Summary Basis of Decision for Resotran ™

3.3.1 Pharmacodynamics

Pharmacodynamic studies assessing various direct and indirect outcome measures suggest that prucalopride may accelerate colonic transit. In a randomized, double-blind, placebo-controlled, parallel-group study and a randomized, double-blind, placebo-controlled, 2-way cross-over study in patients with chronic constipation, prucalopride was associated with a non-significant trend toward an accelerated transit through the stomach, small bowel, and colon in patients with constipation unassociated with a rectal evacuation disorder.

Pharmacodynamic effects related to the gastrointestinal prokinetic activity of prucalopride were studied in healthy subjects and in patients with chronic constipation. Pharmacodynamic studies [number (n) = 5] were primarily randomised, placebo-controlled, cross-over designs and were conducted in healthy subjects (n = 134) with regular bowel habits. Pharmacodynamic data were only obtained from 109 subjects. Subjects were exposed to placebo and/or prucalopride (0.5 mg, 1 mg, 2 mg, or 4 mg) administered as a 10 minute intravenous infusion, or as hydrochloric acid (HCl) capsules, or succinate tablets, once daily for 7-10 days. Subjects were relatively equally distributed between sexes with a median age approximately 30 years (min-max 18-71 years) and median weight approximately 70 kg (min-max 48-105). Studies assessed the effect of prucalopride on various outcomes including, gastrointestinal transit [for example (e.g.), gastric, small bowel, and colonic transit], colonic motility, anorectal physiology, and bowel habits in healthy subjects.

These studies demonstrated a statistically significant reduction or trend toward a reduction in total colonic transit time with 2 mg prucalopride treatment compared to placebo. The magnitude of this reduction was delta 1.39 units; between 2.0 mg prucalopride and placebo at 24 hours post-treatment, however, is not considered to be clinically significant according to the sponsor pre-specified criteria.

Some secondary parameters (e.g., subject’s assessment of bowel habits) suggested an affect of prucalopride on the frequency of bowel movements and a trend toward a more watery stool consistency.

The patient pharmacodynamic studies (n = 5) were primarily randomised, double-blind, placebo-controlled, parallel group designs and were conducted in patients with chronic constipation (n = 182). Patients were exposed to placebo and/or prucalopride (1 mg, 2 mg, or 4 mg) administered as HCl capsules or succinate tablets once daily for 7 days to 24 weeks. Subjects were predominantly female (93%, 169/182) with a median age approximately 40 years (minimum-maximum 18-69 years). Studies assessed the effect of prucalopride on various outcomes including, gastrointestinal transit (e.g., gastric, small bowel, and colonic transit), colonic motility, anorectal physiology, and bowel habits subjects with chronic constipation.

These studies did not demonstrate a statistically significant reduction in total colonic transit time with 2 mg prucalopride treatment compared to placebo. A statistically significant difference in colonic transit time was observed following 4 mg prucalopride once daily for 7 days. The magnitude of this reduction was delta 0.92 to 1.26 between 2 hours and 24 hours post treatment, however, is not considered to be clinically significant according to the sponsor pre-specified criteria.

Some secondary parameters (e.g., subject’s assessment of bowel habits) suggested an affect of prucalopride on bowel habits/properties. These data are limited by the unblinded assessment and lack of dose-response effect.

3.3.2 Pharmacokinetics

The pharmacokinetics and initial tolerability of prucalopride in healthy subjects have been assessed by numerous studies (n = 12). These studies have been conducted in both male and female subjects 18-54 years of age. Both single-dose and repeat-dose trials have been reported. Various dosage forms, including intravenous, subcutaneous, oral solution, oral capsule, and oral tablet have been evaluated. Dosages have ranged from 0.0625 mg to 20 mg and placebo, and have consisted of once- or twice-daily dosing regimes. These studies generally suggest that prucalopride exhibits dose-proportional kinetics within the relative therapeutic dosage range (e.g., 0.5 mg - 4 mg).

Steady-state is attained within 3-5 days following once daily oral tablet administration (once daily dosing). The terminal half-life was approximately one day. Concomitant intake of food did not influence the oral bioavailability of prucalopride.

Absorption

Prucalopride was rapidly absorbed; C_max was attained within 2-3 hours (single-dose) and 1-3 hours (repeat-dose), respectively, following once daily 2 mg oral tablet administration (n = 12 subjects). Plasma concentration fluctuated between 2.5 and 7.5 ng/mL, following once daily 2 mg oral table administration.

Distribution

Resotran™ was rapidly and extensively distributed. After intravenous dosing, prucalopride was rapidly and extensively distributed and showed a large volume of distribution. The volume of distribution at steady state was 567 L. The plasma protein binding of prucalopride was approximately 30%. In whole blood, 66% of the drug was distributed to blood cells.

