View source for Solifenacin

{{Short description|Chemical compound}}
{{Use dmy dates|date=March 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461941706
| image = Solifenacin structure.svg

<!-- Clinical data -->
| tradename = Vesicare, Vesicare LS 
| Drugs.com = {{drugs.com|monograph|solifenacin-succinate}}
| MedlinePlus = a605019
| DailyMedID = Solifenacin
| pregnancy_AU = B3
| pregnancy_US = C
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = [[Oral administration|By mouth]]

<!-- Pharmacokinetic data -->
| bioavailability = 90%
| protein_bound = 98%
| metabolism = [[CYP3A4]]
| metabolites = [[Glucuronide]], [[Amine oxide|''N''-oxide]], others
| onset =
| elimination_half-life = 45 to 68 hours
| duration_of_action =
| excretion = [[Kidney]] (69.2%) and fecal (22.5%)

<!-- Identifiers -->
| IUPHAR_ligand = 7483
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 242478-37-1
| ATC_prefix = G04
| ATC_suffix = BD08
| ATC_supplemental =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01591
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A8910SQJ1U
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1734
| PubChem = 154059
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 135771
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = DG00481
| synonyms = YM905

<!-- Chemical data -->
| IUPAC_name = (3''R'')-1-Azabicyclo[2 2 2]oct-3-yl (1''S'')-1-phenyl-3,4-dihydroisoquinoline-2(1''H'')-carboxylate
| C=23 | H=26 | N=2 | O=2 
| smiles = C1CN2CCC1[C@H](C2)OC(=O)N3CCC4=CC=CC=C4[C@@H]3C5=CC=CC=C5
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C23H26N2O2/c26-23(27-21-16-24-13-10-18(21)11-14-24)25-15-12-17-6-4-5-9-20(17)22(25)19-7-2-1-3-8-19/h1-9,18,21-22H,10-16H2/t21-,22-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = FBOUYBDGKBSUES-VXKWHMMOSA-N
}}
<!-- Definition and medical uses -->
'''Solifenacin''', sold as the brand name '''Vesicare'''{{efn|The name comes from Latin ''vesica'' meaning bladder; and care. Thus literally a drug which "takes care of the bladder"}} among others, is a medicine used to treat [[overactive bladder]] and neurogenic detrusor overactivity (NDO).<ref name=AHFS2019/><ref name="FDA PR">{{cite press release | title=FDA Approves First Treatment for a Form of Bladder Dysfunction in Pediatric Patients as Young as 2 Years of Age | website=U.S. [[Food and Drug Administration]] (FDA) | date=26 May 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-form-bladder-dysfunction-pediatric-patients-young-2-years-age | archive-url=https://web.archive.org/web/20200529230658/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-form-bladder-dysfunction-pediatric-patients-young-2-years-age | url-status=dead | archive-date=29 May 2020 | access-date=26 May 2020}} {{PD-notice}}</ref> It may help with [[urinary incontinence|incontinence]], [[urinary frequency]], and [[urinary urgency]].<ref name=BNF76/> 

Benefits appear similar to other medications in the class.<ref name="TI93">{{cite web |title=[93] Are claims for newer drugs for overactive bladder warranted? |url=https://www.ti.ubc.ca/2015/04/22/are-claims-for-newer-drugs-for-overactive-bladder-warranted/ |website=Therapeutics Initiative |access-date=17 March 2019 |date=22 April 2015}}</ref> It is taken by mouth.<ref name="AHFS2019" />

<!-- Side effects and mechanism -->
Common side effects include dry mouth, constipation, and [[urinary tract infection]].<ref name=AHFS2019/><ref name="FDA PR" /> Severe side effects may include [[urinary retention]], [[QT prolongation]], [[hallucination]]s, [[glaucoma]], and [[anaphylaxis]].<ref name=AHFS2019/><ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=761|edition=76}}</ref><ref name="FDA PR" /> It is unclear if use is safe during [[pregnancy]].<ref name=AHFS2019/> It is of the [[antimuscarinic]] class and works by decreasing [[bladder]] contractions.<ref name=AHFS2019/>

