Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, have occurred in the post-marketing experience. <>>>/MediaBox[ 0 0 612 792]/Contents 104 0 R /Parent 2 0 R /Type/Page>> Intermediate density: 27.82% of the population. Rosuvastatin; Ezetimibe: (Moderate) Do not exceed a rosuvastatin dose of 20 mg once daily if concomitant use of febuxostat is necessary. Identified risk factors among these patients were a medical history of atherosclerotic disease and/or myocardial infarction, or of congestive heart failure. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. 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. The composition of claim 1, wherein said micronized febuxostat form-G has particle size distribution of; D90 less than 30, D 5 o less than 1-5 and D1 0 less than 1 . In a study conducted in healthy adults, coadministration of febuxostat (80 mg PO daily) resulted in increased theophylline Cmax (6%) and AUC (6.5%). Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice). Increased TSH values (>5.5 IU/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). It is in a class of drugs known as xanthine oxidase inhibitors. TEVA-FEBUXOSTAT Page 1 of 32 PRODUCT MONOGRAPH PrTEVA-FEBUXOSTAT Febuxostat Tablets 80 mg febuxostat (as febuxostat hemihydrate) Preparations Inhibiting Uric Acid Production Teva Canada Limited 30 Novopharm Court Toronto, Ontario Canada, M1B 2K9 Date of Revision: January 27, 2020 Submission Control No: 234067 hm| No data is available regarding the safety of febuxostat during other cytotoxic therapy. The CV outcomes study in patients with gout (CARES) was a randomized, double-blinded, allopurinol-controlled, non-inferiority study conducted to evaluate the risk of major adverse cardiovascular events (MACE) in patients with gout who were treated with febuxostat. Primary endpoint in the sub-group of patients with renal impairment. <>>>/MediaBox[ 0 0 612 792]/Contents 116 0 R /Parent 2 0 R /Type/Page>> endobj 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. 11 0 obj An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi. Febuxostat has not been studied in patients with Child-Pugh Class C hepatic impairment or in patients with comorbid hepatic and renal impairment.Renal ImpairmentIn a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 49 mL/minute) or severe renal impairment (CrCl 10 to 29 mL/minute), the Cmax of febuxostat did not change relative to patients with normal renal function (CrCl more than 80 mL/min). Risk of adverse hepatic effects. The range of the discounts will vary depending on the type of prescription and the pharmacy chosen. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.PediatricsSafety and efficacy has not been established in patients under 18 years of age.GeriatricNo clinically significant differences were noted in the pharmacokinetics, pharmacodynamics, and safety of febuxostat based on age.Gender DifferencesNo clinically significant differences were noted in the pharmacokinetics, pharmacodynamics, and safety of febuxostat based on gender in adult populations.Ethnic DifferencesRace-based statistically significant differences in febuxostat efficacy were reported in a 5-year open-label trial, with 87% of Caucasian patients reaching target serum urate concentrations of < 6 mg/dL compared to 65% of non-Caucasian patients (p = 0.025). Consider gout flare prophylaxis with an NSAIA or colchicine; start these agents when febuxostat therapy is initiated. Febuxostat use has not been studied in these populations.Limited available data with the use of febuxostat in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes resulting from fetal exposure during pregnancy. Plasma protein binding of the active metabolites ranges from about 82% to 91%. 24 0 obj Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and oxidation via cytochrome P450 enzymes, including CYP1A2, CYP2C8, and CYP2C9 and non-P450 enzymes. Febuxostat has not been studied in patients with end-stage renal failure receiving dialysis. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose - The recommended febuxostat tablet dosage is 40 mg or 80 mg once daily. It is acceptable to add a small amount of surfactant, if necessary. Thereafter, the frequency of gout flare decreases in a time-dependent manner. A lower target (less than 5 mg/dL) is recommended for patients with severe disease. Abnormal laboratory parameters noted in < 1% of patients include creatinine and blood urea increases, BUN/creatinine ratio increases, and urinary casts.Myelosuppression occurred rarely, less than 1%, in study patients taking febuxostat. <>>>/MediaBox[ 0 0 612 792]/Contents 115 0 R /Parent 2 0 R /Type/Page>> <>>>/MediaBox[ 0 0 612 792]/Contents 99 0 R /Parent 2 0 R /Type/Page>> Manufacturer makes no specific dosage recommendations for patients with severe hepatic impairment (Child-Pugh class C). Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. Clinically significant interactions between febuxostat and drugs that inhibit or induce one particular enzyme isoform are generally not expected. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. risk of anaphylaxis (febuxostat uricosuric effects may interfere w/ laboratory test) topotecan. Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn. 