Public Assessment Report
Scientific discussion
Lansopram
15 mg and 30 mg hard gastro-resistant capsules
(Lansoprazole)
DK/H/2235/001-002/DC
22 February 2016
This module reflects the scientific discussion for the approval of Lansopram. The procedure was
finalised on 1 October 2013. 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 Lansopram 15 mg and 30 mg hard gastro-resistant capsules, from Amneal Pharma
Europe Limited.
The product is indicated for:
Treatment of duodenal and gastric ulcer
Treatment of reflux oesophagitis
Prophylaxis of reflux oesophagitis
Eradication of Helicobacter pylori (H. pylori) concurrently given with appropriateantibiotic
therapy for treatment of H.pylori-associated ulcers
Treatment of NSAID-associated benign gastric and duodenal ulcers in patients requiring
continued NSAID treatment
Prophylaxis of NSAID-associated gastric ulcers and duodenal ulcers in patients at risk (see
section 4.2) requiring continued therapy
Symptomatic gastroesophageal reflux disease
Zollinger-Ellison syndrome.
A comprehensive description of the indications and posology is given in the SmPC.
Lansoprazole is a gastric proton pump inhibitor. It inhibits the final stage of gastric acid formation by
inhibiting the activity of H+/K+ ATPase of the parietal cells in the stomach. The inhibition is
dosedependent and reversible, and the effect applies to both basal and stimulated secretion of gastric
acid.
Lansoprazole is concentrated in the parietal cells and becomes active in their acidic environment,
whereupon it reacts with the sulphydryl group of H+/K+ATPase causing inhibition of the enzyme
activity.
This decentralised procedure concerns a generic application claiming essential similarity with the
reference product Lanzo 15 mg and 30 mg gastro-resistant capsules, which has been registered in
Denmark by Wyeth AB from 1996/1994, respectively, to 2008.
The marketing authorisation is granted based on article 10(1) of Directive 2001/83/EC.
II. QUALITY ASPECTS
II.1 Introduction
Each capsule contains 15 mg or 30 mg of lansoprazole.
The 15 mg hard gastro-resistant capsules are opaque yellow cap and body capsules. Each capsule
contains white or almost white spherical microgranules.
The 30 mg hard gastro-resistant capsules are opaque white cap and body capsules. Each capsule contains
white or almost white spherical microgranules.
The capsules are packed in peelable OPA- Al-PVC/Alu blisters and innon-peelable OPA- Al-PVC/Alu
blisters in pack sizes of 14, 28, 30, 56, 84, 98 and 100 capsules and in HDPE bottles with PP screw caps
containing silica desiccant in pack sizes of 14, 28, 30, 56, 84, 98 and 100 capsules. However, not all
pack sizes may be marketed.
The capsules contain: Sugar spheres (sucrose and maize starch); Sodium laurilsulphate; Meglumine
Mannitol (E421); Hypromellose 6.0 Cp; Macrogol 6000; Talc; Polysorbate 80; Titanium dioxide (E171)
and Methacrylic Acid-Ethyl Acrylate Copolymer, 1:1, Dispersion 30%.
The capsule shell contains: Gelatin; Titanium dioxide (E171) and Quinoline yellow (E104) (15 mg
only).
The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place
for this product type at all sites responsible for the manufacturing of the active substance as well as for
the manufacturing and assembly of this product prior to granting its national authorisation.
II.2 Drug Substance
The active substance is lansoprazole.
Chemical name: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-enzimidazole
Molecular formula: C16H14F3N3O2S
Molecular weight: 369.3 g/mol
Molecular formula:
Lansoprazole is a racemic mixture of two optical isomers. This isomerism is due to the asymmetrical
sulphur atom of the sulfoxide group.
The documentation on the active substance lansoprazole is provided as a CEP. The Applicant’s compiled
active substance specification is presented and contains, in addition to the specifications given by the
Ph. Eur. monograph for lansoprazole, a test for particle size.
The active substance shows polymorphism and the ID test included in applicant’s active substance is
able to distinguish the two different forms.
Re-test period and storage conditions are included in the CEP.
II.3 Medicinal Product
The development of the product has been described, the choice of excipients is justified and their
functions explained. Development of the dissolution method has been described and the use of
surfactants been justified. The discriminatory properties of the dissolution method have been
demonstrated.
