solifenacin (Vesicare)

Introduction

Tradenames: Vesicare (scheduled for release late 2004)

Indications

• urinary frequency, urinary urgency due to overactive bladder, urge incontinence

Contraindications

• use caution in patients with
  • narrow-angle glaucoma
  • gastroparesis & diminished peristalsis
  • obstructive uropathy
  • hepatic insufficiency
  • renal insufficiency

pregnancy category = c

Dosage

5-10 mg PO QD (no dose adjustment in the elderly)

Dosage adjustment in renal failure

• maximum dose 5 mg QD for creatinine clearance < 30 mL/min Dosage adjustment with hepatic insufficiency
• maximum dose 5 mg QD for moderate hepatic impairment (Child-Pugh B)
• avoid with severe hepatic impairment (Child-Pugh C)

Pharmacokinetics

• absorption not affected by food
• peak plasma levels 3-8 hours after oral dose
• absolute bioavailability is 90%
• steady-state plasma levels 32-63 ng/mL for 5 & 10 mg QD
• 98% bound to plasma proteins, mainly orosomucoid
• volume of distribution 600 L
• metabolized in liver primarily by cyt P450 3A4
• 4R-hydroxy solifenacin, active metabolite, unlikely to contribute significant pharmacologic activity
• elimination 1/2life is 45-68 hours with chronic dosing
  • t1/2 is 20-25% longer in elderly
• 62% recovered in urine (< 15% unchanged), 22% in feces

protein binding = 98 %

1/2life = 45-68 hours

Adverse effects

(% for 10 mg QD)

• less drowsiness & dizziness than other anticholinergics
• xerostomia 28%
• constipation 9-13%
  • fecal impaction, intestinal obstruction
• dyspepsia 4%
• blurry vision 5%
• may increase QT interval
• case of angioneurotic edema reported

• drug adverse effects of parasympatholytics

Drug interactions

• drugs that inhibit cyt P450 3A4 may increase 1/2life of solifenacin
  • max dose of solifenacin 5 mg QD when coadministered with ketoconazole or other potent inhibitor of cyt P450 3A4
• drugs that induce cyt P450 3A4 may decrease 1/2life of solifenacin

• drug interaction(s) of parasympatholytic with parasympathomimetic

Mechanism of action

• muscarinic M3 receptor antagonist
• allegedly more selective for the muscarinc M3 receptor than other agents

More general terms

• urinary antispasmodic

Component of

• mirabegron/solifenacin (Myrbetriq/Vesicare)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=216457
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=443937