CMDh/305/2013 March 2018, Rev.02
Summary Public Assessment Report
Generics
Prucalopride Dexcel 1 mg film-coated tablets Prucalopride Dexcel 2 mg film-coated tablets
[Prucalopride (as Succinate)]
MT/H/0334/001-002/DC
Date: 20th January 2020
Summary Public Assessment Report
Generics
Prucalopride Dexcel 1 mg film-coated tablets Prucalopride Dexcel 2 mg film-coated tablets
Prucalopride 1 mg, 2mg film-coated tablets
This is a summary of the public assessment report (PAR) for Prucalopride Dexcel 1 mg, 2mg film-coated tablets. It explains how Prucalopride Dexcel 1 mg, 2mg film-coated tablets was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Prucalopride Dexcel 1 mg, 2mg film-coated tablets.
For practical information about using Prucalopride Dexcel 1 mg, 2mg film-coated tablets, patients should read the package leaflet or contact their doctor or pharmacist.
What is Prucalopride Dexcel 1 mg, 2mg film-coated tablets and what is it used for?
Prucalopride Dexcel 1 mg, 2mg film-coated tablets is a ‘generic medicine’. This means that Prucalopride Dexcel 1 mg, 2mg film-coated tablets is similar to a ‘reference medicine’ already authorised in the European Union (EU) called Resolor 1mg, 2mg film coated tablets.
Prucalopride is used for the treatment of chronic constipation in adults in whom laxatives do not work well enough.
Not for use in children and adolescents younger than 18 years.
How does Prucalopride Dexcel 1 mg, 2mg film-coated tablets work? Prucalopride Dexcel belongs to a group of gut motility enhancing medicines (gastrointestinal prokinetics). It acts on the muscle wall of the gut, helping to restore the normal functioning of the bowel.
How is Prucalopride Dexcel 1 mg, 2mg film-coated tablets used? The pharmaceutical form of Prucalopride Dexcel 1 mg, 2mg film-coated tablets is film-coated tablets and the route of administration is oral.
Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment.
The usual dose of Prucalopride Dexcel for most patients is one 2 mg tablet once a day. If you are older than 65 years or have severe liver disease, the starting dose is one 1 mg tablet once a day, which your doctor may increase to 2 mg once a day if needed. Your doctor may also recommend a lower dose of one 1 mg tablet daily if you have severe kidney disease. Prucalopride Dexcel is only for adults and should not be taken by children and dolescents up to 18 years. The medicine can only be obtained with a prescription.
The medicine can be obtained without a prescription. PAR Scientific discussion 2/21
What benefits of Prucalopride Dexcel 1 mg, 2mg film-coated tablets have been shown in studies? Because Prucalopride Dexcel 1 mg, 2mg film-coated tablets is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Resolor 1mg, 2mg film coated tablets. Two medicines are bioequivalent when they produce the same levels of the active substance in the body.
What are the possible side effects of Prucalopride Dexcel 1 mg, 2mg film-coated tablets?
Because Prucalopride Dexcel 1 mg, 2mg film-coated tablets is a generic medicine and is bioequivalent to the reference medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet.
Why is Prucalopride Dexcel 1 mg, 2mg film-coated tablets approved?
It was concluded that, in accordance with EU requirements, Prucalopride Dexcel 1 mg, 2mg film-coated tablets has been shown to have comparable quality and to be bioequivalent/be comparable to Resolor 1mg, 2mg film coated tablets. Therefore, the Malta Medicines Authority decided that, as for Resolor 1mg, 2mg film coated tablets, the benefits are greater than its risk and recommended that it can be approved for use.
What measures are being taken to ensure the safe and effective use of Prucalopride Dexcel 1 mg, 2mg film-coated tablets?
A risk management plan has been developed to ensure that Prucalopride Dexcel 1 mg, 2mg film-coated tablets is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Prucalopride Dexcel 1 mg, 2mg film-coated tablets, including the appropriate precautions to be followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well.
Other information about Prucalopride Dexcel 1 mg, 2mg film-coated tablets
The marketing authorisation for Prucalopride Dexcel 1 mg, 2mg film-coated tablets was granted on 07th January 2020.
The full PAR for Prucalopride Dexcel 1 mg, 2mg film-coated tablets can be found on the website https://www.hma.eu/mriproductindex.html. For more information about treatment with Prucalopride Dexcel 1 mg, 2mg film-coated tablets, read the package leaflet or contact your doctor or pharmacist.
This summary was last updated in 01-2020.
PAR Scientific discussion 3/21
CMDh/223/2005 February 2014
Public Assessment Report
Scientific discussion
Prucalopride Dexcel 1 mg film-coated tablets Prucalopride Dexcel 2 mg film-coated tablets
[Prucalopride (as Succinate)]
MT/H/0334/001-002/DC
Date: 20th January 2020
This module reflects the scientific discussion for the approval of Prucalopride Dexcel 1 mg, 2 mg film-coated tablets. The procedure was finalised at 23rd December 2019. For information on changes after this date please refer to the module ‘Update’.
