Summary Basis of Decision for Enablex ®

3.3.1 Pharmacodynamics

In in vitro recombinant muscarinic receptor and human bladder tissue studies darifenacin demonstrated a greater potency and selectivity for M₃ receptors than other muscarinic receptor antagonists. In vivo clinical doses of darifenacin had less impact on salivary fluid flow as compared with oxybutinin. Visual accommodation (reflecting M₅ activity) was only affected at supra-therapeutic concentrations of darifenacin (> 500 % the concentration reached following 15 mg darifenacin extended release exposure). Heart rate and cognitive function were not significantly affected.

3.3.2 Pharmacokinetics

Darifenacin extended release tablets were developed to overcome the inconvenience of multiple dosing per day that is necessary with the immediate release formulation. Pharmacokinetics of the extended release formulation were studied in healthy subjects. Time to peak concentration is approximately 7 hours and steady state is achieved after approximately 6 days at the 7.5 mg dose. The T½ is between 12 and 18 hours, reflecting the low rate of absorption. Doubling the dose appeared to more than double the total and steady state exposure suggesting saturation of first pass metabolism. Protein binding is around 98 %. Approximately 10 % of the ingested dose is converted to active metabolite and one third of the latter is excreted by the kidneys. The remainder is metabolized to inactive products.

Darifenacin exposure appears to increase in the very elderly (23 % per decade above the age of 65) and was found to be greater in women than men, as well as in Caucasian populations when compared with Japanese populations. The gene for CYP2D6 expression shows significant polymorphism in Caucasian populations which results in increased exposure to darifenacin in poor metabolizers. Paroxetine, an inhibitor of CYP2D6 metabolism, increased darifenacin exposure by approximately 30 % which is consistent with the difference between subjects that lack the genotype for CYP2D6 and those that have the active form. CYP3A4 inhibitors increased darifenacin exposure according to their potency. Conversely, darifenacin had a minor effect on drugs metabolized by CYP2D6 and CYP3A4. Moderate hepatic damage resulted in a 350 % increase in exposure to darifenacin despite very minor changes in laboratory values. Renal failure did not affect elimination of darifenacin though data is very sparse for subjects with creatinine clearances below 20 mL/min.

3.3.3 Clinical Efficacy

Four 12-week pivotal trials involving 1338 patients suffering from overactive bladder were submitted by the sponsor. All were multi-centre, double-blind, randomized, placebo-controlled, parallel-group studies and were carried out in an outpatient setting. The target population for these studies was restricted to those patients with overactive bladder who had incontinence 5-50 times per week.

The primary efficacy measure was the number of incontinence episodes per week. Secondary endpoints included: number of micturitions per day, number of episodes of urgency per day, volume of urine passed per void, severity of urgency, and number of nocturnal awakenings due to overactive bladder per week.

Darifenacin reduced the number of incontinence episodes per week in a dose-dependant manner compared with placebo. The placebo response in these studies was 50 %, significantly higher than the usual 30 % response rate. This is possibly due to the patient selection insisting on a significant number of incontinence episodes. When 15 mg darifenacin was compared with tolterodine dosing at 12 weeks, no statistical comparison was made because the difference between darifenacin and placebo was not significant. When placebo-treated study groups from other studies were used, the difference did become significant in favour of darifenacin. At 2 weeks, there was a statistically different rate of incontinence episodes when darifenacin was compared with tolterodine.

Many secondary endpoints also showed a significant difference between darifenacin and placebo including number of micturitions per day, volume of urine passed, and frequency and severity of urgency. For most secondary endpoints there was no difference between darifenacin and tolterodine. Age and gender were not found to have any significant effect on the results. Data was insufficient to assess the effect of race or the impact of a diagnosis of neurogenic bladder.

Two long-term open label studies were also performed to assess efficacy and adverse effects. Efficacy was maintained over time and there was a 35 - 37 % dropout rate.

