CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

LEVOSULPIRIDE ARISTO 25 mg, 50 mg, 100 mg tablets

Aristo Pharma GmbH Wallenroder Straβe 8-10 13435 Berlino Germania

IT/H/534/001-003/DC

Date: 15/06/2020

This module reflects the scientific discussion for the approval of Levosulpiride Aristo. The procedure was finalised at 5 June 2019. For information on changes after this date please refer to the module ‘Update’.

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Levosulpiride Aristo, 25 mg, 50 mg and 100 mg tablet, from Aristo Pharma GmbH. Levosulpiride Aristo 25 mg is indicated for: • Short-term treatment of dyspeptic syndrome (anorexia, bloating, a feeling of epigastric tenderness, postprandial headache, heartburn, belching, diarrhoea, constipation) from delayed gastric emptying related to organic factors (diabetic gastroparesis, cancer, etc.) and / or functional factors (visceral somatisation in anxious subjects -depressants) in patients who failed to respond to other therapy. • Symptomatic short-term treatment of nausea and vomiting (induced by anticancer drugs) after failure of first-line therapy. • Symptomatic short-term treatment of dizziness, tinnitus, hearing loss and nausea associated with Meniere’s syndrome.

Levosulpiride Aristo 50 mg and 100 mg is indicated for: • Somatic symptom disorders. • Treatment of chronic schizophrenia with negative symptoms.

A comprehensive description of the indications and posology is given in the SmPC.

The active substance levosulpiride belongs to the pharmacotherapeutic group of psycholeptics, antipsychotics, ATC code: N05AL07. Levosulpride blocks the presynaptic dopaminergic D2 receptors. Like its parent compound (sulpiride), levosulpiride shows antagonism at D3 and D2 receptors present presynaptically as well as postsynaptically. The preferential binding of the presynaptic dopamine receptors decreases the synthesis and release of dopamine at low doses whereas it causes postsynaptic D2 receptor antagonism at higher dose. This receptor profile together with its limbic selectivity explains its effectiveness of levosulpiride in the management of negative symptoms of schizophrenia. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. Levosulpiride has a stimulant effect on 5-HT4 receptors and to a lesser extent on 5-HT3 receptors. Its action on 5-HT receptors is thought to account for the ability to stimulate gastric and small bowel motility and to accelerate gastric emptying in patients suffering from functional dyspepsia and diabetic gastroparesis. Levosulpiride is more effective than domperidone, metoclopramide and at least as effective as cisapride. Levosulpiride has stimulating activity at low doses and sedative effects only at very high doses, due to the blockade of central pre-synaptic autoreceptors and post-synaptic D2 receptors, respectively (this is why it is placed apart as a mainly atypical neuroleptic agent). This is probably the reason why levosulpiride has only a low potential to induce extrapyramidal side-effects at the doses used in gastroenterology.

The marketing authorisation has been granted pursuant to Article 10.1 generic application of Directive 2001/83/EC as amended. Essential similarity is claimed to Levopraid tablets produced by Teopharma srl Italy, registered since 20 November 1985. The application for the Marketing Authorization was a Decentralised Procedure with Italy acting as the Reference Member State (RMS) and Spain as the only Concerned Member State (CMS).

The RMS has been assured that acceptable standards of GMP are in place for this product type at all sites responsible for the manufacture and assembly of the product. Regarding the statement on GMP for the active substance a suitable declaration is provided from the manufacturer responsible for manufacture of the finished product and batch release situated in the EU.

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets In the bioequivalence study report it has been stated that clinical and analytical parts were carried out in accordance with the current GCP/GLP.

II. QUALITY ASPECTS

II.1 Introduction Levosulpiride Aristo is formulated as tablets containing 25 mg, 50 mg and 100 mg of levosulpiride and packed in blister of PVC/PVDC sealed with Aluminium foil. The 25 mg tablets are white, round, convex tablet, with 6 mm diameter, imprinted with “MC” on one side. The 50 mg tablet are white, round, convex tablet, with 8 mm diameter imprinted with “50” on one side. The 100 mg tablets are white, round, convex tablet, with 10.3 mm diameter.