PAR Scientific discussion 4/21
I. INTRODUCTION
“Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Prucalopride Dexcel 1 mg, 2 mg film-coated tablets, from Dexcel Pharma. The product is indicated for: Prucalopride Dexcel is indicated for symptomatic treatment of chronic constipation in adults in whom laxatives fail to provide adequate relief.. A comprehensive description of the indications and posology is given in the SmPC.”
“The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.”
II. QUALITY ASPECTS
II.1 Introduction 1mg: Film-coated tablet.
White to off-white, round biconvex, film-coated tablets embossed with “P1” on one side.
Excipients: Tablet core Lactose monohydrate Microcrystalline cellulose Silica colloidal anhydrous Magnesium stearate
Tablet coating Hypromellose Titanium dioxide (E171) Lactose monohydrate Macrogol 4000 Triacetin
Container system Aluminium/Aluminium blisters in cartons containing 14, 28 or 84 film-coated tablets.
2mg: Film-coated tablet.
Pink, round biconvex, film-coated tablets embossed with “P2” on one side.
Excipients: Tablet core Lactose monohydrate Microcrystalline cellulose Silica colloidal anhydrous Magnesium stearate
PAR Scientific discussion 5/21
Tablet coating Hypromellose Titanium dioxide (E171) Lactose monohydrate Macrogol 4000 Triacetin Iron oxide red (E172) Indigo carmine aluminium lake (E132) Iron oxide yellow (E172)
Container system Aluminium/Aluminium blisters in cartons containing 14, 28 or 84 film-coated tablets.
II.2 Drug Substance
The active substance, Prucalopride succinate is not described in the Ph. Eur. An ASMF is being submitted in support of the application. One source has been proposed for the manufacture of the drug substance.
The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed provisional retest period of 30 months (at no special storage conditions) is acceptable based upon the submitted stability data to-date.
II.3 Medicinal Product
The development of the product has been described, the choice of excipients is justified, and their functions explained. The pharmaceutical development has in general been adequately described. A BE study has been conducted on the 2mg strength and a BCS based biowaiver is being claimed for the 1mg strength. In-vitro data supports the BE study and the requested BCS biowaiver. The manufacturing process is considered as non-standard due to the low content of the active ingredient and has been described with sufficient details. Adequate process validation data has been provided.
The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three batches for each strength at the currently proposed commercial batch size. The batch analysis results show that the finished products meet the specifications proposed.
The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. No significant changes in any parameters were observed. The currently proposed shelf-life of 24 months with no special storage conditions for the drug product can be accepted based upon the submitted stability data to-date.
III. NON-CLINICAL ASPECTS
The applicant has shown data to support the procedure submission marketing authorisation of Prucalopride 1 and 2 mg film coated tablets in accordance with Article 10(1) of Directive 2001/83/EC. The applicant’s Prucalopride 1 and 2 mg film coated tablets for oral use are the generic version of RESOLOR® (prucalopride succinate) film-coated tablet, 1 and 2 mg, Sanico NV, Belgium. In this submission, the applicant seeks approval of Prucalopride 1 and 2 mg film coated tablets for the treatment of chronic idiopathic constipation in adults in whom laxatives failed to provide adequate relief.
PAR Scientific discussion 6/21
Since prucalopride has been marketed for more than 10 years within the European Community, comprehensive information exists on its biochemistry, pharmacology, toxicity (safety) and clinical use. The purpose of this nonclinical overview is to evaluate possible toxicological properties of the medicinal product under question through published scientific literature. The overview has addressed recently published literature up to September 2018.
In July 2009, prucalopride was approved by the European Medicines Agency (EMA) for the symptomatic treatment of chronic constipation for women in whom laxatives fail to provide satisfactory relief.
Prucalopride acts as high-affinity 5-HT4 receptor agonist that exerts an enterokinetic effect by binding with 5-HT4 receptors on enteric neurons and facilitates cholinergic and non-adrenergic, non- cholinergic neurotransmission. The mode of action of prucalopride is well described and recognized among the literature.
Several nonclinical studies, both in vivo and in vitro, have been performed to demonstrate the abilities of prucalopride. In vitro studies revealed that prucalopride is structurally different from earlier serotonergic prokinetic agents, a feature that conferred not only a high degree of affinity for 5-HT4 receptor, but also precluded interactions with other receptors such as 5-HT3, 5-HT1B/D, motilin and CCK receptors or hERG K+ channels at therapeutic doses. It is devoid of anticholinergic or anticholinesterase activity.
Pharmacokinetic parameters have been clearly described and demonstrated as followed: the time to reach the Tmax is 1.0 h, and the Cmax is 21.71±4.28 ng/mL, the t1/2 is 18.21±0.69 h, and the AUC is 59.30±9.43 ngh/mL. Tissue distribution shows the highest level in stomach and intestine, then in liver, which indicated that prucalopride is absorbed firstly in stomach and intestine, and mainly accumulated in liver. With the extent of the time, the concentrations of total prucalopride in most of the tissues decreases, indicating that there is no long-term accumulation of prucalopride.
Prucalopride has a low potential for drug-drug interactions due to lack of significant metabolism by the cytochrome P450 system at therapeutic concentrations and due to lack of extensive binding to plasma protein.
