Drug Criteria & Outcomes
Solifenacin Succinate (Vesicare) Formulary Evaluation
Part 1 of 2: Background, Similar Drugs, Strengths/Dosage, Mechanism of Action, Indications, Preparation and Storage, Pharmacokinetics, Dosage and Administration, Special Populations, and Adverse Drug Reactions
By C. Brock Woodis,
Auburn (AL) University Harrison School of Pharmacy
Overactive bladder (OAB) is a condition that affects almost 17 million people in the United States. OAB is identified by symptoms of urgency and frequent micturitions with or without urge urinary incontinence.
Detrusor muscle activity is the most common cause of OAB, and it is manifested as involuntary muscle contraction during bladder filling. Muscarinic receptors are known to mediate detrusor muscle contraction. The antimuscarinic agents tolterodine (Detrol LA) and oxybutynin (Ditropan XL) have been the mainstay of treatment for OAB, but these agents have had less-than-desirable side effect profiles. Therefore, a need for an antimuscarinic agent with a better efficacy-to-side effect profile exists.
This evaluation will compare a new oral type-3 antimuscarinic receptor antagonist (solifenacin succinate) to both an additional new oral nonselective antimuscarinic receptor antagonist (trospium) and also to one of the more conventional and nonselective therapies for OAB (tolterodine LA).
Similar drugs in class
Drugs that are similar to solifenacin succinate include oxybutynin, tolterodine, trospium chloride (Sanctura), and darifenacin (Enablex).
Strengths/dosage forms available
Solifenacin is available as both a light-yellow 5 mg oral tablet and a light-pink 10 mg oral tablet. Tolterodine tartrate extended release capsules are available as blue-green 2 mg capsules and blue 4 mg capsules. Trospium chloride is available as a 20 mg brownish-yellow, biconvex, glossy coated oral tablet.
Mechanism of action
Solifenacin is a tertiary amine and selective antagonist at type-3 muscarinic receptors, which prevents contractions of bladder smooth muscle. Solifenacin is believed to be 10-20 times more selective for M3 receptors on the urinary bladder than for other muscarinic subtypes. Trospium is a quaternary ammonium compound that has equipotent binding at M2 and M3 muscarinic receptor subtypes. Finally, tolterodine also is a competitive nonspecific muscarinic receptor antagonist.
Solifenacin, trospium, and tolterodine are approved by the Food and Drug Administration for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency. No off-label uses are known at this time.
Preparation and storage
Solifenacin is prepared as round, film-coated tablets, available in bottles of either 30 or 90 tablets and also as a unit dose pack of 100 tablets. Tolterodine is prepared as 30-count bottles, 90-count bottles, 500-count bottles, and unit dose blisters for both the 2 mg and 4 mg capsules. Both solifenacin and tolterodine should be stored at 25° C (77° F) with a permitted range from 15° C to 30° C (59°- 86° F). Trospium is prepared in 60-count, 500-count, and 14-count blister packs. According to the package insert, trospium should be stored at a controlled room temperature of 20° C to 25° C (68° F to 77° F).
Absorption: Following oral administration of solifenacin to healthy volunteers, peak plasma levels (Cmax) were attained within three to eight hours. Steady-state concentrations were found to be 32.3 mg/mL and 62.9 mg/mL for the 5 mg and 10 mg tablets, respectively. Oral bioavailability for solifenacin is approximately 90%. Peak plasma levels (Cmax) of trospium are attained between five and six hours post-dose with less than 10% of the oral dose being absorbed. Maximum serum concentrations of tolterodine are reached two to six hours after dose administration and more than 77% of the oral dose is absorbed.
Distribution: The volume of distribution (Vd) of solifenacin ranged from 599 L to 671 L after a single 5 mg intravenous infusion was administered to healthy male volunteers. Solifenacin is approximately 98% bound to human plasma proteins with alpha 1-acid glycoprotein being the predominant protein. Solifenacin highly distributes to noncentral nervous system tissues. Protein-binding ranged from 50% to 85% and the Vd for a 20 mg trospium dose was 395 + 140 L. Tolterodine is highly bound to plasma proteins, especially alpha1-acid glycoprotein. Tolterodine’s Vd is 113 + 26.7 L.
Metabolism: Solifenacin primarily is metabolized in the liver by cytochrome P450 isoenzyme 3A4. The major metabolic pathway for trospium is ester hydrolysis, and the cytochrome 450 isoenzymes are not thought to significantly contribute to trospium’s elimination. The liver extensively metabolizes tolterodine, with the primary metabolic route involving the oxidation of the 5-methyl group by the CYP2D6 isoenzyme.
Excretion: The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours. The elimination half-life of trospium is approximately 20 hours. The elimination half-life of tolterodine for extensive metabolizers is seven hours while the elimination half-life for poor metabolizers is 18 hours.
Dosing and administration
According to clinical trials examining solifenacin’s use, the most appropriate doses of solifenacin were 5 mg and 10 mg once daily. Twenty milligrams once daily was seen to be more effective than the lower doses, but with a higher incidence of adverse effects. Therefore, it is recommended that 5 mg once daily be the initial dose and if well tolerated, the dose may be increased to a maximum of 10 mg daily.
The recommended initial and maximum dose of trospium is 20 mg twice daily at least one hour before meals or given on an empty stomach.
For tolterodine, the recommended dose is 4 mg once daily with liquids and swallowed whole. The dose of tolterodine may be lowered to 2 mg daily based on individual response and tolerability.
Geriatric patients: Studies showed that Cmax, AUC (area under the curve), and t½ values of solifenacin were all increased 20% to 25% in patients 65-80 years of age as opposed to patients 18 to 55 years of age. Therefore, dose reduction may be necessary in this patient population. Age did not seem to affect the pharmacokinetics of trospium. In one clinical trial, tolterodine concentrations were 20% higher in patients ages 71-81 years as opposed to patients younger than 40 years. However, no overall differences were observed in safety, and there are no recommended dose adjustments for elderly patients using tolterodine.
Pediatric patients: The proper use of solifenacin, trospium, and tolterodine in pediatric patients has not been evaluated.
Renal impairment: Because both a 2.1-fold increase in AUC and a 1.6-fold increase in t½ of solifenacin were seen in patients with severe renal impairment, it is not recommended that a daily dose of more than 5 mg once daily be used in patients with a renal clearance of less than 30 mL/min. Dosage frequency should be adjusted for patients with severe renal insufficiency using trospium due to the increase in both AUC and Cmax. The recommended dose for patients with significantly reduced renal function using tolterodine is 2 mg daily.
Hepatic impairment: A daily dose of more than 5 mg solifenacin per day is not recommended in patients with moderate hepatic impairment (Child-Pugh B). The use of solifenacin is not recommended in those patients with severe hepatic impairment (Child-Pugh C). When administering trospium to patients with moderate and severe hepatic dysfunction, caution should be exercised. For patients with significantly reduced hepatic function, the suggested tolterodine dose is 2 mg daily.
Adverse drug reactions
Adverse reaction information for solifenacin, tolterodine, and trospium can be found in Tables 1-3, respectively. These adverse events were not obtained in a head-to-head comparison between solifenacin, tolterodine, and trospium.
One additional point of interest was solifenacin’s effect on the QTc interval. The QTc changes in msec (90% CI) from baseline at Tmax (relative to placebo) were 2 (-3, 6) and 8 (4, 13) for solifenacin 10 mg and solifenacin 30 mg, respectively.