Metabolism

Metabolism is a minor route of prucalopride elimination. Prucalopride metabolism results in the production of eight metabolites. The metabolites accounted for 6.3-13.8% of the administered prucalopride dose. The major metabolite (R107504; formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) accounted for 2.6-3.5% of the dose and three additional unidentified metabolites accounted for 0.6-1.6% of the dose. Four of the identified metabolites (including R107504) exhibited a similar or lower in vitro affinity to 5-HT₄ receptors as compared to prucalopride.

Excretion

Prucalopride (0.5 mg radiolabelled oral solution) was primarily excreted unchanged in the urine (55.1-73.8%) and to a much lesser degree in the faeces (3.7-8.1%) (n = 3 subjects) by 10 days following single-dose administration in one study.

Within a dosing interval (e.g., 24 hours), 26% of a single-dose 4 mg oral solution was excreted unchanged in the urine (n = 6 subjects). Steady-state renal clearance of 2 mg oral solution prucalopride was 196 mL/minute (n = 12 subjects), indicating both passive glomerular filtration and active tubular secretion.

After intravenous (single) and oral solution (steady-state) administration of 2 mg prucalopride, approximately 60% of the dose was recovered unchanged in the urine (during 72 hours following administration). Half to two-thirds of the renal clearance of prucalopride was attributable to active renal secretion, while passive glomerular filtration of prucalopride was responsible for the remainder.

Drug Interaction Studies

Potential drug interactions were assessed in healthy young (18-40 years) subjects (n = 12-18 per study; relatively equal distribution of males to females per study).

In a randomized, double-blind, placebo-controlled crossover study, prucalopride [2 mg once daily (o.d.), at steady-state] did not result in a clinically significant effect on the pharmacokinetics of warfarin (25 mg single-dose). Co-administration of digoxin (0.25 mg for 8 days) with prucalopride (4 mg o.d., at steady-state) did not affect the pharmacokinetics of prucalopride, while co-treatment of prucalopride with digoxin resulted in an approximate 10% decrease in the bioavailability of digoxin. Co-administration of ketoconazole [200 mg twice a day (b.i.d.)] with prucalopride (2 mg o.d.) for 9-days resulted in an approximate 40% increase in the bioavailability of prucalopride. There is no marked affect of prucalopride on the plasma concentration of ketoconazole; however, the affect of prucalopride on the pharmacokinetics of ketoconazole have not been determined. Co-administration of paroxetine [10 mg b.i.d (Day 1-3); 20 mg o.d. (Day 4-7)] with prucalopride (4 mg o.d.) for 7 days did not result in a clinically significant effect on the pharmacokinetics of prucalopride or paroxetine.

In open-label, three-way crossover studies co-administration of cimetidine (800 mg b.i.d. for 7 days) or probenecid (500 mg b.i.d. for 7 days) with prucalopride (2 mg o.d. at steady-state) did not result in a clinically significant effect on the pharmacokinetics of prucalopride. Co-administration of erythromycin [500 mg four times a day (q.i.d.)] with prucalopride (2 mg o.d.) for 7-days did not result in a clinically significant effect on the pharmacokinetics of prucalopride. Conversely, co-administration of prucalopride resulted in a 20-40% increase in the bioavailability of erythromycin.

Special Populations

Resotran™ (prucalopride) is not recommended for use in the paediatric population due to an incomplete characterisation of the clinical pharmacology and associated safety risks, including a potential risk of cardiac arrhythmia.

The plasma exposure of Resotran™ (prucalopride) were elevated in elderly subjects (≥65 years) relative to young adults. The elevation in plasma prucalopride was attributed to a reduction in renal function associated with age. A lower starting dose should be considered in this group of patients.

Based on a population pharmacokinetic analysis on combined data from Phase I, II, and III studies, it was found that the apparent plasma clearance of prucalopride was similar in healthy subjects and patients with chronic constipation. The apparent clearance of prucalopride was not affected by age, body weight or body mass index, sex, or race, but as expected, creatinine clearance had a significant effect.

