Febuxostat 80 mg film-coated tablets. Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Sie sollten deswegen generell vor der Behandlung mit einem neuen … We searched the MEDLINE and … 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. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. 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. 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. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. 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. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). Figure 1 Mean Serum Uric Acid Levels in Combined Pivotal Phase 3 Studies. Darreichungsform Filmtablette Gelbe, längliche, bikonvexe, 16 mm × 5 mm große Filmtablette mit beidseitiger Bruchkerbe. 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). Same active ingredients; Same company; Bookmark; Email; SmPC; Patient Leaflet; Last updated on emc: 25 Jul 2019. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. AUC and half-life of febuxostat increased in … 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). This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'. For ULORIC 80 mg, 1377 patients were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. Prophylaxis against gout flares was obligatory over the 26-week period. In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events. Clinical Outcomes: proportion of patients requiring treatment for a gout flare. For renally impaired subjects who were randomized to allopurinol, the dose was capped at 100 mg QD. To bookmark a medicine you must sign up and log in. To bookmark a medicine you must sign up and log in. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). 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. Between 46% and 55% of subjects received treatment for gout flares from Week 8 and Week 28. Febuxostat should be taken by mouth and can be taken with or without food. In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. According to Hira et al, 10. 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. Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended. For Adult. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. Febuxostat 80 mg can be used in patients concomitantly treated with theophylline without risk of increasing theophylline plasma levels. Excipient(s) with known effects: Each 80 mg tablet contains 76.50 mg of lactose (as monohydrate). 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. 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. Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. The Patient Information Leaflet (PIL) is the leaflet included in the pack with a medicine. 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. Colchicine/indometacin/hydrochlorothiazide/warfarin. 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. Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see section 4.8). Qualitative and quantitative composition, 4.2 Posology and method of administration, 4.4 Special warnings and precautions for use, 4.5 Interaction with other medicinal products and other forms of interaction, 4.7 Effects on ability to drive and use machines, 6.6 Special precautions for disposal and other handling, 9. May increase dose to 120 mg once daily if serum uric acid is >6 mg/dL after 2-4 weeks. 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. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. Febuxostat should not be used during pregnancy. Severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were associated with fever, haematological, renal or hepatic involvement in some cases. 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. Serious side effects include an increased risk of death as compared with allopurinol At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (see section 4.2). 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. These rates were similar to the rates reported on allopurinol (4.2%) (see section 4.4). The efficacy of febuxostat 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. Therefore, febuxostat may be taken without regard to antacid use. Was sollten Sie beachten? Febuxostat should not be used while breastfeeding. Primary endpoint in the sub-group of patients with renal impairment. No dose adjustment is necessary for warfarin when administered with febuxostat. 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. Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis). Background. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/2 26%). 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%). Common side effects of Febuxostat : Upset stomach or throwing up. No interaction studies have been performed in humans. In most cases, these reactions occurred during the first month of therapy with febuxostat. 4.5). Flares increased following the prophylaxis period and gradually decreased over time. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, have occurred in the post-marketing experience. There was no significant increase in any other tumour type in either male or female mice or rats. 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). Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. 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. 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. 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. … Febuxostat. 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. Febuxostat 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. It is unknown whether febuxostat is excreted in human breast milk. 240 mg febuxostat was used to evaluate the safety of febuxostat at twice the recommended highest dose. Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Continue typing to refine. The ability of febuxostat to lower serum uric acid levels was prompt and persistent. Two studies compared the efficacy and safety of febuxostat with allopurinol and 1 study compared with benzbromarone. View changes ; Print PDF; What is a Patient Information Leaflet … Stevens-Johnson-Syndrome and Toxic epidermal necrolysis are characterised by progressive skin rashes associated with blisters or mucosal lesions and eye irritation. Description of selected adverse reactions. When starting the treatment, your doctor will give you 80 mg strength tablets. Thus, Febuxostat may be taken without regard to food. Maximum dosage: 80 mg … *** See section 5.1 for incidences of gout flares in the individual Phase 3 randomized controlled studies. Plasma protein binding of the active metabolites ranges from about 82% to 91%. 