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Drugs and Health Products

Summary Basis of Decision (SBD) for PrRESOTRANTM

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Contact: Bureau of Gastroenterology Infection and Viral Dieseases (BGIVD)

PrRESOTRANTM
Prucalopride succinate,  1 mg and 2 mg tablets
Janssen Inc.
Submission Control Number 141157
Date Issued 2012/05/16

Foreword

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. For information related to advisories, warnings and recalls as a result of adverse events (AE), interested parties are advised to access the Health Canada Website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada Web site for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

Table of Contents

1 Product And Submission Information

Brand Name:
PrRESOTRANTM
Manufacturer/Sponsor:
Janssen Inc.
Medicinal Ingredient:
Prucalopride (as prucalopride succinate)
International Non-proprietary Name:
Prucalopride
Strengths:
1 mg and 2 mg
Dosage form:
Tablet
Route of Administration:
Oral
Drug Identification Numbers (DINs):
Multiple DINs
02377012 - 1 mg
02377020 - 2 mg
Therapeutic Classification:
Enterokinetic agent
Non-medicinal Ingredients:
Both strengths have colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, macrogol 3000, titanium dioxide, and triacetin.

The 2 mg tablet also has FD&C blue #2 aluminum lake, iron oxide red, and iron oxide yellow.
Submission Type and Control Number
New Drug Submission, Control Number 141157
Date of Submission:
2010/12/17
Date of Authorization:
2011/12/07
All trademark rights used under license.

2 Notice Of Decision

On December 7, 2011, Health Canada issued a Notice of Compliance to Janssen Inc., for the drug product, Resotran™.

Resotran™ contains the medicinal ingredient prucalopride, as prucalopride succinate, which is an enterokinetic agent.

Resotran™ is indicated for the treatment of chronic idiopathic constipation in adult female patients in whom laxatives failed to provide adequate relief.

  • There were an insufficient number of male patients in the clinical trials to demonstrate efficacy.
  • The efficacy of prucalopride has been established in double-blind, placebo-controlled studies for up to 3 months. In case of prolonged treatment, the benefit should be re-assessed at regular intervals.
  • If treatment with prucalopride is not effective during the first 4 weeks, therapy should be discontinued.

Resotran™ increases the frequency of bowel movements to provide a feeling of complete evacuation by stimulating peristalsis, the muscular contractions of the gut needed for bowel movements.

The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Resotran™ was established in three multicentre, randomized, double-blind, 12-week placebo-controlled studies in patients with chronic idiopathic constipation. A total of 1,279 patients [1,124 females and 155 males (based on intent-to-treat population)] were administered Resotran™. The primary efficacy endpoint was the proportion (%) of patients that reached normalization of bowel movements defined as an average of three or more spontaneous, complete bowel movements (SCBM) per week over a 4-week and 12-week treatment period.

In each of the three studies, daily doses of 2 mg and 4 mg were studied. Both doses 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 (vs.) 10.5% (weeks 1-4) and 11.3% (Weeks 1-12) on placebo.

Resotran™ (1 mg and 2 mg prucalopride, as prucalopride succinate) is presented in film-coated tablets. The recommended dose for adults is 2 mg once daily. Due to the specific mode of action of Resotran™ (stimulation of propulsive motility), exceeding the daily dose of 2 mg is not expected to increase efficacy. Dosing guidelines are available in the Product Monograph.

Resotran™ is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Resotran™ is also contraindicated for patients with renal impairment requiring dialysis, as well as patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum. Resotran™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Resotran™ are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Resotran™ is favourable for the indication stated above.

3 Scientific And Regulatory Basis For Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Prucalopride, supplied as prucalopride succinate, is the medicinal ingredient of Resotran™. Prucalopride is an enterokinetic agent and is the first of a new class of dihydrobenzofurancarboxamide compounds with enterokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT4) receptor agonist, which is likely to explain its enterokinetic effects. In vivo and in vitro studies revealed that prucalopride enhances the peristaltic reflex and propulsive motor patterns in the gastrointestinal tract via 5-HT4 receptor activation.

Manufacturing Process and Process Controls

The drug substance is synthetically derived.

The manufacturing process is considered to be adequately controlled within justified limits.

Characterization

The structure of prucalopride succinate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are considered satisfactory.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies.] Control of the impurities and degradation products is therefore considered acceptable.

Control of Drug Substance

Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of prucalopride succinate.

The drug substance packaging is considered acceptable.

