Direction de l’Evaluation des Médicaments et des Produits Biologiques
PUBLIC ASSESSMENT REPORT Scientific Discussion NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium Nicotine FR/H/266/03-04/MR
Applicant: Pierre Fabre Medicament
Date of the PAR: March 2010
20100329_fr266_nicotinepfm_par
Page 1 of 6
Information about the initial procedure: Application/Legal Basis Active substance Pharmaceutical form Strength Applicant EU-Procedure number End of procedure
1.
Well-established use application – Art. 10a Nicotine lozenge 2,5 mg Pierre Fabre Medicament FR/H/266/03-04/MR 03/11/2009
INTRODUCTION
Based on the review of the quality, safety and efficacy data, Afssaps has granted a marketing authorisation for NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGARFREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium from Pierre Fabre Medicament. These products are indicated for the relief of nicotine withdrawal symptoms, in nicotine dependency as an aid to smoking cessation in adults and suitable for smokers with strong or very strong nicotine dependency. A comprehensive description of indications and doses is given in the SPC. This application is based on Article 10a of Directive 2001/83/EC as amended, since nicotine is wellestablished use drug in the claimed indication. With France acting as the Reference Member State in this Mutual Recognition Procedure, the Applicant is applying for the Marketing Authorisations of NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium in Cyprus, Denmark, Germany, Estonia, Greece, Finland, Ireland, Lithuania, Latvia, Norway, Poland, Portugal, Spain, Sweden and United-Kingdom. NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium are presented in the form of lozenge containing 2.5 mg of nicotine. The excipients are isomalt, hypromellose, aspartame (E951), acesulfame potassium, peppermint flavour, long-lasting fresh mint flavour (natural peppermint flavour, carnauba wax, hypromellose, mono and diglycerides of fatty acids, ethylcellulose, partially hydrogenated soya oil) or dry extract of deglycyrrhizinated liquorice root, permaseal masking flavour (natural flavouring substances, maltodextrin, acacia, propylene glycol), sodium hydrogen carbonate and anhydrous sodium carbonate. No new preclinical studies were conducted, which is acceptable for this kind of application. In support of this application, the applicant provides three pharmacokinetic, three efficacy/tolerance studies and an analysis of the data in the literature. The clinical pharmacology, efficacy and safety of nicotine have already been extensively studied and characterized during the development of the several drug products already marketed. During the procedure, no potential serious risk to public health was raised.
20100329_fr266_nicotinepfm_par
Page 2 of 6
2.
QUALITY ASPECTS
2.1 Introduction The medicinal product is presented in the form of a lozenge containing 2.5 mg of nicotine. Two flavours have been developed in parallel: liquorice mint flavour and fresh mint flavour. The excipients for the lozenge with fresh mint flavour are isomalt, hypromellose, aspartame, acesulfame potassium, peppermint flavour, long-lasting fresh mint flavour (natural peppermint flavour, carnauba wax, hypromellose, mono and diglycerides of fatty acids, ethylcellulose, partially hydrogenated soya oil), permaseal masking flavour (natural flavouring substances, maltodextrin, acacia, propylene glycol), sodium hydrogen carbonate and anhydrous sodium carbonate. The excipients for the lozenge with liquorice mint flavour are isomalt, hypromellose, aspartame, acesulfame potassium, peppermint flavour, permaseal masking flavour (natural flavouring substances, maltodextrin, acacia, propylene glycol), dry extract of deglycyrrhizinated liquorice root, anhydrous sodium carbonate and sodium hydrogen carbonate. NICOTINE PIERRE FABRE MEDICAMENT 2.5 mg Lozenge is packed in an opaque, white, threelayer blister pack (PVC/PE/PVDC), sealed with aluminium foil, with 12 lozenges per blister. 2.2 Drug substance The drug substance Nicotine Resinate is a complex of nicotine with a weak cation exchange resin. The manufacturer of Nicotine Resinate has submitted an ASMF. This source is already used by Pierre Fabre Medicament in other nicotine substitute drug products already marketed. Nicotine Resinate is controlled according to the requirements of the European Pharmacopoeia monograph in force supplemented by in-house tests. In-house analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. 2.3 Medicinal product NICOTINE PIERRE FABRE MEDICAMENT 2.5 mg Lozenge is formulated using excipients described in the current Ph Eur. except for the flavouring agents for which satisfactory in-house specifications are described. All raw materials used in the product have demonstrated compliance with Commission Directive 2003/63/EC and the Note for Guidance on Minimising the risk of transmitting Animal Spongiform Encephalopathy Agents via human and veterinary medicinal products (EMEA/410/01). The development is sufficiently described in accordance with the relevant European guidelines. The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed. The data support the shelf life claimed in the SPC, 2 years at a temperature not exceeding 30°C, store in the original package to protect from moisture.