The oral toxicological profile of prucalopride has been investigated in a full set of studies, i.e., single- dose studies in mice and rats, repeat-dose studies in rats and dogs, fertility and pre- and postnatal developmental studies in rats, embryo-fetal developmental studies in rats and rabbits, in vitro and in vivo mutagenicity studies, carcinogenicity studies in rats, mice and neonatal mice, juvenile toxicity studies in rats and dogs, and local tolerance studies.
Overall, the toxicity studies provide little evidence of potential adverse effects associated with prucalopride. Prucalopride has demonstrated a wide safety margin, with physiologically significant effects on electrophysiological and cardiovascular parameters observed only at supra-therapeutic concentrations that were considered clinically irrelevant, however the potential for prucalopride to cause mild CNS related symptoms need further examination in clinical studies. The likelihood of other adverse effects related to the pharmacological activity of prucalopride is low. The carcinogenic potential of prucalopride has been adequately studied and the mechanism of formation of the observed tumors appropriately investigated. A threshold for tumor formation has been demonstrated, with an adequate margin between the threshold exposure level and the clinical exposure level. Animal studies do not indicate direct or indirect harmful effects of prucalopride with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
On the basis of the nonclinical data, the potential benefits of prucalopride outweigh the risks.
Pharmacology Primary pharmacodynamics
PAR Scientific discussion 7/21
Prucalopride, 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7- benzofurancarboxamide butanedioate (1:1), belongs to the group of prokinetic drugs.
Prucalopride is a dihydrobenzofurancarboxamide derivative. It acts as high-affinity 5-HT4 receptor agonist that exerts an enterokinetic effect by binding with 5-HT4 receptors on enteric neurons and facilitates cholinergic and non-adrenergic, non-cholinergic neurotransmission. It is one of the most advanced 5-HT4 receptor agonists in clinical development.
Several preclinical studies showed that prucalopride stimulates colonic motility as well as the contraction of intestinal muscle and high-amplitude propagated colon.
In vitro studies In vitro studies on isolated strips have shown that prucalopride has no effect on serotonin (5-hydroxy- tryptamine; 5-HT) 5-HT2A, 5-HT2B and 5-HT3 receptors and muscarinic cholinoceptors, and does not inhibit cholinesterases. Prucalopride is structurally different from earlier serotonergic prokinetic agents, a feature that conferred not only a high degree of affinity for 5-HT4 receptor, but also precluded interactions with other receptors such as 5-HT3, 5-HT1B/D, motilin and cholecystokinin (CCK) receptors or hERG K+ channels at therapeutic doses. According to published data it is devoid of anticholinergic or anticholinesterase activity.
A study carried out in large intestines from male Sprague Dawley rats (3-6 months) concluded that prucalopride (1 μM) increased the frequency of propagating contractions (by 75 ± 26%) in the majority of preparations studied (10/12), concurrently decreasing the frequency of non-propagating contractions (by 50 ± 11%). The prokinetic action of prucalopride increased the frequency of synchronous contractions along the length of colon, likely explaining increased colonic rate of transit in vivo.
In a range of in vitro gastrointestinal studies on isolated tissue taken from the esophagus, stomach, small intestine and large intestine (up to the distal colon) 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). Prucalopride could also act on 5-HT4 receptors located directly on the smooth muscle cells to relax the smooth muscle layer (reduction of resistance to aboral propulsion). The consequence of these actions was improved propulsion as demonstrated in in vitro experiments on fecal pellet expulsion from the guinea pig colon.
EC50 values obtained in these gastrointestinal tests were low, in the nanomolar range in all species including man (16 to 32 nM human gastric and colon tissue). These in vitro effects induced by prucalopride were blocked by a selective 5-HT4 receptor antagonist, confirming that the effects of prucalopride are likely mediated via 5-HT4 receptors.
Four metabolites of prucalopride found in rat, dog and human were tested to establish and compare their 5-HT4 receptor agonistic properties in vitro. All four metabolites behaved as 5-HT4 receptor agonists with a similar efficacy as prucalopride, but with different potencies. The 3- hydroxy product was virtually equipotent to prucalopride and the two carboxylic acids were both less potent than prucalopride, while the trans-N-oxide was the least potent 5-HT4 receptor agonist. Other metabolites were also tested for their affinity for the human 5-HT4 receptor. They all had affinity for the receptor with Ki values ranging from 21 to 218 nM, being somewhat above the Ki value of prucalopride in the same test system (8.7 nM). In humans, these metabolites with an affinity lower than prucalopride, are formed only to a very limited extent (<4%) and, therefore, their contribution to the clinical effect of prucalopride is expected to be limited .
In vivo studies Prucalopride’s in vivo effects in the canine colon suggest a coordinated, region-specific mechanism, whereby longitudinal smooth muscles demonstrate increased contractile activity in the proximal colon, PAR Scientific discussion 8/21 but reduced contractility in the distal colon. In addition, circular smooth muscle relaxation is negligible in the proximal colon, but increasingly more pronounced towards the distal colon with prucalopride treatment. In conscious, fasted dogs, prucalopride also induces colonic giant migrating contractions (GMC) that propagate along the entire length of the colon to facilitate propulsion of luminal contents. GMC are the canine equivalent to human high amplitude propagated contractions (HAPC). A reduction of HAPC is observed in patients with idiopathic constipation.