II.2 2.2Drug Substance

The active substance used in the manufacture of the applied finished product Levosulpiride tablets is levosulpiride (Sulpiride S-enantiomer) that is not described in the European Pharmacopoea. An ASMF procedure was followed for levosulpiride. INN: Levosulpiride IUPAC Name: (S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulphamoylbenzamide Other Chemical Name: 5-aminosulphonyl-N-(1-ethyl-pyrrolidin-2-ylmethyl)-2-methoxybenzamide CAS Registry Number: 23672-07-3

Structure:

Chirality: Levosulpiride is the S-enantiomer of sulpiride. A chiral center is present in sulpiride molecular structure, but the starting material and the route of synthesis used allow the formation of the S-enantiomer only (see structural formula above (S-enantiomer). Relative molecular mass: 341.4 Molecular formula: C15H23N3O4S Appearance: white crystalline powder Melting Range: 184 – 189 °C Solubility: practically insoluble in water, sparingly soluble in methanol, slightly soluble in alcohol and in methylene chloride; it dissolves in dilute solutions of mineral acids and alkali hydroxides. pKa: measured in methanol:water (1:1) is 8.5. Partition coefficient: observed log P for Sulpiride is 0.42 Polymorphism: the X-ray analysis was performed on several batches and no differences are visible in the obtained diffractograms that are also perfectly super imposable, demonstrating that no polymorphism is present in Levosulpiride (Sulpiride S-enantiomer) production batches manufactured by the proposed manufacturer. So far no other crystalline forms have been described in the literature.

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets The quality of the active substance has been adequately demonstrated and the stability proven. A re- test period of five years was accepted.

II.3 Medicinal Product

The medicinal product is supplied as tablets containing 25 mg, 50 mg and 100 mg of levosulpiride. The excipients are microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, magnesium stearate. Pharmaceutical development The excipients and packaging are usual for this type of dosage form. The development of the product has been described, the choice of excipients is justified and their functions explained. A Bioequivalence study with the higher strength of 100 mg has been performed and a biowaiver has been requested for the other dosage strengths based on the justification that the pharmacokinetics of the active substance is linear in the whole range of strengths, the qualitative composition of the different strengths is the same, the quantitative composition is fully proportional across strengths and the products are manufactured through the same manufacturing process. Comparative dissolution profiles between the test product and the reference product Levopraid (including the batches of 100 mg used in the Bioequivalence study) and between the 100 mg tablet biobatch of the test product and the batches of the lower strengths have been provided and demonstrated to be similar. The active substance exhibits high solubility in the proposed dissolution medium, HCl 0.1N, as well as in the pH 4.5 and pH 6.8 medium, since the percentage dissolved is higher than 85% at 15 minutes (very rapidly dissolving scenario). The pharmaceutical development of the product has been adequately performed. Manufacturing Process The proposed manufacturing process is standard and consists of blending of the levosulpiride powder with the excipients and direction compression of the final powder blend. Sufficient details on equipment and operational parameters have been provided. Validation protocols has been provided. Product specifications The product specification are adequate for the dosage form. The potential contamination of the elemental impurities in accordance to the ICH Q3D guideline has been adequately investigated. The analytical methods have been adequately described and validated. Batch analytical data have been provided demonstrating compliance with the release specification. Stability The stability studies have been conducted in accordance to ICH storage conditions and cover the proposed shelf-life of 36 months with no special storage conditions.

II.4 Discussion on chemical, pharmaceutical and biological aspects

The quality characteristics of Levosulpiride Aristo tablets 25 mg, 50 mg and 100 mg are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk.

III. NON-CLINICAL ASPECTS

This product is a generic formulation of Levopraid, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application.

III.1 Ecotoxicity/environmental risk assessment (ERA)

Since Levosulpiride Aristo 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

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets IV.1 Introduction

No new clinical data have been submitted except for a bioequivalence study. This is acceptable for a generic application and no additional efficacy or safety studies are deemed necessary. A comprehensive summary of published information on efficacy and safety has been presented. The efficacy and safety of levosulpiride in the proposed indications is established. The proposed SmPC is in accordance with the innovator's SmPC.

IV.2 Pharmacokinetics

A bioequivalence study has been performed between Levosulpiride 100 mg Tablets (Test) and Reference product Levopraid 100 mg tablets. The study was a “comparative, randomized, two-period, two-treatment, two-sequence, single dose, open-label, crossover bioequivalence study” in healthy male subjects under fasting conditions. A validated analytical method via LC/MS-MS was used for levosulpiride quantification. The statistical method for testing bioequivalence was based upon the 90% confidence interval for the ratio of the population means (Test/Reference), for the parameters Cmax AUC0-last and AUC0-inf . For levosulpiride the 90% confidence interval for the ratio of test (T) and reference (R) product averages (least square means) for pharmacokinetic parameters Cmax, and AUCo-tlast fell within the acceptance range 80-125% (93.041-107.140 and 99.339-108.146 respectively).

The study was done on the highest strength and the results of this study can be extended to the lower strengths 25mg and 50mg, as all conditions for dose proportionality are met according to the current Guideline on the investigation of bioequivalence.

Levosulpiride shows linear pharmacokinetics in the dose range of 25 – 100 mg, therefore the biowaiver for the lower strenght 25 mg and 50 mg is acceptable.

The study population consisted of 36 healthy, male, mixed skin Arab & Mediterranean subjects aged between 18 and 44, with a body-mass index of 19.0 to 29.0 kg/m2. 36 subjects completed period I and 34 subjects completed period II.