An open-label study in subjects with mild renal impairment [n = 8, 6 males (M)/2 females (F); mean age 62.6 years, minimum to maximum 46-74 years], moderate renal impairment [n = 7 (5M/2F); 62.7 years  (43-69), and severe renal impairment [n = 9 (3M/6F), 51.8 years (45-59)] indicated that a single 2 mg oral capsule dose of prucalopride resulted in a progressively greater AUC_0-∞ and terminal half-life with degree of renal impairment compared to subjects with normal renal function [n = 10 (5M/5F); 59.4 years (52-68)]. AUC_0-∞ increased 1.25-fold (mild), 1.5-fold (moderate), and 2.3-fold (severe), while the terminal half-life increased from 30 hours (normal renal function) to 34 hours (mild), 43 hours (moderate), and 47 hours (severe). The terminal half-life reported in subjects with normal renal function from this study (29.9 hours) was greater (25%) than that observed in most other prucalopride studies (24 hours). There were no observed marked differences in other absorption parameters associated with degree of renal impairment. In patients with severe renal impairment, a dose of 1 mg Resotran™ once daily is recommended. No dose adjustment is required for patients with mild to moderate renal impairment.

Hepatic impairment is unlikely to affect the pharmacokinetics of Resotran™ to a clinically relevant extent; however, for precautionary reasons, a dose of 1 mg Resotran™ once daily is recommended in patients with severe hepatic impairment (e.g., Child-Pugh class C).

3.3.3 Clinical Efficacy

The clinical trials were performed in accordance with Good Clinical Practice. The Phase II and Phase III program for Resotran™ was comprised of 25 Phase II and 10 Phase III studies. In this summary, the focus is on the key studies that supported the selection of the dose, the evidence for a clinically meaningful effect in chronic constipation, and maintenance of that effect during long-term treatment (>12 months) in the proposed indication.

The Phase II dose-response studies differed among themselves in the main inclusion criteria, the primary efficacy parameter selected, and dose regimen utilized. Of the three dose-response studies, Study PRU-USA-3 was considered to be the most adequate study as it used the same inclusion criterion, primary endpoint, and dose regime as the Phase III pivotal efficacy studies. The primary endpoint was the percentage of subjects achieving ≥3 spontaneous complete bowel movements (SCBM) per week, and it evaluated 4 different o.d. doses in a double-blind placebo-controlled, randomized, parallel group design during a 4-week phase. Subjects (231) were mostly females and Caucasian, with a mean of 42.1 [range, 21 to 70] years of age. Patients had a constipation history of approximately 20 years. Most reported very hard and hard stool consistency. Laxative was used always or most of the time in about 80% of patients. Approximately 80% of them reported inadequate relief with laxatives. Patients complained of abdominal pain moderate and severe in 38% to -65% (unbalanced) among the groups in Study PRU-USA-3. Based on these three studies and in particular the results of Study PRU-USA-3, 2 mg o.d. was considered to be the lowest effective dose in the adult population. The 2 mg and 4 mg once daily dose was evaluated in the Phase III pivotal studies.

Study PRU-USA-3 consisted of 3 phases: a 4-week drug-free run-in phase; followed by a 4-week randomized, double-blind, placebo-controlled treatment phase; followed by a 4-week drug-free run out phase. The proportion of patients with ≥3 SCBM/week decreased in all active groups in the first week and remained steady through the 4 weeks of this phase (run-out). The level of response remained above that seen in the run-in phase (baseline). However, it is unknown whether longer treatment time (>4 weeks of Resotran™ treatment) will provide similar no-rebound findings.

The efficacy of Resotran™ was established in three multicentre, randomized, double-blind, 12-week placebo-controlled studies in patients with chronic idiopathic constipation [number of patients (n) = 1,279 (intent-to-treat population)]. The studies consisted of two phases: a 2-week drug-free run-in phase followed by the 12-week randomised, double-blind, placebo-controlled treatment phase. The study population had long-standing chronic constipation, with a mean duration of 20 years [median and range: 16 (0.3; 82)]. Approximately 85% of patients took laxatives/enemas during the previous 6 months and more than 80% of patients reported that their previous therapies were inadequate. Patient reported having ≤2 SCBM/week, as well as the occurrence of one or more of the following for at least 6 months before the selection visit:

• very hard (little balls) and/or hard stools for at least a quarter of the stools;
• sensation of incomplete evacuation following at least a quarter of the stools; or
• straining at defecation at least a quarter of the time.

Exclusion criteria disallowed patients with secondary causes of chronic constipation (drug-induced, and endocrine, metabolic, neurologic disorders), or presence of megacolon or pseudo-obstruction, surgery, and organic disorders of the large bowel. In addition, patients were excluded if were with clinically uncontrolled cardiovascular, liver, or lung disease; neurologic or psychiatric disorders (including active alcohol or drug abuse); cancer or acquired immune deficiency syndrome (AIDS); and other gastro-intestinal or endocrine disorders, as well as patients with insulin-dependent diabetes mellitus. Patients with impaired renal function, that is (i.e.) serum creatinine concentration >2 mg/dL or creatinine clearance ≤50 mL/min were excluded, and those that had clinically significant abnormalities of haematology, urinalysis, or blood chemistry.

