Drug Criteria & Outcomes: Solifenacin succinate (Vesicare) Formulary Evaluation
Drug Criteria & Outcomes
Solifenacin succinate (Vesicare) Formulary Evaluation
Part 2: Interactions, Warnings/Precautions, Contraindications, Pregnancy/Lactation Information, Overdose, Patient/Staff Education, Clinical Trial Summary, Place in Therapy, Formulary Recommendation
By C. Brock Woodis, PharmD CandidateAuburn (AL) University Harrison School of Pharmacy
Interactions
Because solifenacin is a substrate of CYP3A4, inducers or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, and erythromycin) may alter solifenacin pharmacokinetics. It is recommended that dosages of solifenacin higher than 5 mg daily not be administered to a patient who also is receiving therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Caution also must be exercised when solifenacin is coadministered with other medications that may prolong the QT interval (e.g., moxifloxacin).
No clinically relevant drug interactions have been discovered with regard to trospium; however, actively secreted drugs may compete with trospium for renal tubular secretion.
With regard to tolterodine, fluoxetine is a potent inhibitor of CYP2D6 activity and has been shown to result in a 4.8-fold increase in tolterodine AUC. Potent CYP3A4 inhibitors such as azole antifungals, erythromycin, and vinblastine may increase tolterodine concentrations.
Because all three of these medications can cause anticholinergic side effects, caution must be used when any of these medications are used concomitantly with other medications that also have anticholinergic potential (e.g., tricyclic antidepressants).
Solifenacin can be administered with or without food. Administration of a high-fat meal with trospium can result in AUC and Cmax values that are 70%-80% lower than those values obtained when trospium is administered to a fasting patient. Therefore, trospium should be taken at least one hour prior to meals or on an empty stomach. No drug-food interactions have been found to exist with tolterodine.
Warnings and precautions
Patients with bladder outflow obstruction should use solifenacin cautiously due to the risk of urinary retention. Those patients with gastrointestinal obstructive disorders and decreased gastrointestinal motility should be careful when using solifenacin due to possible decreased gastrointestinal motility. Narrow-angle glaucoma is another precaution. Because solifenacin may have a QT interval-prolonging effect, patients with congenital or acquired QT prolongation should be cautious when using solifenacin.
Risk of urinary retention, decreased gastrointestinal motility, controlled narrow-angle glaucoma, and renal and hepatic insufficiencies are all precautions for trospium use.
The risks of urinary retention and gastric retention are precautions regarding the use of tolterodine.
Antimuscarinic agents such as solifenacin have been associated with blurred vision and constipation. Patients should contact their physician or pharmacist if they are constipated for more than three days. Both solifenacin and trospium can cause heat prostration (fever and heat stroke due to decreased sweating).
Contraindications
The use of solifenacin, trospium, or tolterodine is contraindicated in patients with gastric retention, urinary retention, uncontrolled narrow-angle glaucoma, and those patients who have a demonstrated hypersensitivity to the drug substance or any other component of the formulation.
Pregnancy/lactation information
Solifenacin, trospium, and tolterodine are all pregnancy Category C. Solifenacin, trospium, and tolterodine only should be used in pregnant women if the potential benefits outweigh the potential risks to the fetus. It is not known if solifenacin, trospium, or tolterodine are excreted in human breast milk.
Overdose
Although no reports of acute overdosage have been reported, overdose with solifenacin should be treated with gastric lavage and appropriate supportive measures. Overdose with trospium and tolterodine should include supportive care and monitoring of symptoms. ECG monitoring is also recommended when overdosage with either trospium or tolterodine occurs.
Clinical trial summary
Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172:1,919-1,924.
This clinical trial was a randomized, double-blind, placebo-controlled, multicenter, multinational, Phase III clinical trial lasting 12 weeks. Nine hundred eleven patients were randomized with 301 patients receiving placebo, 299 receiving solifenacin 5 mg daily, and 307 patients receiving solifenacin 10 mg daily. The primary efficacy variable was the change from baseline in mean number of micturitions per 24 hours. Secondary efficacy variables included the changes from baseline to endpoint in mean number of urgency episodes per 24 hours, nocturia, urge incontinence, all incontinence episodes, and volume voided per micturition. Safety assessments were performed at weeks 4, 8, and 12, and consisted of vital signs, physical examinations, and adverse event recording. Solifenacin decreased all symptoms of OAB including urgency, urinary frequency, and incontinence.
