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Solifenacin

Solifenacin
Solifenacin structure.svg
Clinical data
Trade namesVesicare
SynonymsYM905
AHFS/Drugs.comMonograph
MedlinePlusa605019
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability90%
Protein binding98%
MetabolismCYP3A4
MetabolitesGlucuronide, N-oxide, others
Elimination half-life45 to 68 hours
ExcretionKidney (69.2%) and fecal (22.5%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC23H26N2O2
Molar mass362.465 g/mol g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder.[1] It may help with incontinence, urinary frequency, and urinary urgency.[2] Benefits appear similar to other medications in the class.[3] It is taken by mouth.[1]

Common side effects include dry mouth and constipation.[1] Severe side effects may include urinary retention, QT prolongation, hallucinations, and glaucoma.[1][2] It is unclear if use is safe during pregnancy.[1] It is of the antimuscarinic class and works by decreasing bladder contractions.[1]

Solifenacin was approved for medical use in the United States in 2004.[1] A month supply in the United Kingdom costs the NHS about 27.62 £ as of 2019.[2] In the United States the wholesale cost of this amount is about 370 USD.[4] In 2016 it was the 170th most prescribed medication in the United States with more than 3 million prescriptions.[5]

Medical use

It is used to treat overactive bladder.[1] It may help with incontinence, urinary frequency, and urinary urgency.[2]

Benefits appear similar to other antimuscarinics such as oxybutynin, tolterodine, and darifenacin.[3]

Contraindications

Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease (Child-Pugh class C),[6] and hemodialysis.[7]

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.[8]

Side effects

The most common side effects of solifenacin are dry mouth, blurred vision, and constipation. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration.[6]

Interactions

Solifenacin is metabolized in the liver by the cytochrome P450 enzyme CYP3A4. When administered concomitantly with drugs that 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.[6]

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 arrhythmia.[9]

Pharmacology

Mechanism of action

Solifenacin is a competitive cholinergic receptor antagonist, selective for the M3 receptor subtype. The binding of acetylcholine to these receptors, particularly M3, 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 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.[7]

Pharmacokinetics

Peak plasma concentrations are reached 3 to 8 hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to plasma proteins, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known active metabolite, 4R-hydroxysolifenacin, and three inactive ones, the N-glucuronide, the N-oxide and the 4R-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 renally and 23% via the feces.[7]

Chemistry

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.[10]

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.[11]

Society and culture

The INN is solifenacin.[12] It is manufactured and marketed by Astellas, GlaxoSmithKline[9] and Teva Pharmaceutical Industries.[13]

Cost

A 2006 cost-effectiveness study found that 5 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.[14] By 2019, with the introduction of generics, the retail cost of a month's supply was down to $20 in the US.

References

  1. ^ a b c d e f g h "Solifenacin Succinate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists.
  2. ^ a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 761. ISBN 9780857113382.
  3. ^ a b "[93] Are claims for newer drugs for overactive bladder warranted?". Therapeutics Initiative. 22 April 2015. Retrieved 17 March 2019.
  4. ^ "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  5. ^ "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  6. ^ a b c Lexi-Comp (December 2009). "Solifenacin". The Merck Manual Professional. Retrieved 10 June 2011.
  7. ^ a b c Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8659–62. ISBN 978-3-85200-181-4.
  8. ^ "Vesicare 5mg & 10mg film-coated tablets". eMC. Retrieved 13 December 2015.
  9. ^ a b Drugs.com: Monograph on Vesicare.
  10. ^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals (14 ed.). 2006. p. 1494. ISBN 978-0-911910-00-1.
  11. ^ Kobayashi, S.; et al. (July 2001). "Effects of YM905, a Novel Muscarinic M3-Receptor Antagonist, on Experimental Models of Bowel Dysfunction In Vivo". Jpn. J. Pharmacol. 86 (3): 281–288. PMID 11488427.
  12. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 47" (PDF). World Health Organization. p. 106. Retrieved 5 February 2017.
  13. ^ "Teva Introduces Generic of Vesicare to Treat Overactive Bladder". Bloomberg Law. 22 April 2019.
  14. ^ Ko Y, Malone DC, Armstrong EP (Dec 2006). "Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder". Pharmacotherapy. 26 (12): 1694–702. doi:10.1592/phco.26.12.1694. PMID 17125433.