CMDh/223/2005 February 2014
Neiratax
solution for injection
Thiamine hydrochloride/Pyridoxine hydrochloride/ Cyanocobalamin/Lidocaine hydrochloride
EE/H/0239/001/DC
Date: 25.08.2017
This module reflects the scientific discussion for the approval of Neiratax. The procedure was finalised at 10.07.2017. For information on changes after this date please refer to the module ‘Update’.
PAR Scientific discussion
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Neiratax (containing 100 mg thiamine hydrochloride, 100 mg pyridoxine hydrochloride, 1 mg cyanocobalamin and 20 mg lidocaine hydrochloride), solution for injection for intramuscular administration from AS Kalceks in member states BG, CZ, HU, LT, LV, NL, PL, RO, SK. The medicinal product is intended for the treatment of haematologic and neurologic symptoms caused by continuous deficiency of vitamins B1, B6 and B12.
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.
The reference product is Milgamma N, 50 mg/50 mg/0.5 mg/10 mg/ml marketed by Wörwag Pharma GmbH & Co. KG, authorised since 1999.
QUALITY ASPECTS
Introduction
Neiratax 100 mg/100 mg/1 mg/20 mg/2 mL solution for injection is intended for intramuscular administration. The drug product consists of B group vitamins: pyridoxine hydrochloride, thiamine hydrochloride, cyanocobalamin and lidocaine hydrochloride as a local anesthetic. The drug product is packed in Type I amber glass ampoules.
Drug Substance(s)
Neiratax (ATC code: A11DB) belongs to pharmacotherapeutic group: vitamin B1 and its combinations with vitamin B6 and/or vitamiin B12. The specifications of the active substances are in line with the current scientific requirements. The adequate quality of the active substances has been demonstrated by submitting the appropriate control data. The stability has been tested under ICH conditions. The results of the stability studies support the established retest-period.
Medicinal Product
The formulation and manufacturing development of the medicinal product have been described. The information provided with regard to manufacturing process of the medicinal product is considered sufficient. The drug product specifications are considered acceptable. The analytical methods are described and validated. The drug product is light sensitive, hence packed in Type I amber glass ampoules. The shelf-life of 18 months, at 2°C to 8°C, with a special requirement “do not freeze, store in the original package, protect from the light”, is considered justified
NON-CLINICAL ASPECTS
No new data were presented. This is acceptable.
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Ecotoxicity/environmental risk assessment (ERA)
Since Neiratax 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.
Discussion on the non-clinical aspects
No new data were submitted. This is acceptable.
CLINICAL ASPECTS
Introduction
Pharmacodynamic, pharmacokinetic and toxicological properties of pyridoxine hydrochloride, thiamine hydrochloride, cyanocobalamin and lidocaine hydrochloride are well known. As pyridoxine hydrochloride, thiamine hydrochloride, cyanocobalamin and lidocaine hydrochloride are widely used, well-known active substances, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
Pharmacokinetics
No pharmacokinetic studies have been presented. The daily requirement is about 1 mg of thiamine. Excess thiamine is excreted with urine. The determination of the activity of a TPP-dependent ensyme - transketolase - is used to determine the B 1 status. Plasma concentration is 2-4 µg/100 ml. Pyridoxine, pyridoxal and pyridoxamine are phosphorylated and oxidated to pyridoxal-5 phosphate (PALP). The main excreted metabolite is 4-pyridoxic acid. Tryptophan test is suitable for the determination of B 6. In adults the average serum PALP value is 1.2 µg/100 ml. The daily requirement of vitamin B 12 is 1 µg. An average of 1.5-3.5 µg of vitamin B 12 is absorbed from food. Normal vitamin B 12 plasma concentration is 200-900 µg/ml, value below 200 µg/ml is regarded as deficit. Circulating vitamin B 12 corresponds to about 0.1% of total vitamin amount. Intramuscular injection of 200 mg 10% lidocaine is reported to give serum concentrations 1.3-1.9 µg/ml. Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Although unchanged lidocaine is excreted into the urine, it is a minor route of excretion and account for less than 11%. Lidocaine has an initial half-life of 7-30 minutes and a terminal half-life of 1.5-2 hours.
IV.3 Pharmacodynamics
No new data were presented.
IV.4 Clinical safety
Summary Pharmacovigilance system
PAR Scientific discussion
The Applicant AS Kalceks has submitted a signed Summary of the Applicant's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
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 Neiratax 100 mg/100 mg/1 mg/20 mg/2 ml solution for injection.
Safety specification Important identified risks Cardiovascular reactions, such as arrhythmias and bradycardia Toxic and allergic reactions in newborns (especially in premature newborns) and in children under 3 years of age Important potential risks None Missing information None
IV.6 Discussion on the clinical aspects
The application contains an adequate clinical overview. There are no clinical studies or bioequivalence studies included in the application. The applicant claims that Neiratax 100 mg/100 mg/1 mg/20 mg/2 ml solution for injection has the same qualitative and quantitative composition in active substances and the same pharmaceutical form compared to Milgamma N 50 mg/50 mg/0.5 mg/10 mg/ml solution for injection.
USER CONSULTATION
Full report has been presented for Neiratax. User testing results were satisfactory.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The risk/benefit ratio is considered positive and the application for Neiratax solution for injection has been recommended for approval.
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