<!-- Society and culture -->
Solifenacin was approved for medical use in the United States in 2004.<ref name=AHFS2019>{{cite web |title=Solifenacin Succinate Monograph for Professionals |url=https://www.drugs.com/monograph/solifenacin-succinate.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists }}</ref><ref name="FDA PR" /><ref name="FDA approval" /> In 2022, it was the 210th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="Top 300 of 2022">{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Solifenacin Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Solifenacin | access-date = 30 August 2024 }}</ref>

==Medical use==
It is used to treat [[overactive bladder]].<ref name=AHFS2019/> It may help with [[urinary incontinence|incontinence]], [[urinary frequency]], and [[urinary urgency]].<ref name=BNF76/>

Benefits appear similar to other antimuscarinics such as [[oxybutynin]], [[tolterodine]], and [[darifenacin]].<ref name=TI93/>

It is also used to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older.<ref name="FDA PR" /> NDO is a dysfunction of the bladder that results from disease or injury in the nervous system.<ref name="FDA PR" /> NDO may be related to congenital conditions (often-inherited conditions beginning at or before birth), such as spina bifida (myelomeningocele), or other conditions such as spinal cord injury.<ref name="FDA PR" /> With NDO, there is overactivity of the bladder wall muscle, which normally relaxes to allow storage of urine.<ref name="FDA PR" /> The bladder wall muscle overactivity results in sporadic bladder muscle contraction, which increases pressure in the bladder and decreases the volume of urine the bladder can hold.<ref name="FDA PR" /> If NDO is not treated, increased pressure in the bladder can put the upper urinary tract at risk of harm, including possible permanent damage to the kidneys.<ref name="FDA PR" /> In addition, spontaneous bladder muscle contractions can lead to unexpected and frequent leakage of urine with symptoms of urinary urgency (immediate urge to urinate), frequency (urinating more often than normal) and incontinence (loss of bladder control).<ref name="FDA PR" />

== Contraindications ==
Solifenacin is contraindicated for people with [[urinary retention]], gastric retention, uncontrolled or poorly controlled closed-angle [[glaucoma]], severe liver disease ([[Child-Pugh score|Child-Pugh]] class C),<ref name=Lexi-Comp>{{cite web|url=http://www.merck.com/mmpe/lexicomp/solifenacin.html |title=Solifenacin |date=December 2009 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]]|access-date=10 June 2011}}</ref> and [[hemodialysis]].<ref name="Austria-Codex">{{cite book|title=Austria-Codex|editor=Jasek, W|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=62nd|isbn=978-3-85200-181-4|pages=8659–62|language=de}}</ref>

[[Long QT syndrome]] is not a contraindication although solifenacin, like [[tolterodine]] and [[darifenacin]], binds to [[hERG]] channels of the heart and may prolong the [[QT interval]]. This mechanism appears to be seldom clinically relevant.<ref>{{cite web|url=https://www.medicines.org.uk/emc/medicine/14900|title=Vesicare 5mg & 10mg film-coated tablets|publisher=eMC|access-date=13 December 2015}}</ref>

Solifenacin is not to be used in people with gastric retention (reduced emptying of the stomach), uncontrolled narrow angle glaucoma (fluid buildup in the eye which raises eye pressure) or hypersensitivity (allergic reaction) to solifenacin or any of its components.<ref name="FDA PR" /> Solifenacin is also not recommended for use in people with severe liver failure, clinically significant bladder outlet obstruction in the absence of clean intermittent catheterization, decreased gastrointestinal motility (slowed intestinal contractions), or at high risk of QT prolongation (an electrical disturbance where the heart muscle takes longer than normal to recharge between beats), including people with a known history of QT prolongation and people taking medications known to prolong the QT interval.<ref name="FDA PR" />