There was a statistically significant decrease in mean number of micturitions per 24 hours, in patients treated with solifenacin 5 mg (-2.37, 95% confidence interval [CI] -1.27 to -0.29) and solifenacin 10 mg (-2.81, 95% CI -1.71 to -0.72). The ANCOVA (analysis of covariance) results for the decrease in mean number of micturitions were -2.41 for solifenacin 5 mg (P = 0.0002) and -2.82 for solifenacin 10 mg (P = 0.0001). The mean number of urgency episodes per 24 hours was -2.84 for solifenacin 5 mg (95% CI -1.44 to -0.28) and -2.90 for solifenacin 10 mg (95% CI -1.49 to -0.35) as compared to placebo (-1.98 urgency episodes). For this endpoint, ANCOVA results were -2.69 for solifenacin 5 mg (P = 0.005) and -2.94 for solifenacin 10 mg (P = 0.0001). The decrease in number of nocturia episodes in patients treated with solifenacin 10 mg was statistically significant (-0.71, 95% CI -0.38 to -0.01) but not with the solifenacin 5 mg study group. ANCOVA results for the mean number of nocturia episodes decrease were -0.59 for solifenacin 5 mg (P = 0.26) and -0.73 for solifenacin 10 mg (P = 0.005).
Treatment with solifenacin 5 mg (-1.63, -60.7%) and solifenacin 10 mg (-1.57, -51.9%) showed a greater decrease in mean number of all incontinence episodes vs. placebo (-1.25, -27.9%). ANCOVA showed statistically significant reductions in terms of this variable for both solifenacin 5 mg (-1.73, P = 0.002) and solifenacin 10 mg (-1.58, P = 0.016). Treatment with solifenacin 5 mg (-1.30, -62.7%) and solifenacin 10 mg (-1.21, -57.1%) also resulted in greater decreases in the secondary endpoint of mean number of urge incontinence episodes vs. placebo (-0.91, -42.5%), and ANCOVA showed reductions that were statistically significant with solifenacin 5 mg (-1.33, P = 0.014) and solifenacin 10 mg (-1.24, P = 0.042). The final secondary endpoint examined in this trial was the mean volume of urine voided per micturition. A 10.67 mL increase was seen with placebo vs. an increase of 30.8 mL with solifenacin 5 mg (95% CI 12.4-27.7, P = 0.0001) and 36 mL with solifenacin 10 mg (95% CI 17.7-33, P = 0.0001).
The most common adverse event seen in this trial was dry mouth with 7.7% and 23% of patients treated with solifenacin 5 mg and solifenacin 10 mg, respectively. Based on these results, the authors of this trial concluded that solifenacin at doses of 5 mg and 10 mg once daily improved all symptoms of OAB. Approximately 50% of those patients treated with either solifenacin 5 mg or solifenacin 10 mg reported no incontinence at study endpoint as opposed to reporting at least one incontinence episode at baseline. Solifenacin also exhibited a good safety and tolerability profile.
This double-blind, randomized, and placebo-controlled trial, limited in that there was no head-to-head comparison between solifenacin and another agent used to treat OAB (e.g., tolterodine). Another limitation is that this trial did not explicitly list the exclusion criteria used to rule out study participants.
Place in therapy/advantages
Due to limited data illustrating the safety and efficacy of solifenacin, solifenacin should be used as an alternative therapy for overactive bladder when one of the older therapies such as oxybutynin or tolterodine is either not effective or the adverse effects are intolerable. Oxybutynin and tolterodine have more data available supporting their use as treatment agents for OAB. More clinical studies, especially those placing solifenacin in a head-to-head comparison against oxybutynin, tolterodine, darifenacin, and trospium need to be conducted. Solifenacin does appear to illustrate a better adverse effect profile than either oxybutynin or tolterodine. In comparison to trospium, solifenacin appears to have a similar efficacy and safety profile. Solifenacin is approximately $0.40 more expensive per day as opposed to trospium and $0.25 less expensive per day than tolterodine (see Table 1 for cost comparison).
| Table 1: Cost comparisons | ||
|
Drug
|
Strength
|
Cost per day at
Huntsville Hospital |
|
Tolterodine
|
2 mg daily
|
$2.61
|
|
Tolterodine
|
4 mg daily
|
$2.67
|
|
Trospium
|
20 mg twice daily
|
$2.38
|
|
Solifenacin
|
5 mg daily
|
$2.84
|
|
Solifenacin
|
10 mg daily
|
$2.84
|
Table 2 provides a summary of the comparative data available on solifenacin, tolterodine, and trospium.
