indication

For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

pharmacology

Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.

mechanism of action

Solifenacin is a competitive muscarinic acetylcholine receptor antagonist. The binding of acetylcholine to these receptors, particularly the M3 receptor subtype, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of incontinence episodes.

toxicity

Overdosage with solifenacin can potentially result in severe anticholinergic effects and should be treated accordingly. The highest solifenacin dose given to human volunteers was a single 100 mg dose. Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg daily (5 times the maximum recommended therapeutic dose).

biotransformation

Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.

absorption

The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.

half life

The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours.

route of elimination

The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist.

drug interactions

Clarithromycin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Donepezil: Possible antagonism of action

Galantamine: Possible antagonism of action

Itraconazole: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Ketoconazole: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Nefazodone: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Nelfinavir: This potent CYP3A4 inhibitor slows darifenacin / solifenacin metabolism

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Solifenacin, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Telithromycin: Telithromycin may reduce clearance of Solifenacin. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Solifenacin if Telithromycin is initiated, discontinued or dose changed.

Trimethobenzamide: Trimethobenzamide and Solifenacin, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Triprolidine: Triprolidine and Solifenacin, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trospium: Trospium and Solifenacin, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of solifenacin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of solifenacin if voriconazole is initiated, discontinued or dose changed.