== Side effects ==
{{Main|Anticholinergic}}
The most common [[adverse drug reaction|side effect]]s of solifenacin are [[dry mouth]], constipation and urinary tract infection.<ref name="FDA PR" /> As all anticholinergics, solifenacin may rarely cause [[hyperthermia]] due to decreased [[perspiration]].<ref name=Lexi-Comp/> Somnolence (sleepiness or drowsiness) has been reported.<ref name="FDA PR" /> Severe allergic reactions, such as angioedema (swelling beneath the skin) and anaphylaxis, have been reported in people treated with solifenacin succinate and may be life-threatening.<ref name="FDA PR" />

== Interactions ==
Solifenacin is metabolized in the liver by the [[cytochrome P450 oxidase|cytochrome P450]] enzyme [[CYP3A4]]. When administered concomitantly with drugs that [[enzyme inhibition|inhibit]] CYP3A4, such as [[ketoconazole]], the metabolism of solifenacin is impaired, leading to an increase in its concentration in the body and a reduction in its excretion.<ref name=Lexi-Comp/>

As stated above, solifenacin may also prolong the QT interval. Therefore, administering it concomitantly with drugs which also have this effect, such as [[moxifloxacin]] or [[pimozide]], can theoretically increase the risk of [[Heart arrhythmia|arrhythmia]].<ref name=AHFS2019 />

== Pharmacology ==

=== Mechanism of action ===
Solifenacin is a [[competitive antagonist|competitive]] [[cholinergic receptor]] [[receptor antagonist|antagonist]], [[binding selectivity|selective]] for the [[M3 receptor|M<sub>3</sub> receptor]] subtype. However, it is said to also act as an antagonist of the other four [[muscarinic acetylcholine receptor]]s.<ref name="LavradorCabralVeríssimo2023">{{cite journal | vauthors = Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM | title = A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity | journal = Pharmaceutics | volume = 15 | issue = 1 | date = January 2023 | page = 230 | pmid = 36678858 | pmc = 9863833 | doi = 10.3390/pharmaceutics15010230 | doi-access = free | url = }}</ref>

The binding of [[acetylcholine]] to these receptors, particularly M<sub>3</sub>, plays a critical role in the contraction of [[smooth muscle]]. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle [[muscle tone|tone]] in the [[urinary bladder|bladder]], allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone.<ref name="Austria-Codex" />

=== Pharmacokinetics ===
Peak plasma concentrations are reached three to eight hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to [[plasma protein]]s, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known [[active metabolite]], 4''R''-hydroxysolifenacin, and three inactive ones, the ''N''-[[glucuronide]], the [[Amine oxide|''N''-oxide]] and the 4''R''-hydroxy-''N''-oxide. The [[elimination half-life]] is 45 to 68 hours. 69% of the substance, both in its original form and as metabolites, are excreted [[Kidney|renally]] and 23% via the feces.<ref name="Austria-Codex" />

== Chemistry ==
[[File:Atropine.svg|thumb|[[Atropine]] for comparison]]
Like other anticholinergics, solifenacin is an [[ester]] of a [[carboxylic acid]] containing (at least) an [[aromatic]] ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic [[atropine]] the bicyclic ring is [[tropane]], solifenacin replaces it with [[quinuclidine]].

The free base is a yellow oil, while the salt solifenacin [[succinate]] forms yellowish crystals.<ref name="MerckIndex">{{cite book|title=The [[Merck Index]]. An Encyclopaedia of Chemicals, Drugs and Biologicals|edition=14|year=2006|page=1494|isbn=978-0-911910-00-1| vauthors = O'Neil MJ |publisher=Wiley }}</ref>