3.
NON-CLINICAL ASPECTS
In accordance to Directive 2001/83/EC as amended, adequate scientific literature has been provided: 143 bibliographical references related to non-clinical tests have been submitted, dated from 1987 to 2005. A favourable opinion is given on the preclinical part of the dossier.
20100329_fr266_nicotinepfm_par
Page 3 of 6
Environmental risk As nicotine is a well-known substance, such an evaluation of the potential environmental risk is deemed unnecessary.
4.
CLINICAL ASPECTS
4.1 Introduction Nicotine is a well-established substance with established efficacy and tolerability in smoking cessation therapy. First registration for a NRT occurred in 1985 (2 mg-gum). The applicant’s objective was to develop a new oral dosage of nicotine lozenge, as a line extension of the previously marketed lozenge containing 1.5 mg of nicotine, with a pharmacokinetic (PK) profile comparable to that of an existing high-dose nicotine gum, which was chosen as reference product. NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium are intended for the relief of nicotine withdrawal symptoms, in nicotine dependency as an aid to smoking cessation in adults. These medicinal products are suitable for smokers with strong or very strong nicotine dependency (score of 7 to 10 in the Fagerström test). 4.2 Pharmacokinetics The applicant provides three pharmacokinetic studies in support of this application: -
One pilot bioavailibility study of three new dosages of nicotine lozenge formulations, after single oral administration in 12 healthy volunteers. Based on this study, the formulation (nicotine 2.5mg lozenge) was selected for the next pivotal bioavailability study.
-
One pivotal study, which was designed to confirm and determine the PK profile of the new lozenge formulation 2.5mg and to compare its nicotine and cotinine bioavailability with that of NICORETTE 4 mg gum, after single oral administration in 36 healthy volunteers. The results of this study showed that the nicotine 2.5mg lozenge appeared safe and presented a PK profile similar (particularly regarding cotinine) to that the reference product (NICORETTE 4 mg gum), whereas the tested product showed higher Cmax and AUC (regarding nicotine).
-
One complementary study designed to compare the PK profile of new medicinal product 2.5mg with that of NIQUITIN 4 mg, after single oral administration in 12 healthy volunteers. The results of this study showed that the nicotine 2.5mg lozenge provided less bioavailable nicotine than the reference product (NIQUITIN 4mg). The nicotine 2.5mg lozenge presented a cotinine PK profile similar to that NIQUITIN 4 mg lozenge.
The relevance of these conditions for clinical use of the lozenges may be questioned, but provided that the ”self titration” concept is accepted for these types of products, this is not considered to be a relevant objection. Moreover, compared with the reference product, nicotine 2.5mg lozenge seemed equivalent in terms of nicotine substitute consumption and cigarettes smoked. In this context, the PK profile of the nicotine 2.5mg was considered as acceptable. 4.3 Pharmacodynamics The applicant makes reference to the pharmacodynamic (PD) of nicotine, which has been extensively described in the literature. The applicant did not conduct any new clinical studies investigating PD of nicotine.
