安斯泰来BPH药物VESOMNI获欧洲首个上市
from post-marketing reporting. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of solifenacin or tamsulosin and their causation cannot be reliably determined. from post-marketing reporting, observed during cataract and glaucoma surgery. see section 4.4 Special warnings and precautions for use. Long –term safety of Vesomni The profile of undesirable effects seen with treatment up to 1 year was similar to that observed in the 12-week studies. The product is well-tolerated and no specific adverse reactions have been associated with long-term use. Description of selected adverse reactions For urinary retention see section 4.4 Special warnings and precautions for use. Older people The therapeutic indication of Vesomni, moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with BPH, is a disease affecting elderly men. The clinical development of Vesomni has been performed in patients 45 to 91 years of age, with an average age of 65 years. Adverse reactions in the elderly population were similar to the younger population. 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 at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Symptoms Overdosage with the combination of solifenacin and tamsulosin can potentially result in severe anticholinergic effects plus acute hypotension. The highest dose taken accidentally during a clinical study corresponded to 126 mg of solifenacin succinate and 5.6 mg of tamsulosin hydrochloride. This dose was well-tolerated, with mild dry mouth for 16 days as the only reported adverse event. Treatment In the event of overdose with solifenacin and tamsulosin, the patient should be treated with activated charcoal. Gastric lavage is useful if performed within 1 hour, but vomiting should not be induced. As for other anticholinergics, symptoms of overdose due to the solifenacin component can be treated as follows: - Severe central anticholinergic effects such as hallucinations or pronounced excitation: treat with physostigmine or carbachol. - Convulsions or pronounced excitation: treat with benzodiazepines. - Respiratory insufficiency: treat with artificial respiration. - Tachycardia: treat symptomatically if needed. Beta-blockers should be used with caution, since the concomitant overdose with tamsulosin could potentially induce severe hypotension. - Urinary retention: treat with catheterisation. As with other antimuscarinics, in case of overdosing, specific attention should be paid to patients with a known risk for QT-prolongation (i.e., hypokalaemia, bradycardia and concurrent administration of medicinal products known to prolong QT-interval) and relevant pre-existing cardiac diseases (i.e., myocardial ischaemia, arrhythmia, congestive heart failure). Acute hypotension, which can occur after overdosage due to the tamsulosin component, should be treated symptomatically. Hemodialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: alpha-adrenoceptor antagonists ATC code: G04CA53 Mechanism of action Vesomni is a fixed dose combination tablet containing two active substances, solifenacin and tamsulosin. These drugs have independent and complementary mechanisms of action in the treatment of lower urinary tract symptoms (LUTS) associated with BPH, with storage symptoms. Solifenacin is a competitive and selective antagonist of muscarinic receptors and has no relevant affinity for various other receptors, enzymes and ion channels tested. Solifenacin has the highest affinity for muscarinic M3-receptors, followed by muscarinic M1- and M2-receptors. Tamsulosin is an alpha1-adrenoceptor (AR) antagonist. It binds selectively and competitively to postsynaptic alpha1-ARs, in particular to subtypes alpha1A and alpha1D and is a potent antagonist in lower urinary tract tissues. Pharmacodynamic effects Vesomni tablets consist of two active substances with independent and complementary effects in LUTS associated with BPH, with storage symptoms: Solifenacin ameliorates storage function problems related to non-neuronally released acetylcholine activating M3-receptors in the bladder. Non-neuronally released acetylcholine sensitizes urothelial sensory function and manifests as urinary urgency and frequency. Tamsulosin improves voiding symptoms (increases the maximum urinary flow rate), by relieving obstruction via relaxation of smooth muscle in prostate, bladder neck and urethra. It also improves storage symptoms. Clinical efficacy and safety Efficacy was demonstrated in a pivotal phase 3 study in patients with LUTS associated with BPH with voiding (obstructive) symptoms and at least the following level of