== History ==
The compound was studied using animal models by the [[Yamanouchi Pharmaceutical]] Co., Ltd. of Tokyo, Japan. It was known as YM905 when under study in the early 2000s.<ref>{{cite journal | vauthors = Kobayashi S, Ikeda K, Suzuki M, Yamada T, Miyata K | title = Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo | journal = Japanese Journal of Pharmacology | volume = 86 | issue = 3 | pages = 281–288 | date = July 2001 | pmid = 11488427 | doi = 10.1254/jjp.86.281 | doi-access = free }}</ref>

Solifenacin was approved for medical used in the United States in 2004 with an indication to treat overactive bladder in adults 18 years and older.<ref name="FDA PR" /><ref name="FDA approval">{{cite web | title=Drug Approval Package: VesiCare (Solifenacin Succinate) NDA #021518 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-518_VesiCare.cfm | archive-url=https://web.archive.org/web/20170119030843/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-518_VesiCare.cfm | url-status=dead | archive-date=19 January 2017 | access-date=26 May 2020}}</ref>

In May 2020, solifenacin was approved for medical use in the United States with an indication to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older.<ref name="FDA PR" />

The efficacy of solifenacin to treat neurogenic detrusor overactivity (NDO) was established in two clinical trials with a total of 95 pediatric NDO participants, ages two to 17 years old.<ref name="FDA PR" /> The studies were designed to measure (as a primary efficacy endpoint) the maximum amount of urine the bladder could hold after 24 weeks of treatment.<ref name="FDA PR" /> In the first study, 17 participants ages two to less than five years old were able to hold an average of 39 mL more urine than when the study began.<ref name="FDA PR" /> In the second study, 49 participants ages five to 17 years were able to hold an average of 57 mL more urine than when the study began.<ref name="FDA PR" /> Reductions in spontaneous bladder contractions, bladder pressure and number of incontinence episodes were also observed in both studies.<ref name="FDA PR" /> The approval of Vesicare LS was granted to Astellas Pharma US, Inc.<ref name="FDA PR" />

== Society and culture ==
The [[international nonproprietary name]] (INN) is solifenacin.<ref name="INN">{{cite web|title=International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 47|url=https://www.who.int/medicines/publications/druginformation/innlists/RL47.pdf|publisher=World Health Organization|access-date=5 February 2017|page=106}}</ref> It is manufactured and marketed by [[Astellas]], [[GlaxoSmithKline]]<ref name=AHFS2019 /> and [[Teva Pharmaceutical Industries]].<ref>{{cite web|url=https://news.bloomberglaw.com/pharma-and-life-sciences/teva-introduces-generic-of-vesicare-to-treat-overactive-bladder|title=Teva Introduces Generic of Vesicare to Treat Overactive Bladder|date=22 April 2019|website=Bloomberg Law}}</ref>

=== Cost ===
A 2006 [[cost-effectiveness]] study found that 5&nbsp;mg solifenacin had the lowest cost and highest effectiveness among [[anticholinergic]] drugs used to treat [[overactive bladder]] in the United States, with an average medical cost per successfully treated patient of $6863 per year.<ref>{{cite journal |vauthors=Ko Y, Malone DC, Armstrong EP | title = Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder | journal = Pharmacotherapy | volume = 26 | issue = 12 | pages = 1694–702 |date=Dec 2006 | doi = 10.1592/phco.26.12.1694 |url=https://www.jstage.jst.go.jp/article/jjp/86/3/86_3_281/_pdf|pmid = 17125433| s2cid = 42046036 | url-access = subscription }}</ref> By 2019, with the introduction of generics, the retail cost of a month's supply was down to $20 in the US.

==Footnotes==
{{notelist|1}}

== References ==
{{Reflist}}

{{Urologicals}}
{{Muscarinic acetylcholine receptor modulators}}
{{Ion channel modulators}}
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[[Category:3-Quinuclidinyl esters]]
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[[Category:Carbamates]]
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[[Category:M1 receptor antagonists]]
[[Category:M2 receptor antagonists]]
[[Category:M3 receptor antagonists]]
[[Category:M4 receptor antagonists]]
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[[Category:Tetrahydroisoquinolines]]
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