20100329_fr266_nicotinepfm_par
Page 4 of 6
4.4 Discussion on the clinical aspects A clinical overview on the clinical pharmacology, efficacy and safety of the active ingredient (with corresponding references from the literature) is provided. Efficacy Efficacy profile of nicotine is already well-established and documented. In order to provide the efficacy profile form the clinical data to the product of this application appears convenient. To support the efficacy of this product, the Applicant provided an analysis of the efficacy data in the literature, a clinical tolerance/behavior study, comparing the nicotine 2.5 mg lozenge with NICORETTE 4 mg nicotine gum (reference product) and two sensory studies. - One clinical tolerance/behavior study: No significant difference has been observed in the level of smoking and the consumption of nicotine substitutes for both groups. This is reflecting the same capacity to combat the withdrawal symptoms. - Two sensory studies: The results of these two studies confirm the good acceptability of the product, enabling good patient compliance. However, regarding the proposed SPC for NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, the RMS considered that the Applicant should updated the product information in line with the other approved products containing liquorice and used in the nicotine replacement therapy. A warning should be added in sections 4.4 and 4.6 of the SPC. Finally, this application is considered adequate, to the wide safety margin of nicotine and its wellestablished use. The available data support the indication: “relief of nicotine withdrawal symptoms, in nicotine dependency as an aid to smoking cessation in adults”. The proposed posology (8 to 12 lozenges per day and should not exceed 15 lozenges daily) corresponds to the established recommendation adopted in the requested indications. Safety No new safety signal arose for the 2.5-mg lozenge formulation from the data submitted. • In the pivotal study, AE were those commonly reported with oral nicotine substitutes during smoking cessation. The most frequently reported events were gastrointestinal disorders (e.g. nausea and upper abdominal pain), nervous system disorders (e.g. headache), general disorders, respiratory thoracic or mediastinal disorders and psychiatric disorders. No major differences were noted between the groups for the incidence of each of these organ system classified events. However, there were trends for a slight higher frequency in the nicotine 2.5mg-group (gastrointestinal disorders, respiratory thoracic or mediastinal disorders and psychiatric disorders), while others AE tended to be more frequent in the reference-group (nervous system disorders and general disorders). Finally, “application site reaction” seemed more frequently associated with reference treatment (12.2 %) than 2.5mg-group (5.7 %). Nevertheless, mouth examination data did not shown significant difference in mucosa inflammation signs (erythema, oedema, ulceration, others) between treatment groups and their similar improvement over the substitute treatment period. No deaths or SAE were reported in the nicotine 2.5mg-group. • Regarding literature data, the studies did not reveal any new safety concerns. Some publications revealed that some smokers may switch their dependence from cigarettes to NRT products. However, this risk probably remains very low and even if a dependence with a NRT product develops, it is likely that the user will nonetheless obtain a benefit for his own health compared with continuous smoking.
20100329_fr266_nicotinepfm_par
Page 5 of 6
• Regarding post-marketing data, since the new medicinal product Lozenge 2.5 mg is not marketed yet in any country, there are no post-marketing data available for this formulation. However, post-marketing data are available for the 1.5 mg-lozenge formulation. Therefore, no new safety signal arose for the 1.5-mg lozenge formulation for the period under assessment. • For future PSUR, the company should commit to: - monitor cases of exposure during pregnancy in future PSURs, - monitor cases of nicotine dependency/addiction, misuse or long-term use in future PSURs, - supply the nicotine lozenge sales sorted by countries in future PSURs, in addition to the total number of lozenges sold during the reference period. • No description of the Risk Management System has been provided since the application is based on well-established use. The RMS has reviewed the safety profile of NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and is of the opinion that, the risk-benefit ratio remains favourable. 5.
OVERALL DISCUSSION , BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The Applicant applied for the registration of NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium in accordance with the article 10a “wellestablished use” of Directive 2001/83/EC. Satisfactory chemical-pharmaceutical documentation of NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE have been provided, assuring consistent and sufficient quality of the product. No new preclinical studies were conducted, which is acceptable for this kind of application. In support of this application, the applicant provides three pharmacokinetic, three efficacy/tolerance studies and an analysis of the data in the literature. The clinical pharmacology, efficacy and safety of nicotine have already been extensively studied and characterized during the development of the several drug products already marketed. No potential serious risk to public health was raised during the procedure. The SPC, Package Leaflet (PL) and packaging are in the agreed template. Comments from CMSs have been received and taken into account. Finally, agreement between Member States was reached during procedure. There was no further discussion at the CMD(h). The mutual recognition procedure for NICOTINE PIERRE FABRE MEDICAMENT FRESH MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame and acesulfame potassium and NICOTINE PIERRE FABRE MEDICAMENT LIQUORICE MINT 2.5 mg SUGAR-FREE, lozenge sweetened with aspartame was successfully finalised on 3rd November 2009.
20100329_fr266_nicotinepfm_par
Page 6 of 6
