Darifenacin

Darifenacin is a drug that is used to treat overactive bladder. It belongs to a family of drugs called antimuscarinics. Other members of this family include atropine, ipratropium (Atrovent), tropicamide (Paremyd), and cyclopentolate. Darifenacin relieves the symptoms of overactive bladder by blocking the muscarinic receptor, a molecule in the bladder that receives signals to contract.

The Food and Drug Administration approved darifenacin in December 2004.

Other Names

Darifenacin is marketed by Novartis under the brand names Enablex and Emselex.

Uses

Darifenacin is used for the treatment of overactive bladder, with symptoms of urge urinary incontinence, urgency, and frequency. Urge urinary incontinence is involuntary urination immediately following an urge to urinate. Urgency is the feeling of needing to urinate, and frequency is an increase in how often a person feels the urge to urinate.

How Darifenacin is Taken

Darifenacin is available in 7.5 mg and 15 mg tablets. The recommended starting dose is 7.5 mg once daily. The dose may be increased to 15 mg once daily after two weeks on the lower dose.

How Darifenacin Works

The chemical structure of darifenacin. Source: Wikimedia Commons

The muscles of the bladder are controlled by the neurotransmitter acetylcholine. Neurotransmitters are chemicals released from nerve cells. These chemicals activate proteins called receptors on the surface of other nerve cells or muscle cells. Acetylcholine acts on muscarinic receptors, which are proteins expressed on cells throughout the body. Acetylcholine binds to a specific type of muscarinic receptor called M3. When acetylcholine stimulates this receptor, it causes the muscle of the bladder to contract. This can lead to overactive bladder.

Darifenacin is an antimuscarinic. Antimuscarinics are drugs that bind to muscarinic receptors and block them from being activated by acetylcholine. Darifenacin, unlike many other antimuscarinics, specifically blocks M3.

How the body affects darifenacin

Peak bloodstream levels of darifenacin are reached about seven hours after several doses. After six days, the blood levels of darifenacin reach a steady-state. Darifenacin is extensively metabolized (broken down) by the liver enzymes CYP2D6 and CYP3A4. About 60% and 40% of darifenacin is excreted in the urine and feces, respectively.

Benefits

Compared to a placebo (inactive) drug, darifenacin reduces the number of episodes of incontinence, and decreases urgency, leakage, voids per day, and nocturnal awakenings. In these respects it works about as well as other antimuscarinic drugs that are used for overactive bladder.^[1]

In one study, darifenacin gave patients 4.3 more minutes' "warning time"—that is, time to get to the bathroom after the urge the urinate is felt—than the placebo drug did.^[2]

Since darifenacin specifically blocks the M3 and not the other types of muscarinic receptors which are found elsewhere in the body, it may be a better choice for patients who have antimuscarinic side effects from other drugs.^[3]

Side Effects

The only side effects that can be attributed to darifenacin are dry mouth and constipation. These effects are due to the inhibition of M3 receptors in the intestine and salivary glands. The side effects appear to be less frequent with the lower dose.^[3]

Risks and Precautions

Because of the effects of darifenacin on the bladder, the drug may increase urinary retention in people with bladder outflow obstruction. And, like other muscarinics, darifenacin could reduce the movement of the intestines, and thus worsen symptoms of severe constipation, ulcerative colitis, and myasthenia gravis.

The eye contains muscarinic receptors that regulate the amount of aqueous humor (fluid in the eye). Blocking these receptors could increase the pressure exerted by this fluid (the intraocular pressure) and worsen symptoms of narrow-angle glaucoma.

Drug Interactions

The risk of side effects is increased if darifenacin is taken with drugs that inhibit the breakdown system in the liver called CYP3A4. (For more information about this breakdown system and its effects on multiple drugs, see Cytochrome P450.) The interactions between drugs are more likely if more than 7.5 mg/day of darifenacin is taken with the CYP3A4-inhibiting drug. Below are some drugs that inhibit CYP3A4:

• Antifungal drugs (e.g., ketoconazole (Nizoral), itraconazole (Sporanox))
• Antiviral drugs (e.g., ritonavir (Norvir), nelfinavir (Viracept))
• Antibiotics (e.g., clarithromycin (Biaxin), erythromycin)
• Nefazodone (Serzone)

Darifenacin may interact with other drugs that are also metabolized (broken down) by the liver system CYP2D6. This interaction may be important for drugs which have a narrow therapeutic index (that is, drugs in which the blood concentrations that are safe and those that are toxic are very close). Some of these drugs include flecainide (Tambocor), thioridazine (Ridazine), and many tricyclic antidepressants (e.g., amitriptyline (Elavil, Endep)).

Research

Darifenacin was evaluated for the treatment of overactive bladder in three studies involving over 1,000 patients.^[1] Fewer weekly urge urinary incontinence episodes was observed across all three studies, and the difference was significant. The number of incontinence episodes per week were reduced by 8 and 11 in patients given 7.5 mg or 15 mg, respectively.

In an analysis of three trials of over 300 elderly patients (65 years of age or older), darifenacin reduced the average number of incontinence episodes per week by 67% and 76% at a dose of 7.5 mg and 15 mg, respectively.^[4]

References

1. ↑ ^{1.0 1.1} Chapple C, Steers W, Norton P et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005 May;95(7):993-1001. Abstract
2. ↑ Cardozo L, Dixon A. Increased warning time with darifenacin: a new concept in the management of urinary urgency. J Urol. 2005;173:1214-8. Abstract
3. ↑ ^{3.0 3.1} Epstein BJ, Gums JG, Molina E. Newer agents for the management of overactive bladder. Am Fam Physician. 2006 Dec 15;74(12):2061-8. Abstract | Full Text
4. ↑ Foote J, Glavind K, Kralidis G, Wyndaele JJ. Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist. Eur Urol. 2005 Sep;48(3):471-7. Abstract

External Links

FDA: Patient Information Sheet