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