3.3.4 Clinical Safety

Overall incidence of adverse events (AEs) in the pivotal trials increased with increasing dose of darifenacin. Darifenacin administered at 3.75 mg daily (a therapeutically ineffective dose) showed a similar incidence of AEs as placebo and there was little increase when the lower effective dose of 7.5 mg daily was given. Adverse events were more frequently reported in the digestive system and increased with increasing dose, however there was no increase in adverse events in the cardiovascular or nervous system with increasing dose. There was a greater incidence of dry mouth, constipation, and dysphagia in the treated patients as compared to placebo and slight increases in urinary tract infections, abnormal vision, and dry eyes were also seen. Acute urinary retention and possibly consequent urinary tract infection appears to be a possible complication of treatment. No new adverse events were detected in the long-term studies. Almost all adverse events occurred during the first three months of treatment and mainly during the first two weeks. Nine rare adverse events occurred at a greater rate than that seen in the placebo group. Though they are unlikely to be related to darifenacin exposure, an open mind should be kept particularly with respect to angioedema and gastritis/esophagitis resulting in hematemesis.

There did not appear to be any relation between the incidence of adverse effects and age, however the number of patients in the very elderly (> 75 years of age) was small and so no definitive conclusions can be made for this group. Gender and race also did not appear to affect incidence of adverse effects. The number of patients studied was too small to confirm whether there was any difference between poor and extensive metabolizers. Moderate hepatic damage caused extensive darifenacin retention. Information is sparse with respect to severe renal disease.

Extensive cardiac safety testing was performed consistent with, and in excess of, those required in the provisional ICH guidelines. Results indicate that no effects are seen until concentrations 50 times greater than that achieved in man following a maximum therapeutic dose. Enablex^® belongs to a group of drugs of which other members have been shown to cause QT prolongation. Enablex^® did not show this effect when tested at the standard of provisional ICH guideline E14. Novartis has successfully conducted a large, definitive QT prolongation study in 188 subjects. The study population was comprised of 80 % CYP2D6 extensive metabolizers (EM) and 20 % CYP2D6 poor metabolizers (PM). Study subjects received standard (15 mg) and supra-therapeutic (75 mg) daily doses of darifenacin. This study confirmed that darifenacin does not result in any increase in QT/QTc prolongation, as also demonstrated in previous studies with a large number of subjects. Post-marketing monitoring of all adverse events including cardiovascular events will be performed by Novartis. No testing was done in subjects with other risk factors of arrhythmias such as hypokalemia and congestive cardiac failure however, and caution should be taken in those particularly at risk.

The discontinuation rate was the same for darifenacin administered at 7.5 mg daily and placebo, but increased in the 15 mg daily group. Discontinuations were mainly due to dry mouth, constipation, and dysphagia. In the long-term studies, most discontinuations occurred in the first three months and showed a similar pattern and cause to that of the short-term studies. Four deaths were reported during the program though none were related to therapy.

3.3.5 Issues Outstanding

Four pivotal clinical studies were submitted by the sponsor to support the use of Enablex^® 7.5 mg and 15 mg extended release tablets in the treatment of overactive bladder. Two of the four pivotal studies employed a clinical research formulation of the 7.5 mg and 15 mg strengths and the other two studies employed the proposed commercial formulation for the same two strengths. The clinical research and proposed commercial extended release tablet formulations have an identical core composition and matrix release system and differ only in shape, colour, and coating. These differences were not considered significant. However, in addition to the modifications to the product formulation there was a manufacturing site change. The proposed commercial product was manufactured at a facility different from the clinical research product. This manufacturing site transfer is a significant change that requires a comparative bioavailability study to support it. Darifenacin also displays non-linear pharmacokinetics that produce greater than proportional increases in AUC with increasing dose. While the tabulation of the composition of the proposed commercial formulations of darifenacin suggests that the
7.5 mg strength is proportional to the 15 mg tablet strength, dissolution data has not been provided to support proportionality between the two strengths.

The sponsor submitted two pivotal bioequivalence studies intended to bridge the clinical research formulations of the 7.5 mg and 15 mg tablets to the proposed commercial formulations of the same strengths. The first study was an open, randomized, multiple-dose, two-way crossover, two cohort study to demonstrate the bioequivalence of darifenacin when administered as the proposed commercial 7.5 mg and 15 mg tablets compared to the 7.5 mg and 15 mg clinical research tablets in the fasted state. The second study examined only the 15 mg commercial and clinical tablets in the fasted state.

The data obtained from Cohort 1 of the first study demonstrated that the proposed commercial 7.5 mg tablets were biocomparable to the clinical research 7.5 mg tablets under multiple-dose fasting conditions. The data from Cohort 2 of the first study pooled with the data from the second study demonstrated that the proposed commercial 15 mg tablets were biocomparable to the clinical research 15 mg tablets under multiple-dose fasting conditions. The standards for biocomparability for both strengths were met from measured data as well as data corrected for measured drug content.