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). (See Interactions.). Everolimus Drug Monograph(Everolimus (AFINITOR)in Breast Cancer MonographAddendum) Evolocumab (REPATHA) Drug Monograph: Exenatide Extended-Release: Ezetimibe: Ezogabine (POTIGA) Drug Monograph: Factor VII, Recombinant Activated (NovoSeven), Drug Monograph: Febuxostat: Fentanyl Transmucosal Immediate-release Monograph (Updated Aug 2016) 32 0 obj Animal studies revealed no evidence of fetal harm at exposures greater than those achieved with maximum recommended human dosage. is the primary source of official quality standards for medicines and their ingredients in Europe. x\]o6}Gii[*db;CK[ux)Sd$YWvP(%{Iz|!}77\N>O6~}_\}|{|w;^^:\{r2O8IWq7<>2bo7G>F D1j$_s'}H+)<>*>>j{(HH``vU2`?Dfh6QvN After single or multiple oral 80 and 120 mg once daily doses, Cmax is approximately 2.8-3.2 g/mL, and 5.0-5.3 g/mL, respectively. Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). Febuxostat inhibits uric acid formation but does not affect xanthine and hypoxanthine formation. 43 0 obj 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%). The study enrolled patients who had a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease. Fatal and nonfatal hepatic failure reported; causal relationship to drug cannot be excluded. In a study of febuxostat in patients with varying degrees of renal function, the renal elimination of febuxostat and metabolites was inversely related to the degree of renal impairment.Febuxostat is not recommended in patients with secondary hyperuricemia (e.g., after organ transplant) or in patients with a greatly increased rate of uric acid synthesis (e.g., those with neoplastic disease, patients on chemotherapy, and patients with Lesch-Nyhan syndrome). Febuxostat is more sensitive toward acidic conditions than oxidation and very resistant toward alkaline, thermal and photolytic degradations. 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. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. Written by ASHP. Does not induce CYP 1A2, 2B6, 2C9, 2C19, or 3A4. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. Not evaluated in patients with secondary hyperuricemia. (See Contraindications under Cautions. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. DailyMed - FEBUXOSTAT tablet The Cmax and AUC of active metabolites increased up to 2- and 4-fold, respectively. Treatment with allopurinol not advisable. VA class: MS400 Avoid/Use Alternative. 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. The ability of febuxostat to lower serum uric acid levels was prompt and persistent. DISCOUNT ONLY - NOT INSURANCE. 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). 116 patients were enrolled and received initially febuxostat 80 mg QD. endobj Febuxostat shares with allopurinol an increased risk of gout flare during therapy initiation, which necessitates the concurrent use of colchicine, NSAIDs, or corticosteroids for prophylaxis against acute gout attacks. Initial dosage is 40 mg once daily. endobj endobj After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of Febuxostat. x[OH#?]=SU.^(YhBp RcR=SN/X.f{7l~^8+pz'jV,KYVdK~{2q\F$OU7{NtqxNAPh"kr~,"2{)zIGFYUiSam-JT,g4uA8x9@Dq9dttL4S07JQv+| nqttK< 'qz9jo&/)Op@`Z~:k?: 9[>xS~c'=KK&=]B6kXB|2&QfX@x Vx endobj XLSX US Pharmacopeia (USP) 54 0 obj bh^ [Content_Types].xml ( N0EHC-J@5*Q>c[iiBj7{2hnmRU^7/%rZY@1__f qR4DAJh>VZ9NV8ji){^-I"{v^P!XS)bRrKs(3`c07M4Zk+|\|z(P6h_-[@! Pk2n}?L %ddN"m,DO97*~8Oc|nEB!$};{[2 PK ! patients post-organ transplant and those with neoplastic disease) have a greatly increased rate of urate formation. Brand name: Uloric }Dg"$4FY.2#59Y]bd@%s"0tB)[ PK ! In placebo- and alternative drug-controlled study, rash (unspecified) was reported in 0.5% of patients taking 40 mg/day, 1.6% of patients taking 80 mg/day, 1.6% of patients taking allopurinol 100-300 mg/day, and 0.7% of those on placebo. Pegloticase: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Febuxostat inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. 40 0 obj Continuous treatment with febuxostat decreases frequency and intensity of gout flares. Febuxostat Generic name: febuxostat [ fe-BUX-oh-stat ] Brand name: Uloric Dosage form: oral tablet (40 mg; 80 mg) Drug class: Antihyperuricemic agents Medically reviewed by Drugs.com on Feb 13, 2023. (See Renal Impairment under Cautions. There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of febuxostat in elderly as compared to younger healthy subjects. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.8). <>]/Type/Catalog/MarkInfo<>/Lang(en-CA)/Metadata 1929 0 R >> Steady-state serum uric acid concentration may be reached within 7 days of therapy initiation. These changes were not considered statistically significant. Cladribine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. Table 1: Adverse reactions in combined phase 3, long-term extension studies and post-marketing experience, Pancytopenia, thrombocytopenia, agranulocytosis*, Anaphylactic reaction*, drug hypersensitivity*, Blood thyroid stimulating hormone increased, Diabetes mellitus, hyperlipidemia, decrease appetite, weight increase, Weight decrease, increase appetite, anorexia, Dizziness, paraesthesia, hemiparesis, somnolence, altered taste, hypoaesthesia, hyposmia, Atrial fibrillation, palpitations, ECG abnormal, Dyspnoea, bronchitis, upper respiratory tract infection, cough, Abdominal pain, abdominal distension, gastro-oesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent stools, flatulence, gastrointestinal discomfort, Rash (including various types of rash reported with lower frequencies, see below), Dermatitis, urticaria, pruritus, skin discolouration, skin lesion, petechiae, rash macular, rash maculopapular, rash papular, 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, Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tightness, bursitis, Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness, Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria, Tubulointerstitial nephritis*, micturition urgency, General disorders and administration site conditions, 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, Blood glucose increase, activated partial thromboplastin time prolonged, red blood cell count decrease, blood alkaline phosphatase increase, blood creatine phosphokinase increase*, * Adverse reactions coming from post-marketing experience. 