The study population consisted of 1,124 females and 155 males (based on intent-to-treat population). The mean age in the pooled studies was 46.9 years (range 17, 95). The patients were predominantly white (89.8%). The Resotran™ oral doses studied in each of these three studies included 2 mg and 4 mg tablets once daily.

Rescue medication was bisacodyl 5 mg tablets. If the patient had not had a bowel movement for 3 or more consecutive days throughout the study, he/she was allowed to take bisacodyl as rescue medication. A maximum single dose of 15 mg (3 tablets) of bisacodyl was prescribed.

Primary Efficacy Endpoint

The primary efficacy endpoint for each of the studies was the proportion of patients with an average of three or more spontaneous, complete bowel movements (SCBM) per week over Weeks 1-4 and Weeks 1-12 of the study. Imputation methods were used for missing diary data (i.e., bowel movement symptoms) and missing times. Sensitivity analyses supported the imputation methods used.

A bowel movement was defined as spontaneous if no laxatives were taken in the 24 hours preceding the bowel movement. A bowel movement was assessed as complete if the patient responded "yes" to the diary question "Did the stool make you feel like you completely emptied your bowels? Yes or No".

The pooled data from the three pivotal studies showed that the 2 mg dose of Resotran™ was efficacious in relieving symptoms of constipation in patients with chronic constipation. Both doses (2 mg and 4 mg Resotran™) were statistically superior to placebo at the primary endpoint in each of the three studies, with no incremental benefit of the 4 mg over the 2 mg dose. The proportion of patients treated with the recommended dose of 2 mg Resotran™ that reached an average of ≥3 SCBM per week was 27.8% (Weeks 1-4) and 23.6% (Weeks 1-12), versus 10.5% (Weeks 1-4) and 11.3% (Weeks 1-12) on placebo. The differences in the percentages of patients with ≥3 SCBM per week between Resotran™ and placebo were 12.3% and 17.3% at Weeks 1-12 and Weeks 1-4, respectively. The number needed-to-treat (NNT) was 5.8 and 5.7 at Weeks 1-12 and Weeks 1-4, respectively. Similar values were found in the 4 mg group.

In all three studies, the efficacy of Resotran™ was more pronounced during Weeks 1-4 as compared to Weeks 1-12, and better efficacy results were obtained at Week 1 of treatment compared to Week 2, 3, or 4.

Secondary Efficacy Endpoints

Secondary efficacy variables were assessed from data collected from daily diaries or scheduled visits.

The daily diaries provided the following data: the proportion of patients with an average increase of ≥1 SCBM/week (key secondary parameter); average number of SCBM or spontaneous bowel movements (SBM) per week; symptoms of constipation [consistency (stool form); straining; sensation of complete evacuation]; average time to first SBM or SCBM after first intake; and rescue bisacodyl intake.

The scheduled visits provided the Patient’s Global Assessment and the Patient’s Symptoms Assessment. In the Patient’s Global Assessment, the patient was asked to record his/her global evaluation of the efficacy of treatment (Visits 3, 4, 5, and 6) using the following 5-point scale: not at all effective (0); a little bit effective (1); moderately effective (2); quite a bit effective (3); and extremely effective (4). At all visits except Visit 1, the severity of his/her constipation over the past 2 weeks using the following 5-point scale: absent (0); mild (1); moderate (2); severe (3); and very severe (4). The Patient’s Symptoms Assessment, conducted with the Patient Assessment of Constipation-Symptom Questionnaire (PAC-SYM), was done at Visit 2 (just prior to the start of double-blind treatment),Visit 3 (after 2 weeks of treatment), Visit 4 (after 4 weeks of treatment), Visit 5 (after 8 weeks of treatment), and Visit 6 (after 12 weeks of treatment) or at discontinuation. The patient recorded the severity of his/her symptoms occurring during the 2 weeks preceding the visit using the PAC-SYM. The PAC-SYM was considered to be a validated instrument. The PAC-SYM is a 12-item subject self-administered instrument that measures the severity of constipation-related symptoms. Items are rated on a 5-point Likert scale: absent (0); mild (1); moderate (2); severe (3); and very severe (4).

During the visits, the quality of life was also evaluated. The primary assessment of patient quality of life was obtained using the Patient Assessment of Constipation-Quality of Life (PAC-QOL) and the 36 short form Health Survey (SF-36™).

For the main secondary efficacy endpoint (the proportion of patients with an average increase of ≥1 SCBM per week), significant improvements were seen for both the 2 mg and 4 mg treatment groups compared with placebo. The proportion of patients with ≥1 SCBM per week during Weeks 1-12 were 43%, 47% and 25%, respectively.