Following an overnight fast of at least 10 hour, a single oral dose of test and reference formulation was administered in the morning of study day 1 of each study period. The study periods were separated by a washout period of 7 days between the administrations of the study drugs. The blood samples were collected pre dosing (-1.00) and 0.50, 1.00,1.50, 2.00, 2.50, 3.00, 3.25, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00 ,48.00 and 72.00 hours after dosing.

The following pharmacokinetic parameters of Levosulpiride were assessed: Cmax, Tmax, AUC0-last, AUC0-inf, Residual area (%), ke, t1/2 and MRTinf. The statistical method for testing bioequivalence was based upon the 90% confidence interval for the ratio of the population means (Test/Reference), for the parameters Cmax AUC0-last and AUC0-inf .

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, (CV%), tmax median, range)

Treatment AUC0-last AUC0-∞ Cmax tmax ng/ml/h ng/ml/h ng/ml h Test 2571.353 2665.296 192.649 4.00 ± ± ±

593.270 585.021 61.966 1.00-6.00 (23.07) (21.95) (32.17)

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets Reference 2488.947 2583.145 189.701 3.00 ± ± ±

622.255 615.849 45.657 1.00-6.00 (25.00) (23.84) (24.07) *Ratio (90% CI) 103.649 99.842

(99.339-108.146) (93.041-107.140)

AUC0-last The area under the plasma concentration-time curve (AUC0 last) will be calculated by the linear trapezoidal rule from measured data points from time of administration until the time of last quantified concentration, where Clast is the last point. AUC0-∞ Area under the plasma concentration curve extrapolated to infinite time. tmax Time until Cmax is reached *ln-transformed values

AUCextr was less than 20% for all subjects enrolled in the study. Pre-dose levels were always below LLOQ except for the subject n.05 after administration of the test product, the concentration detected was less than 5% of Cmax. Based on the ANOVA results, no significant period treatment and sequence effect was observed for ln-transformed PK parameters Cmax, AUC0-last and AUC0-∞.

Concerning the Safety, this was observed during the whole study duration. The subjects was queried on adverse events during the whole study, and voluntarily reporting of adverse events by the Subjects was reported. The following adverse events were observed: headache, dizziness, minimal ST elevation V2-V3, negative T-wave inversion on AVF, sleepiness, increased urea, increased ALT, decreased sodium, and increased AST. In conclusion, the tolerance of the products studied was good. Vital signs did not show clinically significant changes in general and no serious adverse events or unexpected adverse drug reactions occurred in this study.

Conclusion on bioequivalence studies: Based on the submitted bioequivalence study LEVOSULPIRIDE ARISTO is considered bioequivalent with Levopraid.

The results of bioequivalence study performed with 100 mg formulation can be extrapolated to other strengths of 25 mg and 50 mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.

IV.3 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, characterise, prevent or minimise risks relating to Levosulpiride Aristo”

- Summary table of safety concerns as approved in RMP Levosulpiride 25 mg, 50 mg, 100 mg

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets IV.4 Discussion on the clinical aspects

This type of application refers to information that is contained in the pharmacological-toxicological and clinical part of the dossier of the authorisation of the reference product. For this kind of application, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. To this end the MAH has submitted one pivotal bioequivalence study to demonstrate the bioequivalence Levosulpiride Aristo tablets 100 mg to the reference medicinal product Levopraid 100 mg tablets marketed by TEOFARMA s.r.l, Italy. The Applicant provided data to support the PK linearity of levosulpiride in the dose range 25 mg - 100 mg, therefore the biowaiver for the lower strengths 25 mg and 50 mg can be accepted. A bioequivalence study is the widely accepted means of demonstrating that difference of use of different excipients and different methods of manufacture have no influence on efficacy and safety.

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 italian. 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. A bridging study for Levosulpiride 25 mg tablets has been provided, because of the therapeutic different indication between Levosulpiride 25 mg and Levosulpiride 50 mg/ 100 mg. The comparison table “Daughter” PIL (Levosulpiride 25 mg tablets) versus “Parent” PIL (Levosulpiride 50 mg/ 100 mg) has been provided.

The bridging report for Levosulpiride 25 mg tablets PIL is accompanied also by the full Outcome Report concerning Readability Testing of Levosulpiride 50 mg &100mg tablets Package Leaflet, performed in May 2014.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Bioequivalence has been demonstrated for the test product LEVOSULPIRIDE 100 mg Tablets with the reference product LEVOPRAID 100 mg Tablets marketed by TEOFARMA s.r.l, Italy AND the biowaiver for the lower strengths 25 mg and 50 mg is accepted. The quality of the active substance and the finished product has been adequately demonstrated. Benefit risk assessment is positive.

PAR Scientific discussion IT/H/534/001-003/DC Levosulpiride Aristo 25 mg, 50 mg, 100 mg tablets