Decentralised Procedure. Public Assessment Report

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Decentralised Procedure

Public Assessment Report

Articainhydrochlorid mit Epinephrin Pierrel

40 mg/ml + 0.01 mg/ml Injektionslösung

Articainhydrochlorid mit Epinephrin Pierrel

40 mg/ml + 0.005 mg/ml Injektionslösung

Articaine hydrochloride, epinephrine tartrate

DE/H/3094/001-002/DC

Applicant: Pierrel Pharma S.R.L

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I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Orabloc 1:100000 / Orabloc 1:200000, in the treatment of local anaesthesia (infiltration and nerve-block anaesthesia) in dentistry in adults, adolescents and children of 4 years and older, is approved.

II. EXECUTIVE SUMMARY

II.1

Problem statement

This decentralised application concerns a generic version of Articaine-Epinephrine 1:200,000 and Articaine-Epinephrine 1:100,000, solution for injection, submitted as abridged applications according to Art. 10.1 of Directive 2001/83/EC as amended, so-called generic applications. In this Assessment Report, the names Orabloc 1:100000 / Orabloc 1:200000 are used.

The originator products are Ultracain® D-S 1:200,000 and Ultracain® D-S forte, registered in Germany since 29-Apr-1975 by Sanofi-Aventis Deutschland GmbH, Germany.

With Germany as the Reference Member State in this Decentralised Procedure, Pierrel Pharma srl, Italy is applying for the Marketing Authorisations for Orabloc 1:100000 Injektionslösung and Orabloc 1:200000 Injektionslösung in AT, DE, FR, PL and UK.

II.2

About the product

The anaesthetic effect of Orabloc 1:100000 / Orabloc 1:200000 is caused by the pharmacologically active ingredient articaine supplemented with epinephrine.

There is large clinical experience with the use of the composition of Articaine-Epinephrine as local anaesthesia (infiltration and nerve-block anaesthesia) in dentistry due to widespread use of the originator product Ultracain® D-S 1:200,000 and Ultracain® D-S forte 1:100,000 and numerous other generic products. The higher concentration (1:100,000) does improve haemostasis and the local diffusion of articaine, but the lower concentration (1:200,000) should be used where the administration of epinephrine is considered an additional risk factor.

The applicant is applying for the following indication:

“<Invented name> is indicated in adults, adolescents and children of 4 years and older for local anaesthesia (infiltration and nerve-block anaesthesia) in dentistry.

<Invented name> 40 mg/ml + 0.005 mg/ml solution for injection:

Routine interventions such as uncomplicated single and serial extractions, cavity and crown stump preparations.

<Invented name> 40 mg/ml + 0.01 mg/ml solution for injection:

- mucosal and bone surgery requiring stronger ischaemia, - dental pulp surgery (amputation and extirpation), - extraction of fractured teeth (osteotomy), - protracted surgical interventions,

- percutaneous osteosynthesis,

- cystectomy,

- mucogingival interventions,

- apicoectomy.“

II.3

General comments on the submitted dossier

Due to the fact that the test products are to be administered as an aqueous intravenous solution containing the same active substances as the currently approved products, bioequivalence studies are not required (GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE, Appendix II page 23, CPMP/EWP/QWP/1401/98 Rev. 1/ Corr).

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General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

Quality aspects

Drug substance

The active substances articaine hydrochloride and adrenaline tartrate are described in the European Pharmacopoeia (EP). The quality of the active ingredients articaine hydrochloride and adrenaline tartrate is controlled in compliance with the corresponding monographs of the EP. The suitability of the EP monographs to test both active substances has been verified by the EDQM. CEPs are provided for both active substances.

The data indicate that the active substances are stable when stored in the proposed packaging material. The re-test period for articaine hydrochloride is granted per CEP for 3 years. The re-test period for adrenaline tartrate is granted per CEP for 4 years.

Drug product

The finished product is manufactured in two strengths: 40 mg/ml articaine hydrochloride and 0.005 mg/ml adrenaline (1:200,000) resp. 40 mg/ml articaine hydrochloride and 0.010 mg/ml adrenaline (1:100,000). The drug products are parenteral solutions of 1.8 ml each filled into an EP type I clear glass cartridge closed with both a bromobutyl rubber seal and a bromobutyl plunger. The closure material complies with the requirements of type I closures according to EP 3.2.9.