In a study carried out with the aim of investigating the effects of different 5-HT4 receptor agonists, which stimulate excitatory pathways, on a postoperative ileus (POI) model was demonstrated that the newer 5-HT4 receptor agonist, prucalopride, has clear-cut beneficial effects in the postoperative ileus guinea pig model. Prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig.
Prucalopride, given intravenously at a dosage of 1 to 2 mg/kg in fasted rats, increased whole gut transit of activated charcoal, mainly by increasing colonic transit, and without affecting gastric or proximal small bowel transit. On the other hand, in dogs, prucalopride dose-dependently promotes gastric contractility and accelerates gastric emptying.
In a preliminary study on the effects of prucalopride on intestinal motor activity of horses with gut hypomotility was carried out by Laus et al. Results showed that 30 to 90 minutes after oral administration of prucalopride 2 mg/100 kg body weight, horses with postprandial intestinal hypomotility displayed an increased gut motor activity, maximal in the duodenum, with only a minimal increase in the cecum and the left colon. Therefore, results indicated that prucalopride could be used as supplement of specific therapy in horses affected by severe gastroduodenal ulceration causing intestinal hypomotility.
Secondary pharmacodynamics Bianco in a study designed to test whether prucalopride exerted protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge showed that prucalopride promoted a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. These data paved the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect.
Prucalopride has been reported to regulate neurodevelopment. A study aimed to investigate the influence of the prucalopride on glioma cells and unveil underlying mechanism was carried out. As a result, the proliferation, migration and invasiveness of glioma cells were impaired by prucalopride treatment, the apoptosis rate of glioma cells was enhanced by prucalopride stimulation, accompanied by the increased pro-apoptosis proteins Bax and Cleaved caspase-3 and decreased anti-apoptosis protein Bcl-2. Prucalopride significantly promoted autophagy by increased expression level of Beclin 1 and LC3-II, while decreased expression level of p62. Prucalopride administration resulted in obvious inhibitions of key molecules of AKT-mTOR pathway, including phosphorylated- (p-) AKT, p-mTOR and phosphorylated-ribosomal p70S6 kinase. These results indicated that prucalopride may be likely to play an anti-tumor role in glioma cells, which suggests potential implications for glioma promising therapy alternation in the further clinics.
Because strong evidence supports beneficial effects of 5-hydroxytryptamine 5-HT4 receptor agonists in memory and learning, one study to investigate the role of 5-HT4 receptors on amyloid precursor protein (APP) processing in 8 weeks-old male C57BL/6j mice was carried out. Results demonstrated that the 5-HT4 receptor plays a key role in the non-amyloidogenic pathway of APP metabolism in vivo and gave support to the beneficial use of 5-HT4 agonists for Alzheimer's disease treatment.
Safety aspects Prucalopride has demonstrated a wide safety margin, with physiologically significant effects on electrophysiological and cardiovascular parameters observed only at supra-therapeutic concentrations that were considered clinically irrelevant. No relevant effects on cardiovascular and cardiac electrophysiological parameters were observed at prucalopride concentrations of at least 50 times the human therapeutic maximum plasma concentration (Cmax). A study carried out to evaluate the PAR Scientific discussion 9/21 nonclinical cardiovascular profile of the selective 5-HT4 receptor agonist prucalopride. In order to assess its non-5-HT4 receptor-mediated effects on cardiovascular electrophysiological parameters, in vitro studies were performed in human ether-à-go-go-related gene transfected cells, guinea pig ventricular myocytes and papillary muscle preparations, rabbit and dog Purkinje fibers, and the Langendorff rabbit heart. In vivo experiments were performed in a rabbit model for drug-induced pro- arrhythmogenesis, in anesthetized guinea pigs, and anesthetized and conscious dogs. In addition, human platelet aggregation and coronary artery contraction were studied to exclude interactions that have been suggested to mediate the cardiovascular effects of tegaserod. Effects at 5-HT4 receptors were evaluated in piglet and human atrial myocardium, and in anesthetized pigs. Finally, cardiovascular endpoints were investigated in chronic, repeated-dose toxicology studies at very high prucalopride doses in rats and dogs. No relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the therapeutic plasma level. Only in pigs were minor and transient increases in heart rate and blood pressure noted upon first exposure to prucalopride, at plasma levels at least 10 times higher than human therapeutic plasma levels. Prucalopride may thus provide therapeutic benefit without the cardiovascular risks reported for other 5-HT4 receptor agonists such as cisapride and tegaserod.
Pharmacokinetics
A sensitive, reliable and high throughput ultra-high-performance liquid chromatography with tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for the determination of prucalopride in rat plasma and various tissues (including heart, liver, spleen, lung, kidney, stomach, small intestine, large intestine, cecum, cerebrum, cerebellum, and ovary).
The validated analytical method was successfully applied to investigate the pharmacokinetics of prucalopride after oral administration at a dose of 0.5 mg/kg. A plot of plasma concentration versus time for prucalopride in rats is presented in Figure 1. The corresponding pharmacokinetic parameters calculated using non-compartmental analysis are listed as mean±SD and shown in Table 1.
Figure 1. Mean plasma concentration-time profiles of prucalopride following oral administration of prucalopride (0.5 mg/kg) to rats.
