg and febuxostat 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). Interestingly, both patients who stopped febuxostat due to adverse events were undergoing PD and their febuxostat doses were 40 and 80 mg/d, respectively. For the full list of excipients, see Section 6.1. 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. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. 3 PHARMACEUTICAL FORM . Febuxostat is eliminated by both hepatic and renal pathways. The strength of the tablet may be increased after 2-4 weeks to 120 mg, if this is necessary. 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). Vollständige Auflistu ng der sonstigen Be-standteile siehe Abschnitt 6.1. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. Febuxostat contains sodium. When suggestions are available use up and down arrows to review and ENTER to select. 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. Pharmacokinetic modelling and simulation of rat data suggests that, when co-administered with febuxostat, the clinical dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose in order to avoid possible haematological effects (see section 4.4 and 4.5). 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. 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. INR and Factor VII activity were also not affected by the co-administration of febuxostat. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. When suggestions are available use up and down arrows to review and ENTER to select. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. No difference in the proportion of patients requiring treatment for gout flares was observed between the febuxostat 80 mg and 40 mg groups. In November 2017 the FDA released a warning alert on a possible link between febuxostat and cardiovascular disease (CVD) reported in a single clinical trial.Objective. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, have occurred in the post-marketing experience. The recommended oral dose of Febuxostat is 80 mg once daily without regard to food. 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). Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 10 mg/dL. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). Following multiple doses of 80 mg of febuxostat 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. If serum uric acid is > 6 mg/dL (357 µmol/L) after 2-4 weeks, Febuxostat 120 mg once daily may be considered. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. … A risk to a suckling infant cannot be excluded. Sie sollten deswegen generell vor der Behandlung mit einem neuen … Continue, 2. These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use. 116 patients were enrolled and received initially febuxostat 80 mg QD. Desipramine/CYP2D6 substrates. Was sollten Sie beachten? 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. The Cmax and AUC of active metabolites increased up to 2- and 4-fold, respectively. For renally impaired subjects who were randomized to allopurinol, the dose was capped at 100 mg QD. Modelling and simulation analysis of data from a pre-clinical study in rats indicates that, in case of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section 4.4 and 5.3). Common side effects of Febuxostat : Upset stomach or throwing up. The ability of febuxostat to lower serum uric acid levels was prompt and persistent. Two thousand and two hundred-sixty nine (2269) patients were randomized: Febuxostat 40 mg QD (n=757), febuxostat 80 mg QD (n=756), or allopurinol 300/200 mg QD (n=756). However, no dose adjustment is necessary in patients with mild or moderate renal impairment. Febuxostat is approved in the United States for the management of hyperuricemia in patients with gout. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. Qualitative und quantitative Zusammensetzung Jede Filmtablette enthält 80 mg Febuxostat als Hemihydrat. To email a medicine you must sign up and log in. 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%). Two hundred and forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation dose. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). *** See section 5.1 for incidences of gout flares in the individual Phase 3 randomized controlled studies. In a study in healthy subjects, 120 mg Febuxostat 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. 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. Desipramine/CYP2D6 substrates . PVC/PCTFE – Aluminium blister of 14 tablets. Febuxostat was approved by the FDA in 2009 for the treatment of gout and is an important alternative for patients who are intolerant/contraindicated or refractory to allopurinol. Hinweise zu den Bereichen Allergien (betreffend Wirk- und Hilfsstoffe), Komplikationen mit Nahrungs- und Genussmitteln, sowie sonstige Warnhinweise. 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. Same active ingredients; Same company; Bookmark; Email; SmPC; Patient Leaflet; Last updated on emc: 25 Jul 2019. This site uses cookies. The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance <30 mL/min, see section 5.2). The patients should be closely monitored and the dose of mercaptopurine/azathioprine should be subsequently adjusted based on the evaluation of the therapeutic response and the onset of eventual toxic effects. To bookmark a medicine you must sign up and log in. Eighty-eight subjects in the 80-mg febuxostat group, ... Becker MA, Kisicki J, Khosraven R, et al. 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). 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. How should Febuxostat be used: PO- The recommended dose is 40 to 80mg, once daily. Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Similar reductions in gout flares and tophus area occurred in all treatment groups. Administrarea concomitentă de febuxostat 80 mg şi o doză unică de 400 mg de teofilină la indivizi sănătoşi au arătat că nu există interacţiuni farmacocinetice (vezi pct. Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary. No data are available. Yellow, oblong biconvex film-coated tablets, marked on one side with “80”. No patients with organ transplant have been included in these studies (see section 4.2). By continuing to browse the site you are agreeing to our policy on the use of cookies. 2005 Dec 8;353(23):2450-61. doi: 10.1056/NEJMoa050373. Continuous treatment with febuxostat decreases frequency and intensity of gout flares. During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, ATC code: M04AA03. POM: Prescription only medicine. Initially 80 mg once daily, if after 2–4 weeks of initial dose, serum uric acid greater than 6 mg/100 mL then increase dose; increased if necessary to 120 mg once daily. 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. Dosage increases: Your doctor may increase your dosage to 80 mg after 2 weeks if your uric acid level does not fall below 6 mg/dL. May increase dose to 120 mg once daily if serum uric acid is >6 mg/dL after 2-4 weeks. 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%). INR and Factor VII activity were also not affected by the co- administration of febuxostat. 4.5). Febuxostat lowers uric acid. Flares increased following the prophylaxis period and gradually decreased over time. When starting the treatment, your doctor will give you 80 mg strength tablets. The APEX study showed statistically significant superiority of both the febuxostat 80 mg QD and the febuxostat 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). Primary endpoint in the sub group of patients with sUA ≥ 10 mg/dL. PVC/PVDC – Aluminium blister of 14 tablets. Continue typing to refine. No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide. In order to mitigate the risk identified in the CARES trial,1the ULORIC CPM has been updated to include the revised indication for use and additional safety information. Gave me a shot for. No data is available for febuxostat 120 mg. Naproxen and other inhibitors of glucuronidation. 91% and 93% of patients on initial treatment with febuxostat 80 mg and 120 mg, respectively, had sUA <6 mg/dL at Month 36). Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary. In propensity-matched analyses, compared with febuxostat, allopurinol use was associated with lower HR of incident renal disease, 0.61 (95% CI 0.49 to 0.77). Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. ** 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. Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see section 4.8). There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. These rates were similar to the rates reported on allopurinol (4.2%) (see section 4.4). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Gout flares were commonly observed soon after the start of treatment and during the first months. Excipient(s) with known effects: Each 80 mg tablet contains 76.50 mg of lactose (as monohydrate). To view the changes to a medicine you must sign up and log in. Each tablet contains 76.50 mg of lactose (as monohydrate), Each tablet contains 1.89 mg of sodium (as croscarmellose sodium). It is written for patients and gives information about taking or using a medicine. 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. To view the changes to a medicine you must sign up and log in. Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended. 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. If a gout flare occurs during febuxostat treatment, it should not be discontinued. Common side effects include liver problems, nausea, joint pain, and a rash. Febuxostat, sold under the brand names Uloric and Adenuric among others, is a medication used long-term to treat gout due to high uric acid levels. Following multiple oral doses of febuxostat, the Cmax and AUC were 24% and 12% higher in females than in males, respectively. 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. This medicinal product does not require any special storage conditions. Population pharmacokinetics and therapeutic efficacy of febuxostat in patients with severe renal impairment. Gout flare prophylaxis of at least 6 months is recommended (see section 4.4). A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat. Continue. Plasma protein binding of the active metabolites ranges from about 82% to 91%. Your doctor will advise you about the correct dose. 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). Based on modelling and simulation analysis of data from a pre-clinical study in rats, when coadministered with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to the 20% or less of the previously prescribed dose in order to avoid possible haematological effects (see section 4.5 and 5.3). Between 46% and 55% of subjects received treatment for gout flares from Week 8 and Week 28. At least 65% of the patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min). In Phase 2 and 3 clinical studies, a total of 2757 patients with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily. 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. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Febuxostat does not adversely affect performance.
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