Vesicare (solifenacin)

Conclusion

Vesicare (solifenacin) is the forth urological spasmolytic drug on the Danish market, after Detrusitol (tolterodine), Spasmo-lyt (trospium) and Urispadol (flavoxate).

One fase-3 trial has shown significant effect of solifenacin, comparable to that of tolterodine. The adverse effects are dose dependent, and when used in daily recommended doses, is again comparable to tolterodine. Trials comparing solifenacin with other spasmolytic drugs, have not been published. Vesicare is the second most expensive spasmolytic drug on the market, cheaper than Detrusitol.

Vesicare was released for use the 16th August 2004.

Background

Solifenacin is indicated for the treatment of incontinence, frequency and urgency incontinence for patients with overactive bladder (OAB).

Solifenacin is a competitive cholinerge receptor antagonist, which binds specifically to the muscarine M3-subtype receptor, and has a low affinity for other receptors and ion-channels. Solifenacin is a once-daily tablet, of 5mg and 10 mg doses. Start- and maintenance dosage for solifenacin is 5mg/dy, with the possibility of dosage increasement to 10mg/dy, regardless of meals, but must be swallowed complete with water. The AUC is not effected by food consumption.

For patients with mild to moderate kidney impairment, neither AUC or Cmax are significantly altered. Patients with OAB can benefit from non-pharmacological treatment such as pelvic floor muscle training. There is little evidence for this treatment, and not many trials compare pelvic floor muscle training with pharmacological treatment.

Effect

The effect of solifenacin is evaluated in one published placebo-controlled double-blind trial, lasting 12 weeks. 1.281 patients where randomised to four groups: tolterodine 2mg BID, placebo, solifenacin 5mg or 10mg daily. The primary efficacy variables where change from baseline in the mean number of urgency, incontinence and urge incontinence episodes, and change from baseline in voids/24h and mean volume voided/void.

All efficacy variables had positive significant outcome, the calculations where based on a “per protocol” analysis.

Primary efficacy assessment per day		placebo	solifenacin 5 mg	solifenacin 10 mg	tolterodine 2 BID
urge-	baseline	5,30 (n=248)	5,77 (n=264)	5,82 (n=261)	5,45 (n=250)
episodes	endpoint	3,89 (D -1,41)	2,93 (D -2,84)	2,75 (D -3,07)	3,40 (D -2,05)
inconti-nence	baseline	2,71 (n=153)	2,64 (n=141)	2,59 (n=158)	2,32 (n=157)
episodes	endpoint	1,96 (D -0,75)	1,22 (D -1,42)	1,14 (D -1,45)	1,18 (D -1,14)
urge- inconti-	baseline	2,02 (n=127)	2,33 (n=113)	2,14 (n=127)	1,86 (n=119)
nence	endpoint	1,40 (D -0,62)	0,92 (D -1,41)	0,77 (D -1,37)	0,94 (D -0,92)

Urgency episodes per day were reduced 1,43 and 1,66 (solifenacin 5mg and 10mg, respectively) compared to placebo. Incontinence episodes per day were reduced 0,67 and 0,70 (solifenacin 5mg and 10mg, respectively) compared to placebo. Urge-incontinence episodes per day, were reduced 0,79 and 0,75 (solifenacin 5mg and 10mg, respectively), compared to placebo.

The tolterodine group had no statistical significant effect on efficacy assessments, noted in the table, compared to placebo.

Tolterodine had significant effect on reduction of mictions per day (from 12,1 to 10,2) and increase of mean volume voided per void (147ml to 171ml). Solifenacin had a better effect then tolterodine.

A great placebo response was observed in all efficacy assessments, making the judgement of solifenacin’s clinical effect, more difficult.

There are three non-published fase-3 trials, double-blind and placebo-controlled with 2.265 patients in all, lasting 3-weeks, which support the pivotal trial.

Two of the trials compared solifenacin 10mg to placebo, and the third compared solifenacin 5mg and 10mg to placebo. Primary efficacy assessments were urge episodes, incontinence and urge incontinence episodes, number of mictions per day, and volume voided per void. Solifenacin 5mg and 10mg had statistical significance concerning all efficacy assessments compared to placebo. Also, two of the studies showed that solifenacin 10mg, had significant effect compared to placebo in reducing the amount of episodes of nycturia.

Adverse effects

Anti-cholinergic adverse effects were observed in the trials, such as dry mouth, constipation and blurred vision.

Adverse effects	placebo	solifenacin 5 mg	absolute risk increase	solifenacin 10 mg	absolute risk increase	tolterodine 2 mg x 2	absolute risk increase
dry mouth	4,9 %	14,0 %	9,1 %	21,3 %	16,4 %	18,6 %	13,7 %
constipation	1,9 %	7,2 %	5,3 %	7,8 %	5,9 %	2,6 %	0,7 %
blurred vision	2,6 %	3,6 %	1 %	5,6 %	3 %	1,5 %	1,1 %
sum			15,4 %		25,3 %		15,5 %

The risk for anti-cholinergic adverse effects increased in all three groups, mostly for solifenacin 10mg/dy. Approximately every sixth patient will experience dry mouth , constipation or blurred vision when taking solifenacin 5mg/dy or tolteriodine 2mg BID. For solifenacin this will account for every forth patient. The number needed to harm (NNH) is 6 for patients receiving solifenacin 5mg or tolterodine 2mg BID. For solifenacin 10mg/dy NNH is 4.

The number of patients discontinuing from the trials, due to adverse effects was small, and in all four trails comparable in size.

In general solifenacin induced dosage related anti-cholinergic adverse effects, that besides dry mouth constipation and blurred vision, were dyspepsia and impaired accommodation. The same adverse effects are known for tolteriodine, trospium and flavoxate.

Interactions

Drugs with anti-cholinergic properties, can increase solifenacin’s therapeutic, and adverse effects.
Solifenacin is metabolised by CYP3A4, and pharmacological interactions are possible with other CYP3A4 substrates with a greater affinity (e.g. verapamil and diltiazem). It has also been shown that ketoconazol (a CYP3A4 inhibitor) doubles solifenacin’s AUC. Therefore maximum solifenacin 5mg/dy is recommended with concomitant treatment with e.g. itraconazol or ritonavir.

Price

Prices from the 16th August 2004 for the largest package on the market are used for each drug. Vesicare 5mg, 90 tablets is app. 11% cheaper then Detrusitol and more expensive then Spasmo-lyt and Urispadol. Solifenacin is subsidised.

Drug	Content	Price per recommended daily dose, Kr.	Price for 1 month treatment, Kr.
Vesicare 5 mg 90 stk.	solifenacin	14,45	432
Detrusitol 2,8 mg 100 stk.	tolterodine	16,05	481
Spasmo-lyt 20 mg 60 stk.	trospiumklorid	13,30	399
Urispadol 200 mg 250 stk.	flavoxate	10,45	312

More information can be found at the following web site.

http://www.produktresume.dk/docushare/dscgi/ds.py/View/Collection-96

References

Chapple CR, Rechberger T, Al-Shukri S, Meffan P, Everaert K. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int. 2004;93:303-10.