Resotran™ significantly improved the time to first bowel movement when compared with placebo. The median time to first SCBM was 375 hours in the placebo group versus 56 hours and 38 hours in the Resotran™ 2 mg and 4 mg groups, respectively. The median time to the first SBM was 26.5 hours in the placebo group, and 2.5 hours and 1.8 hours in the 2 mg and 4 mg groups, respectively.

Pooled data from the pivotal studies on the average number of SCBM/week confirmed individual studies. Resotran™ improved the average frequency of weekly SCBM when compared with placebo. However, the average number of SCBMs per week was less than 3, indicating that the majority of patients did not achieve a non-constipated state.

Other secondary efficacy endpoints derived from daily diaries (bowel movement symptoms) supported the primary variable findings however, the changes between Resotran™ and placebo were of small clinical significance (straining, consistency, and feeling of incomplete evacuation). At Weeks 1-12, Resotran™ 2 mg reduced the %SBM with hard/very hard consistency by 11% while increasing the %SBM with normal consistency by 5%. At Weeks 1-12, Resotran™ 2 mg reduced the %SBM with severe/very severe straining by 7%, while increasing the %SBM with no straining by 4.4%. At Weeks 1-12 Resotran™ 2 mg improved the %SBM with the feeling of complete evacuation over placebo by 5.8%. Similar findings were found with the 4 mg dose. Overall, the majority of patients did not normalize their bowel movement symptoms. The slightly better results in stool consistency during the studies may be secondary to the shorter time the faeces stayed in the colon.

The score in the PAC-SYM questionnaire improved from baseline in a very small magnitude (<0.5 step in a scale of 5 steps). The differences between the Resotran™ and placebo groups were small. The proportion of patients with an improvement of at least 1 point in the scores of the overall PAC-SYM and each of the subscales (stool symptoms, abdominal symptoms, and rectal symptoms) was, however, statistically significantly higher in the Resotran™ groups compared to the placebo group at Weeks 4 and 12 (except for the rectal symptoms subscale in the Resotran™ 4 mg group). The most marked effect of Resotran™ treatment was observed on the stool symptom and abdominal symptom clusters. The fact that there was less impact on the rectal symptoms was not surprising because these symptoms are more indicative of outlet problems rather than motility problems.

Patients continued using laxatives during treatment. When the number of laxatives used prior to the study were compared to the number used during the study, it was found that the mean average number of bisacodyl tablets taken per week was reduced during the 12-week treatment period from approximately 2 to 1 tablet per week in the Resotran™ groups while in the placebo group no reduction was found.

The primary quality of life parameter was the satisfaction subscale of the PAC-QOL. This subscale (a composite score of 5 questions) measured satisfaction with overall bowel movements and satisfaction with treatment. The proportion of patients in the Intent-to-Treat Analysis Set with an improvement of at least 1 point in the score of the PAC-QOL satisfaction subscale was statistically significantly higher in the Resotran™ 2 mg (45.3% and 44.0%) and 4 mg (45.9% and 43.3%) groups than in the placebo group (21.3% and 22.2%) at Weeks 4 and 12, respectively. A similar level of improvement was seen in each of the three pivotal studies.

The clinical relevance of the PAC-QOL results was assessed by looking at the correlation between improvements in the quality of life and other efficacy assessments. This analysis showed that patients with a 1-point improvement on the satisfaction subscale also had improvements on other efficacy parameters. The effects of Resotran™ on the results of the SF-36™ Health Survey were limited.

Subgroup Analysis

Sex

There were fewer males than females enrolled in the studies (approximately 10% of the study population). The female patients appeared to be more sensitive to the beneficial effects of Resotran™ than males. Males appeared to require the higher dose of 4 mg to achieve similar success rates as females, albeit without statistical significance as compared to placebo. Males are not included in the authorized indication.

Age

A Phase III study, Study PRU-INT-12, evaluated the efficacy of Resotran™ in the elderly (≥65 years of age). This study was a double-blind, placebo-controlled efficacy and safety study that compared the effects of 1, 2, and 4 mg of Resotran™ with placebo. In this study, the number of patients with ≥3 SCBM per week was 39.5% on 1 mg Resotran™, 32.0% on 2 mg, 31.6% on 4 mg, and 20.0% on placebo. At the dose of 1 mg, the difference from placebo was 19.5%. The 1 mg dose appears to be more efficacious than the placebo, 2 mg and 4 mg doses. Statistical significance versus placebo was only achieved in the 1 mg group. No advantage was gained by increasing the dose beyond 1 mg. Therefore, elderly patients are not excluded from Resotran™ treatment and the recommended starting dose is 1 mg.