Stability

Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance when packaged as proposed is supported and is considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Resotran™ is available as film-coated tablets containing 1 mg or 2 mg of prucalopride (as prucalopride succinate). Both strengths of Resotran™ film-coated tablets are available in aluminium/aluminium perforated unit dose blisters containing 7 tablets. Each pack contains 28 film-coated tablets. The 1 mg tablet is white to off-white, round, and biconvex with the markings "PRU 1" on one side. The 2 mg tablet is pink, round, and biconvex with the markings "PRU 2" on one side.

Both strengths of Resotran™ contain the following inactive ingredients in the tablet core: lactose monohydrate; microcrystalline cellulose; colloidal silicon dioxide; and magnesium stearate.

The coating for the 1 mg tablet contains hypromellose, lactose monohydrate, triacetin, titanium dioxide, macrogol 3000. The coating for the 2 mg tablet contains hypromellose, lactose monohydrate, triacetin, titanium dioxide, macrogol 3000, iron oxide red, iron oxide yellow and FD&C blue Number 2 aluminum lake.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of prucalopride succinate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Manufacturing Process and Process Controls

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Resotran™ is tested to verify that its identity, appearance, content uniformity, assay, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.

Validation results of the analytical methods used for the determination of prucalopride succinate and the drug-related impurities are considered acceptable.

Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.

Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.

Stability

Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life for Resotran™ is considered acceptable, when the product is stored between 15-30°C and protected from moisture.

The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Resotran™ are considered suitable for the activities and products manufactured.

All sites are compliant with Good Manufacturing Practices.

3.1.4 Adventitious Agents Safety Evaluation

The excipient, lactose monohydrate, is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered safe for human use. No other excipients are of animal or human origin.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Resotran™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-clinical Basis for Decision

3.2.1 Pharmacodynamics

The primary and secondary pharmacodynamics of prucalopride have been adequately characterized.

Prucalopride is highly selective for the 5-HT4 receptor showing a receptor affinity (Ki) of 8.7 nM, with in vitro affinity for other receptors and ion channels at least 150 times lower, suggesting a low potential for off-target effects. However, an apparently weak interaction with rat dopamine D2 receptors (Ki = 5.9 µM) in the pituitary gland at high prucalopride serum and tissue concentrations was likely responsible for increased serum prolactin levels seen in rats. Prucalopride binding to human dopamine D2 receptors occurred at high levels (Ki = 14 µM). In human and porcine right atrial tissue, prucalopride behaved as a partial 5-HT4 receptor agonist with a half maximal effective concentration (EC50) of 40-100 nM (2-5 times the maximum human therapeutic plasma concentration).

In a range of in vitro studies on isolated gastrointestinal tissues from mouse, rat, guinea pig, dog, pig, and man, prucalopride facilitated the release of neurotransmitters. Depending on the location of the 5-HT4 receptor, these were acetylcholine from myenteric neurons (enhanced amplitude of contractions), calcitonin-gene-related-peptide (CGRP) and acetylcholine from intrinsic sensory neurons (stimulation of peristalsis), or nitric oxide from myenteric nerves (improved relaxation). The consequence of these actions was shown to be improved propulsion. In several in vivo gastrointestinal motility studies prucalopride was shown to stimulate gastrointestinal motility, with a pronounced effect on the large bowel.

Reduced colonic motility in dogs after repeated prucalopride doses indicative of tachyphylaxis was associated with systemic exposures in other studies in dogs that are close to those in patients at the therapeutic dose of 2 mg/kg.

Prucalopride appeared relatively specific with respect to its pharmacology, since it was devoid of effects on overt or conditioned behavior or effects suggesting interaction with other various receptor types (α1, α2, β2, D1, D2, H1, H2, muscarine, nicotine, 5-HT1A, 5-AH2A, µ-opioid, K-opioid, substance P, and glucocorticoid), neurotransmitter uptake (serotonin, norepinephrine, or dopamine); endogenous enzymes (monoamine oxidase, cyclooxygenase, methohexital metabolizing enzymes), pain perception and reflexes, numerous body functions, convulsions, and cardioprotection.

Prucalopride did not affect the delayed rectifying potassium (IKr) current in human Ether-à-go-go-Related Gene (hERG)-transfected HEK293 or COS-7 cells, at a concentration up to 1 μM (49 times the therapeutic plasma concentration). Prucalopride had no effects on action potential duration up to 1 μM in experiments using various isolated tissues, such as rabbit and dog Purkinje fibers, rabbit heart, and guinea pig papillary muscles.