1 UNITS 2S (USP34) Table 1. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Administration with food does not appear to affect efficacy. A risk to a suckling infant cannot be excluded. No data are available. No data is available for febuxostat 120 mg. During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). Manufacturer states that febuxostat may be used with caution in patients with lesser elevations of ALT or bilirubin if an alternate probable cause of liver function test abnormalities determined. > xl/_rels/workbook.xml.rels ( J0n""Ej}Lm2ef2k&WP%&w Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Severe renal impairment: AUC is increased by 9698%. Cardiovascular Death: In a CV outcomes study, there was a higher rate of CV death in patients treated with Febuxostat Tablets compared to allopurinol; in the same study Febuxostat Tablets was non-inferior to allopurinol for the primary endpoint of major adverse cardiovascular events (MACE). Liver function abnormalities, nausea, arthralgia, rash. <>>>/MediaBox[ 0 0 612 792]/Contents 113 0 R /Parent 2 0 R /Type/Page>> After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Analysis of renal excretion revealed that within 24 hours, approximately 49% was eliminated in the urine; 3% was excreted as febuxostat, 30% as the acyl glucuronide, 13% as known oxidative metabolites and their conjugates, and 3% as unknown metabolites. The primary endpoint was the time to the first occurrence of MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. Strength - Testing methods and acceptable ranges for the potency of a . Patients should always consult their physician with any questions regarding a medical condition and to obtain medical advice and treatment. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Physicians and patients should remain alert for adverse CV signs and symptoms. 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. Report a suspected side effect or falsified product to the MHRA Yellow Card scheme. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat is rapidly (tmax of 1.0-1.5 h) and well absorbed (at least 84%). In most cases, these reactions occurred during the first month of therapy with febuxostat. endobj The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving . Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. bha [Content_Types].xml ( MO0H*WfZGqhi=n!]kg4Y6[AD])@d*cI9wP FM 8a) %V The gout flare should be managed concurrently as appropriate for the individual patient. Centre, also called Centre-Val-de-Loire, rgion of France encompassing the central dpartements of Cher, Indre, Indre-et-Loire, Loir-et-Cher, Loiret, and Eure-et-Loir. The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance <30 mL/min, see section 5.2). Febuxostat was similar to allopurinol for nonfatal MI, nonfatal stroke, and unstable angina with urgent coronary revascularization. <>/ProcSet[/PDF/Text/ImageB/ImageC/ImageI]/Font<>>>/MediaBox[ 0 0 612 792]/Contents 101 0 R /Parent 2 0 R /Type/Page>> 29 0 obj Molecular formula: C16H16N2O3S If a gout flare occurs during febuxostat treatment, it should not be discontinued. 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 mol/L). No difference in the proportion of patients requiring treatment for gout flares was observed between the febuxostat 80 mg and 40 mg groups. The easiest way to lookup drug information, identify pills, check interactions and set up your own personal medication records. If liver function test abnormalities develop during treatment: Interrupt treatment and establish the probable cause. "ay[rYP,q-L~.w*]PxPiy)[5:KkU)`rq0)Wq;0-0IIoxoF~.I'qPO'U>qQm9p~Z" RL'59D\1g*QP#TnVI0h!CB}oSr"jg?M|;^FgSc Serious skin and hypersensitivity reactions including anaphylaxis, anaphylactoid reactions, generalized rash, erythema multiforme, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN). Description of selected adverse reactions. Between 46% and 55% of subjects received treatment for gout flares from Week 8 and Week 28. After the initiation of febuxostat therapy, liver-function testing is recommended at 2 months, 4 months, and periodically thereafter. Reserve febuxostat use for patients with an inadequate response to maximum recommended dosages of allopurinol or in whom allopurinol is not tolerated or is not recommended; evaluate risks and benefits of initiating or continuing febuxostat therapy. However, weight-corrected Cmax and AUC were similar between the genders. Seven hundred sixty (760) patients were randomized: febuxostat 80 mg QD (n=256), febuxostat 120 mg QD (n=251), or allopurinol 300 mg QD (n=253).
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