Fesoterodine: Muscarinic Receptor Antagonist Prodrug for Overactive Bladder

Fesoterodine (trade name Toviaz, Pfizer) is an oral prodrug that, after absorption, is rapidly hydrolysed by non specific plasma esterases to the active metabolite 5 hydroxymethyltolterodine (5 HMT). 5 HMT is also the active metabolite of tolterodine, with the difference that 5 HMT formation from fesoterodine is not dependent on CYP2D6. This makes fesoterodine an interesting option for patients with tolterodine tolerability problems or uncertain CYP2D6 status.

Fesoterodine was approved in Europe in 2007 for the treatment of overactive bladder (OAB). For the indication of overactive bladder, it is available alongside tolterodine, solifenacin, darifenacin, trospium chloride and the non anticholinergic mirabegron as a therapy option. Selection depends on tolerability, comorbidities and individual response.

Mechanism of Action

Fesoterodine itself has no pharmacological action. In plasma it is rapidly and completely converted by non specific esterases to 5 HMT. 5 HMT is a competitive antagonist at muscarinic receptors with similar affinity for M1, M2, M3, M4 and M5 subtypes, without pronounced selectivity.

In the detrusor of the urinary bladder, 5 HMT blocks the contractile function of the M3 receptors and reduces detrusor activity. This results in increased functional bladder capacity, reduced urinary urgency and decreased pollakiuria. The effect is comparable to other antimuscarinics in overactive bladder therapy.

Pharmacokinetically, fesoterodine is rapidly converted to 5 HMT after oral administration, with bioavailability of approximately 52 percent for 5 HMT. Half life approximately 7 hours, allowing once daily administration. Elimination via CYP3A4 metabolism and renal excretion.

Indications

• Overactive bladder (OAB): symptoms of urinary urgency, pollakiuria, urge incontinence
• Neurogenic detrusor overactivity: after stroke, in multiple sclerosis, Parkinson's, spinal cord injury
• In failure or intolerance of tolterodine: fesoterodine may be an alternative because 5 HMT levels are independent of CYP2D6

Dosage and Administration

Adults: initial dose 4 mg once daily, with insufficient response increase to 8 mg once daily after at least 8 weeks.

In severe renal insufficiency (eGFR less than 30 ml/min): maximum dose 4 mg daily. In moderate hepatic insufficiency: maximum dose 4 mg daily. In severe hepatic insufficiency: contraindicated.

With strong CYP3A4 inhibitors: maximum dose 4 mg daily.

Administration: with or without food, ideally at the same time of day. Swallow tablet whole with sufficient water (extended release tablet, do not split or chew).

Therapeutic success: first improvement usually within 1 to 2 weeks, full effect after 8 to 12 weeks.

Adverse Effects

Very common (anticholinergic): dry mouth (most common adverse effect, around 30 percent), constipation, visual disturbance (accommodation disorder), dry eyes.

Common: fatigue, dizziness, headache, urinary retention especially in men with prostatic hyperplasia, confusion especially in older adults, tachycardia, nausea.

Rare: acute angle closure glaucoma, severe allergic reactions, anaphylaxis, paralytic ileus, QT prolongation.

Important, anticholinergic burden: fesoterodine contributes to the so called anticholinergic load, which is associated with cognitive decline, dementia and fall risk. Especially in older patients and in polypharmacy, the indication should be regularly critically reviewed; alternative therapies such as mirabegron are a non anticholinergic option.

Interactions

• Other anticholinergic substances (tricyclic antidepressants, diphenhydramine, atropine): additive anticholinergic burden
• Cholinesterase inhibitors (donepezil, galantamine, rivastigmine): mutual cancellation of effects
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, HIV protease inhibitors): increased 5 HMT levels, maximum dose 4 mg
• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St. John's wort): reduced levels, action may decrease
• QT prolonging substances: additive QT prolongation
• Alcohol: enhances fatigue and cognitive effects

Special Considerations

Pregnancy and breastfeeding: data are limited, use only after strict indication. If needed, in pregnancy, behavioural measures and pelvic floor training are preferred.

Angle closure glaucoma: fesoterodine can increase intraocular pressure and is contraindicated in untreated angle closure glaucoma.

Urinary retention: patients with residual urine or bladder emptying disorder should be evaluated urologically before therapy.

Driving ability: fesoterodine can cause blurred vision, dizziness and fatigue, which may affect driving ability.

Advantage in CYP2D6 polymorphism: with tolterodine, drug levels strongly depend on the CYP2D6 metaboliser type. Fesoterodine is activated by non specific esterases, leading to more uniform levels. In patients with tolterodine level fluctuations or efficacy problems, switching to fesoterodine may make sense.

You may also be interested in

• Tolterodine, another muscarinic receptor antagonist with the same active metabolite
• Solifenacin, M3 selective antagonist
• Mirabegron, beta 3 adrenoceptor agonist as non anticholinergic alternative
• Oxybutynin, older anticholinergic
• Trospium, quaternary anticholinergic with fewer central effects

Frequently Asked Questions

Sources

• EMA, Toviaz (Fesoterodine) EPAR
• DGU S2k Guideline overactive bladder
• Gelbe Liste, Fesoterodine active substance profile
• BfArM, German Federal Institute for Drugs and Medical Devices