3.2.2 Pharmacokinetics

Absorption

After single oral (gavage) doses, prucalopride was rapidly absorbed in all of the species tested with peak plasma concentrations generally attained within 0.3 to 1.5 hours. Absolute oral bioavailability of parent prucalopride was very low in rabbits (≤5%) due to extensive first-pass metabolism, low to intermediate in rats (depending on dose and gender, ≤8% in males given 0.63 mg/kg; 36% in males and 53% in females given 5 mg/kg) and high in dogs (77%). After repeated oral dosing in mice, rats, and dogs, the maximum plasma concentration (Cmax) and systemic drug exposure [area under the curve (AUC)] values increased dose-proportionally or more than dose-proportionally.

Distribution

The plasma protein binding of prucalopride was low in all species tested, ranging from 27% to 37%. The blood-to-plasma concentration ratio in mice, rats, rabbits, and dogs indicate a preferential distribution to the blood cells in the different species.

The highest tissue concentrations of prucalopride were in the gastrointestinal tract, liver, kidney, adrenal gland, and lungs (>10x plasma), while lowest levels were in the brain, white fat, and muscle (< plasma). The placental transfer of prucalopride and/or its metabolites to the foetus was limited in rats. Concentrations in foetuses were similar to those in maternal blood, and foetal tissue levels were clearly lower than levels in corresponding maternal tissues.

Metabolism

Prucalopride was extensively metabolized in the rat, with the main routes being hydroxylation to R106569 and ensuing partial dehydration to R104068 in both sexes, and O-demethylation to R112718 followed by oxidation to R129531 in males.

Prucalopride was somewhat less extensively metabolized in mice with the main pathway being hydroxylation to R106569 followed by dehydration to R104068 in both sexes.

The main metabolic pathway in rabbits was N-glucuronidation.

Prucalopride was not extensively metabolized in dogs, with O-demethylation and subsequent oxidation to the carboxylic acid (R107504) and hydroxylation to R106569 being the main routes. Prucalopride is least extensively metabolized in humans, with O-demethylation and oxidation resulting in the formation of R107504 to a lesser extent than in dogs.

Excretion

In the radiolabelled prucalopride studies conducted in rats, radioactivity was excreted into the faeces (63%) via the biliary route, or distributed to systemic circulation and excreted in the urine (36%). In mice, the excretion of radioactivity via the urine (37-57% of the dose) was somewhat more extensive than via the faeces, compared to rats. In rabbits and dogs, a larger proportion of radioactivity was excreted in the urine (53% and 72%, respectively) compared with the faeces (44% and 21%, respectively).

Drug Interactions

In vitro data indicate that prucalopride has a low drug interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the cytochrome P450 (CYP) mediated metabolism of co-administered medicinal products. Although prucalopride may be a weak substrate for P-glycoprotein (P-gp), it is not considered to be an inhibitor of P-gp at clinically relevant concentrations.

3.2.3 Toxicology

Single-Dose Toxicity

Prucalopride demonstrated a moderate degree of acute toxicity with mortality seen after oral doses of ≥320 mg/kg in mice and at 548 mg/kg in rats.

Repeat-Dose Toxicity

In the repeat-dose oral toxicity studies [1, 6, and 12 (dogs only) months], the doses of 5 and 10 mg/kg/day were the No-Observed-Adverse-Effect-Levels (NOAEL) in rats and dogs, respectively. The systemic drug exposure ratios at NOAEL versus humans (dosed at 2 mg daily) were 5 and 12 in male and female rats, respectively, and 244 in dogs.

In rats, slight toxicity was observed by increased liver and heart weights, that were without notable microscopic correlates with the exception of slight increases in focal infiltration of chronic inflammatory cells in the heart of males at 80 mg/kg, and prolactin-mediated changes considered due to prucalopride antagonism of the dopamine D2 receptors in the pituitary gland at ≥20 mg/kg. The latter consisted of mammary gland stimulation in females at ≥20 mg/kg and males at 80 mg/kg and in the female genital tract, indicative of decreased estrus cycle activity, at 40 and 80 mg/kg. Other anatomic pathology changes consisted of increased thymus weight at ≥20 mg/kg, and slight individual cell necrosis and phagocytosis in the thymus at 80 mg/kg in the 6-month study; increased kidney and pancreas weight at ≥40 mg/kg and increased adrenal weight at 80 mg/kg without microscopic correlates, and increased thyroid weight at ≥40 mg/kg in the 4-week study; and a slight increase in thyroid follicular epithelial height at 80 mg/kg in the 6-month study.

