- Aust Prescr 2006;29:138-43
- 1 October 2006
- DOI: 10.18773/austprescr.2006.082
7.5 mg and 15 mg prolonged-release tablets
Approved indication: overactive bladder
Australian Medicines Handbook section 13.1.1
The contraction of detrusor smooth muscle involves stimulation of muscarinic receptors by acetylcholine. Anticholinergic drugs have therefore been used to relax the bladder in patients with urge incontinence. These drugs have unwanted systemic effects so there is a need for a drug with an action that is more specific to the bladder. The M3muscarinic receptor has been a target for drug development as it is thought to be the subtype responsible for bladder contraction.
Darifenacin is an anticholinergic drug which has a greater affinity for the M3 receptor than for other subtypes. Its action diminishes the frequency of detrusor contractions and increases bladder capacity.
Once-daily dosing is possible with the prolonged-release formulation. Peak plasma concentrations are reached seven hours after an oral dose, with a steady state reached in six days. Bioavailability depends on the patient's metabolism. Darifenacin is extensively metabolised in the liver and its pharmacokinetics are affected by moderate hepatic impairment. As the metabolism involves cytochrome P450 2D6 and 3A4, there are several potential drug interactions. The risk of adverse events may be increased by CYP2D6 inhibitors such as cimetidine, fluoxetine and paroxetine. Daily doses of darifenacin should not exceed 7.5 mg if the patient is taking an inhibitor of CYP3A4 such as itraconazole. The anticholinergic adverse effects of tricyclic antidepressants and drugs for Parkinson's disease may be increased by darifenacin.
In one trial 561 patients were randomised to take darifenacin 3.75 mg, 7.5 mg, 15 mg or a placebo for 12 weeks. The respective median reductions in weekly incontinence episodes were 8.6, 9.0, 10.4 and 7.6. The reduction in weekly incontinence episodes was 68% with 7.5 mg and 73% with 15 mg. This was significantly greater than the 56% reduction with placebo.1Other placebo-controlled studies had similar results so the recommended starting dose is 7.5 mg daily, increasing if necessary after two weeks to 15 mg daily. In a dose titration trial, 59% of patients needed to increase to 15 mg daily.
Compared with placebo, patients taking darifenacin complain more frequently of dry mouth and constipation. These adverse effects appear to increase with the dose. Other adverse effects include altered vision, dyspepsia and abdominal pain. Caution is needed if darifenacin is considered for patients with decreased gastrointestinal motility or at risk of urinary retention.
Darifenacin has been studied in people with overactive bladder. These people have urinary urgency, but not all of them have urge incontinence. The benefits of darifenacin may be less certain in these patients. Although it achieved statistical advantages over placebo, the absolute changes may be small. For example, a patient given darifenacin 15 mg will have one less micturition per day than a patient given a placebo. They may also have one less episode of urgency per day. Darifenacin does not decrease the number of times a patient is awoken by their overactive bladder significantly more than placebo.1
Comparative studies are limited, but tolterodine has been included in a placebo-controlled trial of darifenacin. Unfortunately, a comparative analysis of the 15 mg dose of darifenacin was not done for all the outcomes. Darifenacin only achieved a statistical advantage, over tolterodine, for some outcomes if it was given at a daily dose of 30 mg. It appears that darifenacin's selective action does not give it a large clinical advantage.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.