Solifenacin
Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder and neurogenic detrusor overactivity. It may help with incontinence, urinary frequency, and urinary urgency. Benefits appear similar to other medications in the class. It is taken by mouth.
Common side effects include dry mouth, constipation, and urinary tract infection. Severe side effects may include urinary retention, QT prolongation, hallucinations, glaucoma, and anaphylaxis. It is unclear if use is safe during pregnancy. It is of the antimuscarinic class and works by decreasing bladder contractions.
Solifenacin was approved for medical use in the United States in 2004. A month's supply in the United Kingdom costs the NHS about £27.62 as of 2019. In the United States the wholesale cost of this amount is about 370 USD. In 2017, it was the 283rd most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical use
It is used to treat overactive bladder. It may help with incontinence, urinary frequency, and urinary urgency.Benefits appear similar to other antimuscarinics such as oxybutynin, tolterodine, and darifenacin.
It is also used to treat neurogenic detrusor overactivity, a form of bladder dysfunction related to neurological impairment, in children ages two years and older. NDO is a dysfunction of the bladder that results from disease or injury in the nervous system. NDO may be related to congenital conditions, such as spina bifida, or other conditions such as spinal cord injury. With NDO, there is overactivity of the bladder wall muscle, which normally relaxes to allow storage of urine. 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. 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. In addition, spontaneous bladder muscle contractions can lead to unexpected and frequent leakage of urine with symptoms of urinary urgency, frequency and incontinence.
Contraindications
Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease, and hemodialysis.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.
Solifenacin is not to be used in people with gastric retention, uncontrolled narrow angle glaucoma or hypersensitivity to solifenacin or any of its components. 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, or at high risk of QT prolongation, including people with a known history of QT prolongation and people taking medications known to prolong the QT interval.
Side effects
The most common side effects of solifenacin are dry mouth, constipation and urinary tract infection. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration. Somnolence has been reported. Severe allergic reactions, such as angioedema and anaphylaxis, have been reported in people treated with solifenacin succinate and may be life threatening.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.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.
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.
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 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.Chemistry
Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing 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.
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.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.
In May 2020, solifenacin was approved for medical use in the United States with an indication to treat neurogenic detrusor overactivity, a form of bladder dysfunction related to neurological impairment, in children ages two years and older.
The efficacy of solifenacin to treat neurogenic detrusor overactivity was established in two clinical trials with a total of 95 pediatric NDO participants, ages two to 17 years old. The studies were designed to measure the maximum amount of urine the bladder could hold after 24 weeks of treatment. 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. 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. Reductions in spontaneous bladder contractions, bladder pressure and number of incontinence episodes were also observed in both studies. The approval of Vesicare LS was granted to Astellas Pharma US, Inc.