PAR Scientific discussion 10/21
As seen in the above mentioned figure an table the plasma concentrations of prucalopride increased rapidly after oral administration and all reached the Cmax at 1.0 h, which demonstrated that the compound was rapidly absorbed in rat plasma. And then the concentrations descended with the elimination half-life (t1/2) values of 17.55–18.93 h, indicating prucalopride could be cleared slowly from the rat plasma. area under the curve (AUC)0-t and AUC0-∞ were 55.59 and 59.30 ngh/mL, respectively. These values showed that the prucalopride shared low plasma concentrations. Previous pharmacokinetic studies in rats showed a similar phenomenon. The apparent volume of distribution (Vd) for prucalopride was more than 100 L/kg, which can be implied that drug concentration in tissues was higher than plasma; it might because that prucalopride had strong liposolubility and bond tightly with tissues .
The tissue distribution of prucalopride was investigated in Sprague-Dawley rats at 0.25, 1, 2, 4 and 8 h after oral administration 0.5 mg/kg by collecting tissues including the heart, liver, spleen, lung, kidney, stomach, small intestine, large intestine, cecum, cerebrum, cerebellum, and ovary. The concentration- time profile of prucalopride in various tissues is shown in Figure 2. The results of the present study indicated that prucalopride underwent a rapid and wide distribution into tissues. With the extent of the time, the concentrations of total prucalopride in most of the tissues decreased obviously in 8 h, indicating that there was no long-term accumulation of prucalopride [Zuo, 2016].
Figure 2: The concentration–time profile of prucalopride in various tissue homogenates after an oral administration of prucalopride (0.5 mg/kg) to rats.
PAR Scientific discussion 11/21
Within 15 min of oral administration, the highest tissue concentration of prucalopride was detected in stomach (970.87 ng/g), followed by small intestine (219.54 ng/g), the liver (166.31 ng/g), cecum (150.64 ng/g) and large intestine (141.65 ng/g). From the results, it was found that the maximum concentration of the analyte was observed in stomach which may be mainly attributed to the oral mode of administration. The concentration of total prucalopride in liver was significantly higher than that in other tissues, demonstrating that prucalopride was mainly accumulated in liver suggesting a potential role of this organ in the metabolism of prucalopride. Cecum and large intestine was the target organ of prucalopride, and the result implies the drug arrived at the target organs rapidly to produce therapeutic effect. The total prucalopride exhibited a litter lower concentration in the heart, spleen, lung and ovary, which indicates that blood flow and perfusion rate of the organ did not play a key role in the distribution of prucalopride. The lower level of concentration of prucalopride in the heart and lung can reduce the toxicity. In addition, prucalopride could be detected in cerebrum and cerebellum, which illustrated that it could transfer across the blood-brain barrier.
The pharmacokinetic parameters were demonstrated as followed: the time to reach the Tmax was 1.0 h, and the Cmax was 21.71±4.28 ng/mL, the t1/2 was 18.21±0.69 h, and the AUC was 59.30±9.43 ng*h/mL. Tissue distribution showed the highest level was observed in stomach and intestine, then in liver, which indicated that prucalopride was absorbed firstly in stomach and intestine, and mainly accumulated in liver. This was the first study to investigate the tissue distribution of prucalopride in rats following oral administration.
Pharmaockinetic drug interactions No pharmacokinetic drug interactions of prucalopride in animals have been found in the literature. Therefore, information regarding pharmacokinetic drug interactions has been referenced to humans. Prucalopride has a low potential for drug-drug interactions. It is not expected to alter the pharmacokinetics of drugs metabolized by the cytochrome P450 system, nor are these drugs expected PAR Scientific discussion 12/21 to affect the disposition of prucalopride. Although prucalopride may be a weak substrate for P- glycoprotein (P-gp), it is not an inhibitor of P-gp at clinically relevant concentrations. No effect on the plasma concentrations of prucalopride was observed with erythromycin, paroxetine, cimetidine and probenecid. Ketoconazole, at a high dose of 200 mg twice daily, increased the area under the curve of prucalopride by approximately 40% which is likely attributable to inhibition of P-gp mediated renal transport. Prucalopride may also be secreted via other renal transporters and inhibition of all transporters involved in the active secretion of prucalopride may theoretically increase its exposure by up to 75%.
Because of the mechanism of action, the use of atropine-like substances may reduce the 5-HT4 receptor mediated effects of prucalopride.
Toxicology
The oral toxicological profile of prucalopride has been investigated in a full set of studies, i.e., single- dose studies in mice and rats, repeat-dose studies in rats and dogs, fertility and pre- and postnatal developmental studies in rats, embryofetal developmental studies in rats and rabbits, in vitro and in vivo mutagenicity studies, carcinogenicity studies in rats, mice and neonatal mice, juvenile toxicity studies in rats and dogs, and local tolerance studies.
Single dose toxicity Single oral gavage administration of prucalopride did not lead to mortality up to 320 mg/kg in male mice and up to 160 mg/kg in female mice. In rats, the highest oral dose tested of 640 mg/kg did not cause mortality in males, while in females mortality occurred at 548 mg/kg, but not at 320 mg/kg. A single intravenous dose of 40 mg/kg in rats and of 80 mg/kg in mice was devoid of lethal effects
Repeat dose toxicity Repeat dose toxicity with prucalopride was examined in mice (up to 3 months), rats (up to 6 months) and dogs (up to 12 months). Studies were conducted with both the hydrochloride salt and the succinate salt of prucalopride
In mice after oral administration, there were mild liver changes at 80 and 160 mg/kg. There was also hypertrophy in the pituitary, increased development in the mammary gland and reduced cyclic activity in the genital tract which is likely to be related to increased prolactin levels.