| Table 2: OAB drug therapy comparative summary | |||
| Solifenacin | Tolterodine LA | Trospium | |
| Dosage forms | 5 mg and 10 mg oral tablets | 2 mg and 4 mg oral capsules | 20 mg oral tablet |
| Antimuscarinic blockade | M-3 selective tertiary amine | Non-selective tertiary amine | Non-selective quaternary ammonium compound |
| Oral bioavailability | 90% | > 77% | < 10% |
| Volume of distribution | 599-671 L | 113 ± 26.7 L | 395 ± 140 L |
| Metabolism | Hepatic by CYP3A4 | Hepatic by CYP2D6 | Non-CYP enzymes; mostly ester hydrolysis |
| Elimination T½ | 45-68 h | 7 h (extensive metabolizers); 18 (poor metabolizers) |
20 h |
| Initial dose | 5 mg once daily | 4 mg daily; may be lowered to 2 mg daily based on individual response and tolerability |
20 mg twice daily; 20 mg daily can be used if age > 75 years or Clcr < 30 mL/min |
| Maximum dose | 10 mg daily | 4 mg daily | 20 mg twice daily |
| Dose adjustment in pediatric patients | Use not evaluated | Use not evaluated | Use not evaluated |
| Dose adjustment in renal impairment | No more than 5 mg once daily for Crcl < 30 mL/min | 2 mg daily for severe impairment | May require dose adjustment |
| Dose adjustment in hepatic impairment | No more than 5 mg daily if moderate hepatic impairment and use not recommended in severe hepatic impairment | 2 mg daily if severe impairment | Caution should be used |
| Drug-drug interactions | CYP3A4 inducers and inhibitors | CYP3A4 and CYP2D6 inhibitors or inducers | None yet identified |
| Drug-food interactions | None noted | None noted | Interaction with high fat meal; take at least one hour prior to meal or two hours after meal |
| Effect on QT Interval | May increase QTc interval; according to the package insert, the QTc changes in msec (90%CI) from baseline at Tmax (relative to placebo) was 2 (-3,6) and 8 (4,13) for solifenacin 10 mg and solifenacin 30 mg, respectively |
QTc interval prolonged at doses 68 times higher than recommended dose in dogs, no QT prolongation seen in humans at 8 mg daily | No effect documented |
| Warnings and precautions | Patients with bladder outflow obstruction, gastrointestinal (GI) obstructive disorders, narrowangle glaucoma, congenital or acquired QT prolongation, or decreased GI motility | Urinary retention and gastric retention | Urinary retention, decreased GI motility, controlled-angle glaucoma, renal and hepatic insufficiencies |
| Contraindications | Patients with gastric retention, urinary retention, uncontrolled narrow-angle glaucoma, or known hypersensitivity to either drug or any formulation component |
Patients with gastric retention, urinary retention, uncontrolled narrow-angle glaucoma, or known hypersensitivity to either drug or any formulation component | Patients with gastric retention,urinary retention, uncontrolled narrow-angle glaucoma, or known hypersensitivity to either drug or any formulation component |
Formulary recommendation
Solifenacin should be placed on a trial status. For a 120-day period, solifenacin could be prescribed and the safety and efficacy of solifenacin should be monitored. Because no head-to-head trials have been conducted between solifenacin and other drug therapies for OAB, precise equivalent doses between solifenacin and the other drug therapies cannot be given at this time. Solifenacin is competitively priced when compared to other agents used for the treatment of overactive bladder. It is recommended that solifenacin be reserved for second- or third-line therapy for OAB when more conventional therapies such as oxybutynin or tolterodine have failed until further studies prove otherwise.
Resources
• Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: Results of the OPERA trial. Mayo Clinic Proc 2003;78:687-695.
• Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York City: McGraw Hill; 2002.
• GlaxoSmithKline. Vesicare [package insert]. Research Triangle, NC; November 2004.
• MICROMEDEX Healthcare Series. Greenwood Village, CO: MICROMEDEX; (Edition expires March 2005).
• Pharmacia. Detrol LA [package insert]. Kalamazoo, MI; April 2004.
• Odyssey. Sanctura [package insert]. East Hanover, NJ; July 2004.
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