In dogs, toxicity was seen at 20 and 30 mg/kg [central nervous system (CNS) effects, histological changes in the liver and female genital tract, and lethality in 3/8 dogs at 30 mg/kg where the exposure margin was more than 500 times that at the 2 mg human dose].

Genotoxicity

Of principal concern in the non-clinical safety evaluation were some positive genetic toxicity findings and increased tumour incidences in rodents. While most of the genetic toxicity studies were negative [most Salmonella typhimurium and Escherichia coli strains, SOS-repair, L5178Y mouse lymphoma cell, human peripheral blood lymphocyte, mouse micronucleus, in vivo unscheduled deoxyribonucleic acid (DNA) synthesis, and transgenic Big Blue assays], prucalopride was positive in Salmonella typhimurium TA100 at high concentrations, in an in vitro unscheduled DNA synthesis study at high cytotoxic concentrations, and an investigative in vivo DNA adduct assay. The latter study was only positive for liver under non-standard assay conditions and the small amount of adducts formed were similar to normal nucleotides rather than prucalopride or its metabolites; however there is no explanation for why this occurred. DNA adducts were not detected in mammary gland of rats and mice or in the adrenal and thyroid of the rat. A subsequent in vivo Good Laboratory Practices (GLP) compliant study using the transgenic Big Blue rat model that evaluates mutagenicity as well as potential DNA adduct formation in the liver was negative, mitigating concerns regarding the positive findings in the initial study. It is concluded that, from an overall weight of evidence perspective, the mutagenic potential of prucalopride is low.

Carcinogenicity

The increased tumor incidences in the prucalopride carcinogenicity studies all occurred at an exposure margins of 60 or more relative to that in humans at the 2 mg therapeutic dose and the no-effect margins were close to or greater than 25-fold with the exception of the liver tumours in the mid dose male rats where the margin is only 6 times that at the 2 mg human dose. The neonatal mouse carcinogenicity study, a test that has been considered sensitive to a wide range of genotoxic chemicals believed to initiate the tumour response (particularly in liver) via the formation of covalently bound carcinogen-DNA adducts, was negative, suggesting that the liver tumor findings in rats were not related to adduct formation. Since there is a plausible epigenetic mechanism based on a CAR- (constitutive androstane receptor) mediated pleiotopic response by the rat liver that includes microsomal enzyme induction and increased liver weight that presumably does not occur in humans, the increased liver tumour finding in rats is not considered to represent a significant risk to humans.

With respect to the other tumour types, the increased incidence of thyroid tumours in male rats at 80 mg/kg and female rats at 40 mg/kg was likely a consequence of hepatic microsomal enzyme induction resulting in increased metabolism and excretion of thyroxine and stimulation of the thyroid gland. The increased incidences of mammary gland adenocarcinoma in female mice (80 mg/kg) and male and female rats (80 and 40 mg/kg, respectively) and pituitary adenomas in male rats (80 mg/kg) were likely related to increased prolactin stimulation, which is considered relatively rodent specific and occurred at exposures about 200 times that of humans at the 2 mg therapeutic dose in mice and 400-600 times higher in rats. The increased incidences of pheochromocytomas and pancreatic islet cell adenoma in male rats given 80 mg/kg were reported as possibly prolactin-related. The pheochromocytomas may also be due to stimulation by higher serum calcium levels resulting from increased chronic age-related nephropathy. The high exposure margin of more than 500 times that at the 2 mg human dose indicates that these tumours are not likely a significant concern for patient safety.

Mechanistic studies indicated that the increased tumour incidences may be due to rodent specific epigenetic mechanisms and/or occurred at >60-times human exposure at the 2 mg human dose.

According to current ICH Guidance, positive tumorigenicity findings in rodents at doses above those producing a 25-fold exposure over that in humans would not generally be considered likely to reflect a relevant risk to humans. The increased tumour incidences in the carcinogenicity studies all occurred at exposure (AUC) margins >60 times that in humans at the 2 mg therapeutic dose and the no-effect margins were close to or greater than 25-fold with the exception of the liver tumours in the mid-dose male rats where the margin was only 6 times that at the 2 mg human dose. However since there is a plausible epigenetic mechanism based on microsomal enzyme induction that presumably does not occur in humans, the increased liver tumour finding is not considered to represent a significant risk to patients.