In rats after oral administration, there were changes in bodyweight, hematology parameters, clinical chemistry parameters and organ weights noted at the higher dose levels which were mostly resolved after the recovery period. The persistent changes were those likely to be related to prolactin induction; an increase in granulocyte infiltration of the prostate, an increase in interstitial tissue in the ovaries and glandular development in the mammary glands. The no-observed-adverse-effect levels (NOAEL) in the 6 months (plus recovery) study was 20 mg/kg/day (76 and 142 times the clinical exposure based on AUC, in males and females, respectively). There were no differences observed between the hydrochloride and succinate salts of prucalopride. After IV administration for one month, no toxicity was observed up to 10 mg/kg/day (138 and 382 times the clinical exposure based on AUC in males and females, respectively). Similar toxicity was observed after SC administration for one month, with a NOAEL of 5 mg/kg/day (20 times the clinical exposure based on AUC).
In dogs after oral administration, there was no evidence of toxicity after one month at 20 mg/kg/day but clinical signs of CNS related toxicity were evident at 30 mg/kg/day and 40 mg/kg/day. After 6 months, 3 males given 30 mg/kg/day died. The deaths were preceded by CNS-related toxicity. Other toxicity included ocular changes, organ weight changes and some evidence of reduced cyclic activity related to prolactin levels. There were no changes in blood pressure or clear evidence of electrocardiogram (ECG) changes. The NOAEL was 10 mg/kg/day (251 times the clinical exposure based on AUC). After IV administration, no toxicity was observed at doses up to 5 mg/kg/day for one month (99 times the clinical exposure based on AUC). No toxicity was observed after SC administration at doses up to 10 mg/kg/day for one month (229 times the clinical exposure based on AUC). PAR Scientific discussion 13/21
This data was confirmed by Conlon et al. in a repeat-dose toxicity study. After 6 and 12 months’ oral administration of prucalopride in rats and dogs, the NOAEL were 5 and 10 mg/kg per day, respectively. The corresponding exposure was at least five times higher in rats and 244 times higher in dogs, than that observed in humans who received a daily dose of 2 mg. The highest doses of prucalopride tested were 80 and 30 mg/kg per day in rats and dogs, respectively. In male rats, increases in heart weight (up to 9%) were observed at doses of 20 mg/kg per day or higher [at least 75 times the human therapeutic AUC . Cardiac histology revealed an increase in focal infiltration of chronic inflammatory cells in the heart at a dose of 80 mg/kg per day (at least 785 times the human therapeutic AUC). In dogs, no changes in heart rate, blood pressure, ECG parameters, heart weight, or cardiac histology were observed at any dose tested (the highest dose of 30 mg/kg per day was 572 times the human therapeutic AUC).
Genotoxicity Genotoxicity studies revealed a slight but reproducible positive result in the in vitro Ames reverse mutation test using the TA100 strain with and without metabolic activation.
Prucalopride also increased unscheduled DNA synthesis (UDS) in rat hepatocytes in vitro at cytotoxic concentrations ≥100 μg/mL, but not at ≤50 μg/mL. DNA adduct formation occurred in mouse and rat liver (but not other tissues) after oral prucalopride administration, although only under non-standard assay conditions and adducts did not contain prucalopride or its known metabolites and therefore any relationship to treatment is unclear. However, prucalopride was negative in the majority of the genetic toxicity assays that consisted of: most bacterial strains used in the Ames assay, SOS-repair, mouse lymphoma cell, human peripheral blood lymphocyte, in vivo mouse micronucleus, in vivo UDS, and in vivo transgenic Big Blue (evaluates mutagenicity and adduct formation in rat liver) assays. A Structural Alert Relationship analysis did not show any alert for genotoxicity of prucalopride or its metabolites. Therefore prucalopride is considered to have low in vivo genotoxic potential.
Carcinogenecity No carcinogenicity studies in animals have been found in published domain. Information regarding carcinogenicity has been taken from the reference product product monograph (RESOTRAN Product Monograph).
Carcinogenicity studies with prucalopride resulted in an increased incidence of tumours in the two- year mouse and rat bioassays, while no drug-related tumor incidence increases were found in the neonatal mouse carcinogenicity study. The increased incidences consisted of: mammary gland adenocarcinomas in female mice at the high dose level of 80 mg/kg and in male and female rats at the high dose levels of 80 and 40 mg/kg, respectively. Other increases in rats consisted of pheochromocytomas, pancreatic islet cell adenomas, and pituitary adenomas in males at 80 mg/kg, hepatocellular adenomas in males at 40 and 80 mg/kg and females at 40 mg/kg, and thyroid follicular adenomas in males at 80 mg/kg and females at 40 mg/kg. According to recent ICH Guidance, positive tumorgenicity 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 prucalopride carcinogenicity studies all occurred at exposure (AUC) margins greater than 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 is only six times that at the 2 mg human dose.