Race

Approximately 90% of the patients were White and approximately 5% were Black. The number of subjects in subgroups other than White was too small to draw meaningful conclusions.

Baseline SBM/SCBM

The improvement with Resotran™ treatment compared to placebo was below clinical significance in patients with no SBM/SCBM at baseline. Text is included in the Product Monograph under the Indication and Doses and Administration sections to inform patients and healthcare professionals that if treatment with Resotran™ is not effective during the first 4 weeks of treatment, therapy should be discontinued. This information should provide a protection for patients to avoid prolonged treatment failure.

Laxative use

Although laxatives were not to be used except for the rescue medication, patients continued using bisacodyl and some patients took concomitant laxatives during treatment. Approximately 85% of the patient population used laxatives for their condition in the 6 months preceding the study. At Weeks 1-12 of treatment, the proportion of subjects using laxatives was not changed in the placebo group and slightly reduced (8%) in the 2 mg Resotran™ group. Thus Resotran™ treated patients may still need to use laxatives.

Long-Term Efficacy in Chronic Constipation

A total of 2,595 patients with chronic constipation were treated with Resotran™ in follow-up open-label studies. A total of 1,490 subjects (57%) were treated for 6 months, and 869 subjects (33%) were treated for more than 1 year (>365 days). The maximum treatment duration was 952 days (136 weeks, or 2.6 years). The mean treatment duration was 284.4 days (40.6 weeks, 10 months). The primary objective of all of these studies was the collection of long-term safety data, but long-term efficacy was also assessed using either the PAC-QOL scale or the visual analogue scale (VAS) to assess the patient’s perception of treatment effectiveness and severity of constipation. Analysis of the efficacy data from the three 12-week pivotal studies demonstrated a correlation between improvements in the PAC-QOL and the clinical efficacy parameters including the primary endpoint used in those studies. Hence, the long-term data collected in the two open-label Phase III studies using the PAC-QOL satisfaction scale can be considered to provide a meaningful assessment of whether or not efficacy is maintained beyond the 12 weeks of the pivotal studies. The results from the open-label Phase II studies using the VAS data provided additional support for the long-term efficacy.

In the two open-label Phase III studies, data were available from approximately 700 patients who received mostly 2 or 4 mg doses of Resotran™ (1 mg dose was taken by only 14% of subjects) for at least 12 months. These data show an improvement in the mean quality of life scores during the first 3 months of treatment for all Resotran™-treated patients, which was maintained over the 12 months.

3.3.4 Clinical Safety

In the controlled clinical studies (pooled data of Phase II and Phase III studies), Resotran™ was administered orally to 2,717 patients with chronic constipation. Of these patients, 938 patients received Resotran™ at the recommended dose of 2 mg per day, while 1,361 patients were treated with 4 mg Resotran™ daily, 110 patients received 0.5 mg daily and 308 patients received 1 mg daily, for a treatment duration of 4 to 12 weeks.

The most frequently reported adverse events [(AEs) >10.0% of patients in all patients treated with Resotran™] were: headache; nausea; abdominal pain; and diarrhoea. These AEs were more commonly reported in the Resotran™ groups compared with the placebo grou

p. In most cases, both Resotran™ groups (2 mg and 4 mg) had a similar incidence rate of AEs, but other events such as diarrhoea and headache were dose-related (i.e., increased with the dose). In all of the Resotran™ groups, the onset at which these gastrointestinal (GI) disorders and central and peripheral nervous system (CNS) disorders (mainly headache and dizziness) were observed was during the first 4 weeks of treatment and appeared to be transient. The highest proportion (approximately 50-60%) of AEs of nausea, diarrhoea, and headache in both Resotran™ groups occurred on the first day of treatment. For abdominal pain, the proportion was lower (approximately 30%).

The majority of treatment-emergent AEs during the treatment period were considered to be mild or moderate in severity by the investigators. Severe events with the highest frequency, reported by at least 2 patients, were related to GI and CNS disorders. These included abdominal pain, diarrhoea, nausea, flatulence, vomiting, headache, dizziness and migrane (in some studies). Although diarrhoea was a frequently reported AE during treatment with Resotran™ there were no complaints of dehydration in most of the patients with severe diarrhoea.

In the Phase II and Phase III double-blind, placebo-controlled clinical studies in patients with chronic idiopathic constipation, the incidence of a composite endpoint of atrial rhythm-related AEs (atrial fibrillation, supraventricular extrasystoles, atrial flutter, supraventricular tachycardia, arrhythmia supraventricular, sinus arrhythmia, sinus tachycardia) was higher with Resotran™ 1-2 mg (0.6%) than with placebo (0.1%).