Reproductive and Developmental Toxicity

No major reproductive or developmental toxicity was identified. Prucalopride did not affect fertility in rats and was not teratogenic in rats and rabbits. It is concluded that prucalopride does not have any major reproductive liabilities with maternal and foetal toxicity occurring at exposure margins ≥38 times that of humans at the 2 mg therapeutic dose.

3.2.4 Summary and Conclusion

The non-clinical studies for this drug submission are considered suitable. The pharmacological studies have provided adequate evidence to expect that Resotran™ can be beneficial in the treatment of chronic idiopathic constipation. The toxicology database was considered adequate to assess the safety profile of Resotran™. Overall, based on the non-clinical studies, there were no major safety concerns that would predict unexpected adverse effects in patients treated with Resotran™ at the recommended therapeutic dose. Overall, the non-clinical pharmacology and toxicology studies support the use of Resotran™ for the proposed indication.

3.3 Clinical Basis for Decision

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; Cmax 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 AUC0-∞ 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)]. AUC0-∞ 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 group. 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.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Chronic idiopathic constipation is a condition that affects a large number of people independent of age or sex. Overall, constipation affects up to 28% of individuals in the Western World, with a two-fold higher prevalence in women than in men. In addition to the symptoms associated with this condition, health-related quality of life is negatively impacted in people with chronic constipation. Constipation may result in serious consequences if not properly managed, such as faecal impaction, intestinal obstruction or perforation. In addition chronic constipation may lead to complications such as megacolon, volvulus, anal fissure, diverticular disease, and rectal prolapse. Currently in Canada, no treatment is available for patients with chronic idiopathic constipation. These patients rely on laxatives, diet, and bulk-forming agents, but the therapeutic effect is sometimes unsatisfactory or inadequate.

The data in this submission provided evidence in support of Resotran™ for the treatment of symptoms of chronic idiopathic constipation. Efficacy was demonstrated in the primary efficacy variable (proportion of patients with ≥3 SCBM/week) and the principal secondary efficacy variable (proportion of patients with ≥1 SCBM/week) in females older than 18 years of age. In addition, Resotran™ reduced the time to first SCBM/SBM and improved the quality of life. Thus the strength of the findings is acceptable. Data in this submission however, was not sufficient to demonstrate efficacy in male patients.

Previous experience with other 5-HT4 receptor agonists, tegaserod and cisapride, raised concern for potential cardiac, and GI adverse events. However, tegaserod and cisapride are not selective for 5-HT4 receptors. Unlike Resotran™ (prucalopride), tegaserod shows a relatively high affinity to 5-HT1 receptors as compared to 5-HT4 receptors, and that could explain the cardiovascular ischemic events. This is not the case for prucalopride which is highly selective for 5-HT4 receptors with an in vitro affinity for other receptors at least 150 times lower. In well-designed clinical studies, prucalopride was shown not to affect the QT interval, unlike cisapride that does have QT interval prolongation effects.

Due to the fact that Resotran™ is a 5-HT4 receptor agonist and that there are many receptor types for serotonin widely distributed in the GI tract, CNS, urinary bladder, heart (atrial) and adrenal gland, Resotran™ may elicit tissue specific AEs such as diarrhoea, palpitations, ischaemic cardiac events, atrial rhythm related events, ischaemic colitis, anxiety/depression, urinary incontinence, unintended pregnancies, and spontaneous abortions under certain conditions. Many of these adverse events can be managed by proper labeling. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Resotran™ Product Monograph. A Risk Management Plan (RMP) was submitted by the sponsor and the Marketed Health Products Directorate (MHPD) reviewed the RMP and proposed post-market actions. Overall, the benefit/risk assessment is favourable for the use of Resotran™ for the approved indication.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Resotran™ is favourable in the treatment of chronic idiopathic constipation in adult female patients in whom laxatives failed to provide adequate relief. The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: Resotran
Submission Milestone Date
Pre-submission meeting: 2010/08/25
Submission filed: 2010/12/17
Screening
Screening Acceptance Letter issued: 2011/02/10
Review 1
Biopharmaceutics Evaluation complete: 2011/09/27
Quality Evaluation complete: 2011/11/17
Clinical Evaluation complete: 2011/12/01
Labelling Review complete: 2011/12/01
Notice of Compliance issued by Director General: 2011/12/07