The tumor profile was considered to reflect rodent-specific epigenetic responses related to a weak CAR-mediated pleiotropic response in the liver including organ weight increases and microsomal enzyme induction (rat) with respect to the liver tumors and thyroid tumors, and stimulation of prolactin secretion (rat and mouse) in the case of the mammary and pituitary tumors. The increased incidence of thyroid tumors 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 prolactin levels were likely due to prucalopride antagonism of the dopamine D2 receptors in the pituitary gland. It is concluded that the tumorigenic risk from prucalopride to humans is low.
PAR Scientific discussion 14/21
Reproductive and development toxicity Oral reproductive toxicology studies in rats did not elicit adverse effects up to 20 mg/kg in Segment I and Segment III studies. Increased precoital interval and pre-implantation loss at 80 mg/kg may have been due to maternal prolactin-mediated effects in the segment I study. In the Segment III study, a slight decrease in the weight of the gravid uterus and a marginal decrease in the number of corpora lutea were seen in the 80 mg/kg high dose group. In the oral Segment II studies in rats and rabbits, no teratogenicity or other embryotoxicity was seen up to the highest doses of 80 mg/kg, corresponding with exposure ratios versus humans of 938 in rats (based upon Cmax; AUC was not available) and 38 in rabbits (based upon AUC0-24h). Further, one-week and one-month neonatal/juvenile toxicity studies were performed in rats and dogs, resulting in a NOAEL of 5 mg/kg in the dog; however effects, including reduced body weight gain, occurred at all prucalopride dose levels (5-80 mg/kg) tested.
However, as stated in the SmPC for RESOLOR, as originator product, animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Local tolerance Primary irritation in rabbits was examined following treatment with formulations containing 1.55 mg/mL of prucalopride hydrochloride via the intramuscular (IM), intravenous (IV), intraperitoneal (IP), subcutaneous (SC) or perivenous (PV) routes. No irritation was noted after IM, IV or IP routes. Hematomas were occasionally found following administration via other routes. Treatment with formulations containing 8 mg/mL of prucalopride succinate produced no irritation after administration via the IM, IV, SC, IP or PV routes but slight irritation was observed after the intra-arterial (IA) route. Prucalopride treatment at dose levels up to 10 mg/kg did not increase ultraviolet (UV) induced phototoxicity in rats.
III.1 Ecotoxicity/environmental risk assessment (ERA)
Since Prucalopride Dexcel 1 mg, 2 mg film coated tablets is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
IV. CLINICAL ASPECTS
IV.1 Introduction
The applicant claims that:
Prucalopride film-coated tablets has been formulated with Prucalopride succinate as drug substance, which is a highly soluble, high permeable Biopharmaceutics Classification System (BCS) Class I compound, in an immediate-release solid oral pharmaceutical form for systemic action that presents very rapid in vitro dissolution (> 85% within 15 minutes, as well as the reference product). Therefore, based on the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/ Corr), it is possible to apply for a waiver of in vivo bioequivalence studies for the test product as it is in compliance with the established requirements for the BCS-based biowaiver approach of the Appendix III of the mentioned guideline.
Even though the above exposed rationale, in order to ensure the bioavailability/bioequivalence of the test product in front of the reference product, a clinical pivotal study in fasting conditions was conducted with the 2 mg strength of both products.
Biowaiver for the 1mg strength
PAR Scientific discussion 15/21
The biowaiver is requested on the basis of the requirements stated in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/ Corr), Appendix III, which in the case of Prucalopride 1 mg film-coated tablets, are all fulfilled, as detailed in the following pages. Therefore, no bioequivalence study is necessary to prove that the test product has a similar bioavailability to that of the reference product.
Drug Substance The drug substance in the test product and reference product is identical (Prucalopride succinate) and it does not belong to the group of narrow therapeutic index drugs. The solubility and permeability characteristics of Prucalopride succinate indicate that it is a Biopharmaceutics Classification System (BCS) Class I compound, showing high solubility and complete absorption.
Solubility According to the information from the drug substance manufacturer in section 3.2.S.1.3 General Properties, Prucalopride succinate is freely soluble (> 100 mg/mL) in acidic aqueous media (pH 1.0 – 6.8) at 37 ºC, soluble in N,N-dimethylformamide, dimethylsulfoxide and N,N-dimethylacetamide, and sparingly soluble in methanol. The pKa of Prucalopride is 8.5. This pKa value is mainly attributable to its piperidine moiety. Basicity of the aniline group is expected to be very low due to the electron withdrawing effect of its conjugated chlorine and amide groups. In order to confirm that the drug substance is highly soluble, meaning that the highest single dose administered as immediate release formulation (2 mg, according to the information in the SmPC of the reference product Resolor®) is completely dissolved in 250 ml of buffers within the range of pH 1 – 6.8 at 37±1 °C, as described in the requirements of Appendix III of the above mentioned guideline, drug substance solubility studies have been conducted.
