Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Astellas Pharma Ltd., SPACE, 68 Chertsey road, Woking, Surrey, GU21 5BJ, UK
Pharmacotherapeutic group: alpha-adrenoceptor antagonists
ATC code: G04CA53
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 M3receptors, 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.
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.
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.
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.
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.
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:
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%.
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.
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.
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).
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%.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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