Less common AEs (<1%) were fever, chest pain, anorexia, tremors, migraine, anxiety, and urinary incontinence. The overall incidence of serious treatment-emergent AEs (regardless of causality) was low and similar between all of the Resotran™ groups (2.1%) and the placebo group (1.9%).

Serious adverse events (SAEs) reported by up to 3 Resotran™-treated patients (0.1%) during the double-blind controlled studies are listed below:

• Infections and infestations: bronchitis; pneumonia.
• Surgical and medical procedures: abdominoplasty; hysterectomy.
• Gastrointestinal disorders: abdominal pain; constipation.
• Nervous system disorders: headache.
• Cardiac disorders: supraventricular tachycardia.
• Reproductive system and breast disorders: vaginal hemorrhage.
• General disorders: chest pain.
• Psychiatric disorders: anxiety.

SAEs reported during the open-label follow-up studies (n = 2,595) in at least 3 cases (0.1%) to at most 0.3% are listed below:

• Surgical and medical procedures: hysterectomy; cholecystectomy; colectomy.
• Gastrointestinal disorders: abdominal pain; constipation; vomiting; nausea; diarrhoea; pancreatitis.
• Infections and infestations: gastroenteritis; pneumonia; sinusitis; urinary tract infection.
• Nervous system disorders: headache; syncope.
• Cardiac disorders: angina pectoris; MI; atrial fibrillation.
• Hepatobiliary disorders: cholelithiasis; cholecystitis.
• Pregnancy puerperium and perinatal conditions: pregnancy; abortion spontaneous.
• Reproductive system and breast disorders: ovarian cyst.
• Psychiatric disorders: confusional state; depression.
• General disorders and administration site conditions: chest pain.
• Respiratory, thoracic and mediastinal disorders: dyspnea.

SAEs reported in the Compassionate study: (in at least 2 cases) included colectomy.

Adverse Events of Special Interest

QT Prolongation and Atrial Rhythm-Related Events

Electrocardiograms were analysed in healthy volunteers to assess the potential for QT interval prolongation. A thorough double-blind QT study as well as two other QT studies in healthy volunteers demonstrated that the incidence of QT-related AEs and ventricular arrhythmias were low and comparable to placebo. There were however, small but consistent increases in heart rate and a shortening of the PR interval. These findings were also found in the clinical studies with chronic constipation patients. Overall, the clinical data showed that the administration of Resotran™ did not result in QT prolongation, but that it had positive chronotropic and dromotropic effects that were evident at the therapeutic 2 mg dose. Dose-dependency of these effects was not evident over the 2 mg to 10 mg dose range studied. The absence of dose-relation suggests that binding of the drug to the cardiac 5-HT₄ receptors is saturated at the therapeutic dose.

Drug-induced PR interval shortening raises concern that accelerated conduction over the atrioventricular (AV) node might promote re-entry arrhythmias, especially atrial fibrillation, in patients with pre-excitation syndromes or AV nodal rhythm disorders. Caution has been recommended for patients with conditions that might be worsened by an increase in heart rate, such as ischaemic heart disease or tachyarrhythmias. Caution should also be observed in patients with preexcitation syndromes such as Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome, or AV nodal rhythm disorders, such as AV junctional rhythms with retrograde activation or ectopic atrial rhythms originating near the AV node.

Palpitations

In the Phase II and III controlled clinical studies, a similar incidence of palpitations were elicited in the placebo group and Resotran™ 0.5 mg, 1 mg and 2 mg groups. Doses of 4 mg elicited a higher incidence of palpitations compared to placebo (1.9% versus 0.7%). Palpitations were not more frequent in patients below or above 65 years of age.

Ischaemic-related Events

The incidence of ischaemic-related events (stable angina, unstable angina, myocardial infarction) in Resotran™ (0.2%) and placebo (0.1%) treated patients was similar in the double-blind placebo-controlled studies. All these patients had a history of cardiac disease. Nevertheless, caution is recommended in patients with severe and clinically unstable concomitant disease (e.g., liver, cardiovascular, or lung disease; neurological or psychiatric disorders; cancer or acquired immune deficiency syndrome (AIDS); and other endocrine disorders). Caution should be exercised when prescribing Resotran™ to patients with these conditions. In particular Resotran™ should be used with caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.

Ischaemic Colitis

Ischaemic colitis is a potential and rare adverse event. No cases of ischaemic colitis have been reported with Resotran™ during the clinical studies. Nonetheless, patients should be advised to discontinue Resotran™ therapy and consult their physician if they develop severe, persistent, and/or worsening abdominal symptoms, bloody diarrhoea or rectal bleeding.