storage (irritative) symptoms: ≥ 8 micturitions/24 hours and ≥ 2 urgency episodes/24 hours. Vesomni showed statistically significant improvements from baseline to end of study compared with placebo in the two primary endpoints, total International Prostate Symptom Score (IPSS) and Total Urgency and Frequency Score, and on the secondary endpoints urgency, micturition frequency, mean voided volume per micturition, nocturia, IPSS voiding sub-score, IPSS storage sub-score, IPSS quality of life (QoL), Overactive Bladder questionnaire (OAB-q) Bother score and OAB-q Health Related Quality of Life (HRQoL) score including all sub-scores (coping, concern, sleep and social). Vesomni showed superior improvement compared with tamsulosin OCAS on Total Urgency and Frequency Score, as well as on micturition frequency, mean voided volume per micturition and IPSS storage sub-score. This was accompanied by significant improvements in IPSS QoL and OAB-Q HRQoL total score including all sub-scores. Furthermore, Vesomni was non-inferior to tamsulosin OCAS on total IPSS (p <0.001), as expected. 5.2 Pharmacokinetic properties Vesomni The information below presents the pharmacokinetic parameters after multiple dosing of Vesomni. A multiple dose relative bioavailability study demonstrated that the administration of Vesomni results in comparable exposure to that of the co-administration of the separate tablets of solifenacin and tamsulosin OCAS of the same dose. Absorption After multiple dosing of Vesomni, the tmax of solifenacin varied between 4.27 hours and 4.76 hours in different studies; the tmax of tamsulosin varied between 3.47 hours and 5.65 hours. The corresponding Cmax values of solifenacin varied between 26.5 ng/mL and 32.0 ng/mL, while the Cmax of tamsulosin varied between 6.56 ng/mL and 13.3 ng/mL. The AUC values of solifenacin varied between 528 ng.h/mL and 601 ng.h/mL, and of tamsulosin between 97.1 ng.h/mL and 222 ng.h/mL. The absolute bioavailability of solifenacin is approximately 90%, while for tamsulosin 70% to 79% is estimated to be absorbed. A single dose food effect study was performed with Vesomni dosed under fasted conditions, after a low fat, low caloric breakfast and after a high fat, high caloric breakfast. After a high fat, high caloric breakfast, a 54% increase in Cmax for the tamsulosin component of Vesomni was observed compared to the fasted state while the AUC increased by 33%. A low fat, low caloric breakfast did not affect the pharmacokinetics of tamsulosin. The pharmacokinetics of the solifenacin component were not affected by either a low fat, low caloric, or a high fat, high caloric breakfast. Concomitant administration of solifenacin and tamsulosin OCAS resulted in a 1.19-fold increase in the Cmax and 1.24-fold increase in the AUC of tamsulosin as compared to the AUC of tamsulosin OCAS tablets administered alone. There was no indication of an effect of tamsulosin on the pharmacokinetics of solifenacin. Elimination After a single administration of Vesomni, the t1/2 of solifenacin ranged from 49.5 hours to 53.0 hours and of tamsulosin from 12.8 hours to 14.0 hours. Multiple doses of verapamil 240 mg q.d. co-administered with Vesomni resulted in a 60% increase in Cmax and a 63% increase in AUC for solifenacin, while for tamsulosin Cmax increased by 115% and AUC by 122%. The changes in Cmax and AUC are not considered clinically relevant. Population pharmacokinetic analysis of the phase 3 data showed that intra-subject variability in tamsulosin pharmacokinetics was related to differences in age, height and α1-acid glycoprotein plasma concentrations. An increase in age and α1-acid glycoprotein was associated with an increase in AUC, while an increase in height was associated with a decrease in AUC. The same factors resulted in similar changes in the pharmacokinetics of solifenacin. In addition, increases in gamma glutamyl transpeptidase were associated with higher AUC values. These changes in AUC are not considered clinically relevant. Information from the individual active substances used as single entity products complete the pharmacokinetic properties of Vesomni: Solifenacin Absorption For solifenacin tablets, tmax is independent of the dose and occurs 3 to 8 hours after multiple dosing. The Cmax and AUC increase in proportion to the dose between 5 to 40 mg. Absolute bioavailability is approximately 90%. Distribution The apparent volume of distribution of solifenacin following intravenous administration is approximately 600 L. Approximately 98% of solifenacin is bound to plasma proteins, primarily α1-acid glycoprotein. Biotransformation