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). Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of Febuxostat. At least 65% of the patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min). Continue. It is generally recommended only for people who cannot take allopurinol. Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine. There are two strengths of tablet - 80 mg and 120 mg. 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. Usually you’ll start with 80 mg daily, but your doctor will take regular blood tests and may increase the dose to 120 mg daily if your blood urate level doesn’t come down far enough for the crystals to dissolve. In two Phase III trials, significantly more febuxostat-treated gout patients met the primary endpoint [serum urate (sUA) <6 mg/dl (<360 μmol/l) at the last three visits] (48 and 53% with 80 mg; 65 and 62% with 120 mg), compared with those receiving allopurinol 300 mg (22 and 21%; P < 0.001 in both studies). This site uses cookies. 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. Population pharmacokinetics and therapeutic efficacy of febuxostat in patients with severe renal impairment. Febuxostat is eliminated by both hepatic and renal pathways. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Take one tablet each day. The Cmax and AUC of active metabolites increased up to 2- and 4-fold, respectively. 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. This site uses cookies. A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat. Start typing to retrieve search suggestions. 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. 2005 Dec 8;353(23):2450-61. doi: 10.1056/NEJMoa050373. INR and Factor VII activity were also not affected by the co-administration of febuxostat. Gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits (see section 4.8 and 5.1). About febuxostat. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds. Qualitative und quantitative Zusammensetzung Jede Filmtablette enthält 80 mg Febuxostat als Hemihydrat. Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 10 mg/dL. Where the combination cannot be avoided, a reduction of the dose of mercaptopurine/azathioprine is recommended. 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. 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 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). Febuxostat 80 mg is available in pack sizes of 14, 28, 56 and 98 film-coated tablets. 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. 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. Each tablet contains 76.50 mg of lactose (as monohydrate), Each tablet contains 1.89 mg of sodium (as croscarmellose sodium). As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended (see section 5.1). Patients in the febuxostat group were given febuxostat orally (80 mg and 120 mg tablets; Patheon France [Bourgoin Jallieu, France] or Menarini [Dresden, Germany]) at 80 mg daily for the first 2 weeks after randomisation. 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. In patients in whom the rate of urate formation is greatly increased (e.g. 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. Hinweise zu den Bereichen Allergien (betreffend Wirk- und Hilfsstoffe), Komplikationen mit Nahrungs- und Genussmitteln, sowie sonstige Warnhinweise. 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%). No data are available. INR and Factor VII activity were also not affected by the co- administration of febuxostat. 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. Following multiple oral doses of febuxostat, the Cmax and AUC were 24% and 12% higher in females than in males, respectively. To conduct a systematic review and meta-analysis and assess the risk of major adverse cardiovascular events (MACE) in patients receiving febuxostat compared to a control group.Methods. In a post-market CV outcome study (the CARES trial),1 a higher rate of CV fatal outcomes has been reported in patients with gout and established cardiovascular disease treated with ULORIC, when compared to those treated with allopurinol (see Background section for more details). Two hundred and forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation dose. No patients with organ transplant have been included in these studies (see section 4.2). No dose adjustment is needed based on gender. 3. Back to top. No data is available for febuxostat 120 mg. Naproxen and other inhibitors of glucuronidation. The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dL (357 μmol/L). A risk to a suckling infant cannot be excluded. Each 120 mg tablet contains 114.75 mg of lactose (as monohydrate). It allows continued monitoring of the benefit/risk balance of the medicinal product. If the serum urate is > 0.36 mmol/L, increase the dose of febuxostat to 120 mg* once daily, aiming for a serum urate of < 0.36 mmol/L. About 69 % of patients required no treatment change to achieve a final stable treatment. To view the changes to a medicine you must sign up and log in. 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). 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 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. Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn. In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to patients with normal renal function (Clcr greater than 80 mL/min). However, weight-corrected Cmax and AUC were similar between the genders. INR and Factor VII activity were also not affected by the co- administration of febuxostat. as inhibition of xanthine oxidase by febuxostat may cause increased plasma concentrations of mercaptopurine/azathioprine that could result in severe toxicity. It may be administered with or without food, and it can be taken with antacids. 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. I did run a gout fever cold/sweat/shakes which my Dr. Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgment (see section 5.1). 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. Gout flares were commonly observed soon after the start of treatment and during the first months. 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). The safety and the efficacy of Febuxostat in children aged below the age of 18 years have not been established. 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. This information is intended for use by health professionals. 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.