Psychiatric Disorders

Resotran™ may act on receptors in the brain having the following 5-hydroxytryptamine (5-HT) receptors: 5-HT₁; 5-HT₂; and 5-HT₃; that could be involved in anxiety and depression. It is unclear whether 5-HT₄ may be related to depression and anxiety. However, anxiety has been reported in many clinical studies and some cases were reported as serious events. The open-label studies recorded anxiety in 1.9% of the patients treated with the 2 mg dose, and similar results were found with 4 mg dose. In these studies, depression was elicited at a higher incidence than anxiety (3.5% versus 1.9%) with the 2 mg dose.

Events Possibly Related to Cancer

In the double-blind studies, a slightly higher incidence of neoplasms including cysts and polyps were reported in the 2 mg (0.6%) and 4 mg (0.4%) Resotran™ groups as compared to the placebo group (0.2%). The incidence of breast disorders, such as breast mass, was similar between the placebo and the Resotran™ groups. The incidence of breast cyst was found only in the 4 mg group.

The exposure-adjusted incidence of carcinogenic events in the long-term studies was similar to those in both the placebo and Resotran™ groups in the double-blind studies. The strong body of non-clinical evidence combined with the detailed review of the clinical database indicates that there may not be a carcinogenic risk in humans.

The adrenal, mammary, and thyroid glands were identified as target organs in the non-clinical studies.

In the open-label clinical studies, there were 2 cases of adrenal cancer (adrenal adenoma and adrenal neoplasm) in the 2 mg group that occurred after more than 50 days of treatment, and were considered unrelated to treatment by the investigator. Both patients underwent an adrenolectomy, recovered after surgery and continued treatment for several weeks after the intervention.

Four cases of breast cancer were reported: two cases occurred in the 2 mg group in the open-label studies; 1 case in the 4 mg group in the open-label studies; and 1 case in the 4 mg group in the double-blind studies. All cases were considered unrelated to treatment by the investigator. Patients were treated with chemotherapy and/or surgery, and continued the study for several weeks. There was 1 additional case of breast cancer in the placebo group.

One patient in the open-label studies who was on treatment with 4 mg Resotran™ had an event of thyroid adenoma and two patients had thyroid neoplasm after ≥285 days of treatment with Resotran™. The events were of mild or moderate intensity, and considered not or possibly related to treatment by the investigator.

Prolactin-related Events

The results from the Phase I studies indicated no difference in mean prolactin levels between placebo and Resotran™ treatment (up to steady state of 20 mg once daily). In addition, no correlation between prolactin levels and prucalopride plasma concentration was found. Prolactin plasma concentrations were assessed in a limited number of patients in one of the double-blind studies (n = 63). Mean prolactin values showed a decrease from baseline after 4 and 12 weeks of treatment in all treatment groups, including placebo. In the open-label studies, in a few patients exposed to Resotran™, no differences in mean prolactin plasma levels were found compared to baseline at Month 12 and Month 24. The number of prolactin samples were smaller than the total number of patients exposed to Resotran™ therefore there is no a complete picture of the prolactin plasma levels in patients treated with Resotran™.

In all of the Phase II and Phase III double-blind studies, the incidence rate of prolactin-related events in the 2 mg group was higher (0.9%) than in the placebo group (0.5%). Most common prolactin-related AEs were breast tenderness: 2 cases (0.2%) in the 2 mg group; 4 cases (0.3%) in the 4 mg group; and 1 case in the placebo group (0.1%). The incidence of breast pain was lower in patients treated with Resotran™ (0.1%) compared to patients treated with placebo (0.3%). The majority of these AEs (breast tenderness and breast pain) were mild to moderate in severity.

In the Phase II and Phase III open -label studies, 4 cases (0.4%) of breast pain were reported in the 2 mg group and 4 cases (0.3%) were reported in the 4 mg group, while breast tenderness was reported only in the 4 mg group, 2 cases (0.2%).

Pregnancy and Spontaneous Abortions

Although females of childbearing potential were expected to take adequate contraceptive protection during the studies, there were unintended pregnancies with consequences. During the open-label studies, there were 26 cases of unintended pregnancies, 4 cases of foetal death, and 8 cases of foetal malformation. The foetal malformations reported during the development program was said to be the result of misclassification by the investigators. The efficacy of oral contraceptives may be reduced with the use of Resotran™ and the use of an additional contraceptive method is recommended to prevent possible failures of oral contraception. Spontaneous abortions in females <35 years were higher in patients treated with Resotran™ compared to those treated with placebo.