Solifenacin has a low first pass effect, being metabolised slowly. Solifenacin is extensively metabolised by the liver, primarily by CYP3A4. However, alternative metabolic pathways exist, that can contribute to the metabolism of solifenacin. The systemic clearance of solifenacin is about 9.5 L/h. After oral dosing, one pharmacologically active (4R-hydroxy solifenacin) and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxyl-N-oxide of solifenacin) have been identified in plasma in addition to solifenacin. Elimination After a single administration of 10 mg [14C-labelled]-solifenacin, about 70% of the radioactivity was detected in urine and 23% in faeces over 26 days. In urine, approximately 11% of the radioactivity is recovered as unchanged active substance; about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite and 8% as the 4R-hydroxy metabolite (active metabolite). Tamsulosin Absorption For tamsulosin OCAS, tmax occurs 4 to 6 hours after multiple dosing of 0.4 mg/day. Cmax and AUC increase in proportion to the dose between 0.4 and 1.2 mg. The absolute bioavailability is estimated to be approximately 57%. Distribution The volume of distribution of tamsulosin following intravenous administration is about 16 L. Approximately 99% of tamsulosin is bound to plasma proteins, primarily α1-acid glycoprotein. Biotransformation Tamsulosin has a low first pass effect, being metabolised slowly. Tamsulosin is extensively metabolised by the liver, primarily by CYP3A4 and CYP2D6. The systemic clearance of tamsulosin is about 2.9 L/h. Most tamsulosin is present in plasma in the form of unchanged active substance. None of the metabolites were more active than the original compound. Elimination After a single dose of 0.2 mg [14C-labelled]-tamsulosin, after 1 week about 76% of radioactivity is excreted in urine and 21% in faeces. In urine, approximately 9% of the radioactivity is recovered as unchanged tamsulosin; about 16% as the sulphate of o-deethylated tamsulosin, and 8% as o-ethoxyphenoxy acetic acid. Characteristics in specific groups of patients Older people In the clinical pharmacology and biopharmaceutical studies, the age of the subjects varied between 19 and 79 years. After Vesomni administration, the highest mean exposure values were found in elderly subjects, although there was an almost complete overlap with individual values found in younger subjects. This was confirmed by population pharmacokinetic analysis of phase 2 and 3 data. Vesomni can be used in elderly patients. Renal impairment Vesomni Vesomni can be used in patients with mild to moderate renal impairment, but should be used with caution in patients with severe renal impairment. The pharmacokinetics of Vesomni have not been studied in patients with renal impairment. The following statements reflect the information available on the individual components regarding renal impairment. Solifenacin The AUC and Cmax of solifenacin in patients with mild or moderate renal impairment were not significantly different from that found in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), exposure to solifenacin was significantly greater than in the controls, with increases in Cmax of about 30%, AUC of more than 100% and t1/2 of more than 60%. A statistically significant relationship was observed between creatinine clearance and solifenacin clearance. Pharmacokinetics in patients undergoing haemodialysis have not been studied. Tamsulosin The pharmacokinetics of tamsulosin have been compared in 6 subjects with mild to moderate (30 ≤ CrCl < 70 mL/min/1.73 m2) or severe (< 30 mL/min/1.73 m2) renal impairment and 6 healthy subjects (CrCl > 90 mL/min/1.73 m2). While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to α1-acid glycoprotein, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Patients with end stage renal disease (CrCl < 10 mL/min/1.73 m2) have not been studied. Hepatic impairment Vesomni Vesomni can be used in patients with mild to moderate hepatic impairment, but is contraindicated in patients with severe hepatic impairment. The pharmacokinetics of Vesomni have not been studied in patients with hepatic impairment. The following statements reflect the information available on the individual components regarding hepatic impairment. Solifenacin In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the Cmax was not affected, AUC increased by 60% and t½ doubled. The pharmacokinetics of solifenacin in patients with severe hepatic impairment have not been studied. Tamsulosin The pharmacokinetics of tamsulosin have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh score of 7 to 9) and 8 healthy subjects. While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to α1-acid glycoprotein, the unbound (active) concentration of tamsulosin did not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin. Tamsulosin has not been studied in patients with severe hepatic impairment. 