Permeability According to the literature, pharmacokinetic studies in humans show that Prucalopride is rapidly and extensively absorbed from the gastrointestinal tract after oral dosing. Peak plasma concentration of 4.34 ng/ml (mean) was achieved in 2.1 hours after a single 2 mg dose in 14 healthy adult subjects. Absolute oral bioavailability of prucalopride exceeds 93% and is not affected by food intake. Prucalopride displays linear pharmacokinetics with exposure to drug, increasing proportionally with increasing dosage over the dose range 1 to 20 mg daily. Plasma protein binding is low at 28% to 33%. Extensive distribution is reflected in a steady state volume of distribution of 567 l. This fact is also supported in the SmPC of the reference product Resolor, where it is stated “Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, Cmax was attained in 2-3 hours. The absolute oral bioavailability is > 90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride”. This information confirms that the substance is completely absorbed after oral administration, assuming complete absorption when the extent of the absorption is ≥ 85%, as defined in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/ Corr), Appendix III. Therefore, Prucalopride succinate is considered as a highly permeable drug substance.
Drug product The test product, Prucalopride 1 mg film-coated tablets, is an immediate-release solid pharmaceutical product for oral administration and systemic action, as well as the reference product, Resolor® 1 mg film-coated tablets. As it can be ascertained below, the excipients of the test product that might affect bioavailability are qualitatively are qualitatively the same and used in similar amounts than the ones of the reference product. Additionally, both products, test and reference product, show very rapid in-vitro dissolution characteristics (> 85 % dissolved within 15 minutes) after comparative dissolution studies conducted
PAR Scientific discussion 16/21 taking into account the specific requirements defined in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/ Corr), Appendix III.
Bioequivalence studies
Study MED-P7-148 2mg
Method
This was a two stage, randomised, single centre, open-label, balanced, two-period, two sequence, single dose, crossover comparative oral bioavailability study to establish comparative bioequivalence of Prucalopride 2mg film coated tablets in healthy, adult, male and female subjects under fasting conditions. The objective of the study was to compare the rate and extent of absorption of both products and to monitor the adverse events to ensure the safety and tolerability of a single dose of Prucalopride 2mg film coated tablets.
Table 1. Summary of Pharmacokinetic Parameters for Prucalopride 2mg under fasting conditions (n=21)
Table 2. ANOVA 90% CI (Log transformed) and CV% for primary parameters of Prucalopride 2mg (test vs. reference) (Fasting, n=21).
Conclusion on bioequivalence studies: Based on the submitted bioequivalence study/ies Prucalopride Dexcel 2mg film coated tablet is considered bioequivalent with Resolor 2mg film coated tablet
PAR Scientific discussion 17/21
The results of study MED-P7-148 with 2mg formulation CAN be extrapolated to other strengths 1mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, Appendix III.
The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be accepted.
IV.2 Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks relating to Prucalopride Dexcel 1 mg film-coated tablets Prucalopride Dexcel 2 mg film-coated tablets.
Safety specification According to the Guideline on good pharmacovigilance practices (GVP), Module V-Risk management systems, for generic medicinal products, if the originator product has an RMP, Module SVIII should include the summary of the safety concerns, in line with the originator product. According to the Guideline on good pharmacovigilance practices (GVP), Module V-Risk management systems, for generic medicinal products, if the originator product has an RMP, Module SVIII should include the summary of the safety concerns, in line with the originator product. The applicant prepared a RMP according to the published summary of the RMP in the EMA and based on the current SmPC of the reference medicinal product in EU.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures Description of routine risk minimization measures by safety concern:
PAR Scientific discussion 18/21
Summary of the RMP
The submitted Risk Management Plan, version 1.0 signed 10.10.2018 data lock point 08.10.2018 is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. PAR Scientific discussion 19/21
An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimization) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
Periodic Safety Update Report (PSUR)
With regard to PSUR submission, the MAH should take the following into account:
• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
• In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.
IV.3 Discussion on the clinical aspects
The application is made under reference to article 10(1) of Directive 2001/83/EC as amended. Abridged applications avoid the need for repetitive tests on animals and humans.
V. USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was acceptable. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.
PAR Scientific discussion 20/21
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
From a quality point of view, the benefit/risk ratio for the product is positive. The application is approvable from a quality point of view, given that the applicant committed to perform a number of post authorisation follow- up measures to be reported back to the Member States within predefined timeframes. A list of such follow-up measures is in section VI of this report.
The application contains an adequate review of published non-clinical and clinical data and the bioequivalence has been shown. Approval is recommended from the clinical and non- clinical point of view.
The results of study MED-P7-148 with 2 mg formulation CAN be extrapolated to other the 1mg strength, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, Appendix III.
Recommendations not falling under Article 21a/22 of Directive 2001/83
Regarding the risk assessment to be conducted for the risk of nitrosamine presence in line with the requirements outlined in the EMA (EMA/428592/2019) and CMDh (CMDh/405/2019) guidance documents published in September 2019. The marketing authorization Holder (Dexcel Pharma GmbH) commits to provide the necessary information to Competent Authorities as soon as possible at the latest within 6 months of the publication of “Information on nitrosamines for marketing authorisation holders”, but before planned placing of the first batch of the drug product on the market, irrespectively of results of above risk assessment. Dexcel Pharma GmbH, will also inform the competent authorities immediately in line with CMDh requirements if should a high risk be identified for this product. – Due date: as per CMDh requirements
PAR Scientific discussion 21/21