The excipients are conventional pharmaceutical ingredients. The function of each ingredient included in the product has been described.

The manufacturing process comprises compounding of the bulk solution followed by sterile filtration and aseptic filling in cartridges.

The finished product specification is in compliance with the general pharmacopeial requirements for parenterals and the requirements laid down in the relevant EU-guidelines. The analytical methods are well described and validation reports are submitted. Acceptable batch data are submitted. All batch results are in line with the specification limits.

Stability data according to ICH requirements are provided. The data comprise results of long term storage (24 months) as well as intermediate (12 months) and accelerated storage (6 months). All results are well within limits.

A shelf life of 24 months is accepted with the storage conditions “Do not store above 25°C” and “Store in the orginal package in order to protect from light”.

III.2

Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of articaine hydrochloride and epinephrine (adrenaline) are well known. As both active substances are well-known and widely used in combination products, no further non-clinical studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. The provided non-clinical overview is considered appropriate.

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III.3

Clinical aspects

Pharmacokinetics

The elimination half-life of articaine after intraoral submucosal injection is 25.3 ± 3.3 min. Unlike other local anaesthetics of the amide type articaine is metabolised in the liver by only about 10% . The major amount of articaine is inactivated by hydrolysis (non-specific esterases) of carboxyl group in blood plasma and tissues. The metabolite articainic acid is excreted renally. The plasma protein binding is 95%, i.e. relatively high.

Pharmacodynamics

The anaesthetic effect of Ultracain 1:200000 and Ultracain 1:100000 is caused by the pharmacologically active ingredient articaine supplemented with epinephrine.

Articaine (used as water-soluble hydrochloride salt) belongs to the local anaesthetics of amide type. When applied locally to nerve tissue in appropriate concentrations, articaine is able to prevent or relieve pain by interrupting nerve conduction. In general, the loss of pain occurs before loss of sensory and motor functions. The action of local anaesthetics is reversible. Primary site of action is the membrane of nerve cells. Due to their direct interaction with voltage-dependent Na+ channels, they inhibit the increase in Na+-permeability of excitable membranes and, therefore, formation of the action potentials. In dentistry articaine is used for infiltration and nerve block anaesthesia. Infiltration anaesthesia is the superficial injection into intraoral mucosa; nerve block anaesthesia is produced by injection into or around a peripheral nerve or a nerve plexus supplying the area that should be anaesthetized.

Epinephrine (adrenaline) is characterized as potent agonist for - and -adrenergic receptors with complex effects on different target organs. The vasoconstrictor action of epinephrine is mediated by stimulation of 1- and 2- receptors. Vasoconstriction decreases the absorption of articaine and, thereby, prolongs its action. In addition, the delayed absorption also reduces undesirable systemic effects of the local anaesthetic.

Clinical efficacy

Therapeutic efficacy of 4% articaine solutions supplemented with epinephrine 1:200,000 and 1:100,000 has been demonstrated adequately in dental patients. A sufficient anaesthetic effectiveness and good clinical success rates have been indicated after intraoral infiltration as well as after nerve block anaesthesia. Studies comparing articaine with lidocaine or with mepivacaine revealed equality or even advantages of articaine.

Clinical safety

Several clinical studies published in the literature since 2003 have concluded a good tolerability of 4% articaine (with epinephrine 1:100,000 and 1:200,000). Both compounds are in clinical use as single compounds and in combination for more many years. In summary, articaine solutions with epinephrine can be considered as safe local anaesthetics for dental infiltration and nerve block anaesthesia.

User Testing

Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). Both the first and the second test round met the success criteria of 90% of the participants are able to find the requested information in the PIL, and of those, 90% being able to give the correct answer, to indicate that they can understand and properly interpret the information. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test is accepted.

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Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH'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/Rapporteur considers the Summary acceptable.

IV. BENEFIT RISK ASSESSMENT

There is large clinical experience with the use of the composition of Articaine-Epinephrine as local anaesthesia (infiltration and nerve-block anaesthesia) in dentistry due to widespread use of the originator product and numerous other generic products. The higher epinephrine concentration (1:100,000) does improve haemostasis and the local diffusion of articaine, but the lower concentration (1:200,000) should be used where the administration of epinephrine is considered an additional risk factor.

The application contains an adequate review of published nonclinical and clinical data. Bioequivalence studies are not required for this application, as it concerns a solution for injection. The application is approved.

Decentralised Procedure. Public Assessment Report