5.3 Preclinical safety data Non-clinical studies have not been conducted with Vesomni. Solifenacin and tamsulosin have been extensively evaluated individually in animal toxicity tests and findings were consistent with the known pharmacological actions. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and carcinogenic potential and do not raise a concern for potentiation or synergism of adverse effects when solifenacin and tamsulosin are combined. 6. Pharmaceutical particulars 6.1 List of excipients Mannitol (E421) Maltose Macrogol 7.000.000 Macrogol 8000 Magnesium stearate (E470b) Butylhydroxytoluene (E321) Colloidal silica anhydrous (E551) Hypromellose (E464) Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage The medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Aluminium blister packs containing 10, 14, 20, 28, 30, 50, 56, 60, 90, 100 or 200 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Astellas Pharma Ltd. 2000 Hillswood Drive Chertsey Surrey KT16 0RS United Kingdom 8. Marketing authorisation number(s) PL 00166/0404 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 23/10/2013 10. Date of revision of the text 23/10/2013 New Drugs Online Report for solifenacin + tamsulosin Information Generic Name: solifenacin + tamsulosin Trade Name: Vesomni Synonym: EC905 Entry Type: New formulation Developmental Status UK: Launched EU: Launched US: None UK launch Plans: Available only to registered users Actual UK launch date: February 2014 Comments Feb 14: Launched in the UK for treatment of men with lower urinary tract symptoms. Net price: £27.62 for 30 x 6mg/0.4mg tabs [7]. 03/02/2014 11:45:13 Nov 13: Launched in the Netherlands for the treatment of moderate to severe storage symptoms (urgency and increased micturition frequency) and voiding symptoms associated with BPH, in patients not responding adequately to monotherapy [6]. 06/12/2013 17:52:19 May 13: Approved in the EU [6]. 06/12/2013 17:50:43 Mar 12: Filed in the Netherlands via the EU decentralised procedure [3]. 28/03/2012 15:45:23 PIII in the EU [1]. 07/03/2011 14:36:09 Trial or other data Mar 13: NCT01018511 was completed in March 2011 [5]. 08/03/2013 16:01:23 NEPTUNE II is a PIII open-label extension study (NCT01021332) investigating long-term efficacy & safety of the solifenacin/tamsulosin oral controlled absorption system (OCAS) over 52 weeks. The study will recruit 800 pts & will complete in May 11. The primary outcome measures include incidence & severity of AEs; secondary outcome measures are change from baseline to endpoint in data from micturition diary, & I-PSS questionnaire [2]. 02/03/2011 10:38:56 The PIII NEPTUNE (NCT01018511) study is examining the efficacy, safety & tolerability of combination therapy of tamsulosin and solifenacin compared to monotherapy of tamsulosin in the treatment of males with LUTS associated with BPH with a substantial storage component. Two fixed dose combinations of 6mg and 9mg solifanacin with 400micrograms tamsulosin will be studied over 12 weeks a& the primary outcome is change from baseline to endpoint in total International Prostate Symptom Score. 1,713 patients will be enrolled at sites in the UK, Austria, Belarus, Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland, Russia & Slovakia. The study is expected to complete in Feb 11 [2]. 02/03/2011 10:32:49 Evidence Based Evaluations EPAR http://db.cbg-meb.nl/Pars/h111622.pdf SMC References Available only to registered users Category BNF Category: Drugs for urinary retention (07.04.01) Pharmacology: Antimuscarinic agent & alpha-blocker combination Epidemiology: BPH affects the quality of life of about a third of men over 50 years, the numbers increasing markedly with years. Histological evidence of BPH occurs in up to 90% of men by the age of 80. [4] Indication: Benign prostatic hyperplasia Additional Details: Method(s) of Administration Oral Company Information Name: Astellas US Name: Astellas NICE Information Anticipated Commissioning route (England) - In timetable: - |
当前位置:药品说明书与价格首页 >> 上市新药 >> Vesomni(solifenacin/tamsulosin release tablets)
Vesomni(solifenacin/tamsulosin release tablets)简介:
安斯泰来BPH药物VESOMNI获欧洲首个上市安斯泰来(Astellas)欧洲子公司—Astellas Pharma Europe B.V 23日宣布,荷兰药品评价委员会(MEB)已批准了VESOMNI的上市许可申请(MAA),用于对单药疗法无足够 ... 责任编辑:admin
|
最新文章更多推荐文章更多热点文章更多
|