The product consists of hard gelatine capsules filled with sugar spheres coated with a suspension of the
active substance and then with an acid resistant polymer. The two strengths are manufactured from the
same granules with the fill weight determining the strength. Process validation data are presented for
production granule batch sizes. In addition, process validation data are provided for the filling of 10 %
of the maximum batch size. Stability data supporting bulk holding times of 12 months for the granules
and of 12 months for the capsules have been provided. Storage of bulk is at 25C/60% RH using food
grade LDPE bags with desiccant.
The product specifications cover appropriate parameters for this dosage form. Validation data for the
analytical methods has been presented. Batch analysis has been performed on several batches. The batch
analysis results show that the finished products meet the specifications proposed. The proposed
specification limits for two impurities, impurity E and bezopral caboxylate isomer, have been tightened
to the qualification threshold of NMT 0.2 % since they are not considered toxicologically qualified at
the initially proposed limits of NMT 0.4 %. Batch and stability data demonstrates that the finished
product complies with these limits throughout the proposed shelf-lives.
The conditions used in the stability studies are according to the ICH stability guideline; using a worst
case scenario bracketing approach to support the packaging materials and pack sizes applied for. The
control tests and specifications for drug product are adequately drawn up, and specification limits for
dissolution have been tightened in order to reflect the performance of the product.
In-use stability data supporting 6 months in-use stability for the HDPE bottle have been provided.
The following shelf-lives are accepted:
OPA-Al-PVC/Al blister: 3 years/do not store above 30 C, store in the original container in order to
protect from moisture.
HDPE bottle with PP screw cap containing silica desiccant: 4 years/do not store above 30°C, store in
the original container in order to protect from moisture, keep the bottle tightly closed in order to protect
from moisture. Use within 6 months after opening.
III. NON-CLINICAL ASPECTS
III.1 Introduction
Pharmacodynamic, pharmacokinetic and toxicological properties of lansoprazole are well known. As
lansoprazole is a widely used, well-known active substance, the MAH has not provided additional
studies and further studies are not required. Overview based on literature review is, thus, appropriate.
The non-clinical overview report refers 27 publications up to year 2010. The non-clinical overview on
the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
III.2 Ecotoxicity/environmental risk assessment (ERA)
Since lansoprazole 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
IV.1 Introduction
Lansoprazole is a well-known active substance with established efficacy and tolerability. As
lansoprazole is a widely used, well-known active substance, the MAH has not provided additional
studies (apart from supportive bioequivalence studies referenced below) and further studies are not
required. Overview based on literature review is, thus, appropriate.
The clinical report refers 56 publications up to year 2011. The clinical overview on the clinical
pharmacology, efficacy and safety is adequate.
IV.2 Pharmacokinetics
To support the application, the MAH has submitted as report two bioequivalence studies, where the 30
mg formulation strength has been compared with the same strength of the reference product under
fasting and fed conditions.
Biowaiver
The MAH applied for a waiver of the 15 mg strength capsules. A justification according to EU guideline
on investigation of bioequivalence was provided.
The following regulatory requirements are fulfilled:
a) The pharmaceutical products are manufactured by the same manufacturing process.
b) The qualitative pellet composition of the different strengths is the same.
c) The composition of the strengths are quantitatively proportional
d) Appropriate in vitro dissolution data confirms the adequacy of waiving the 15 mg strength.
Bioequivalence study
30 mg study – fed conditions
The study was an open-label, randomized, two treatments two-period, two-way crossover, single-dose
bioavailability study conducted under fed conditions in male and females with a wash out period of 7
days between the two administrations. 30 mg was administered in each period.
The test product was compared to Opiren 30 mg capsules by Almirall Prodesfarm, Spain, from the
Spanish market.
36 healthy male/female subjects participated in the study. 35 subjects completed the study.
The primary variables for the evaluation of bioequivalence were AUC0-t and Cmax.
90% standard confidence interval for ln-transformed AUC(0-inf), AUC(0-t) and Cmax should be within
80.00% to 125.00% in order for bioequivalence to be concluded.
Results
Table 1. Mean values of lansoprazole primary pharmacokinetic parameters
Table 2. Summary of the statistical analysis of the lansoprazole pharmacokinetic parameters
The mean bioequivalence ratio (T/R) for Cmax, AUC0-t and AUC0-t were 0.95301, 1.01445 and 1.01296,
respectively. The calculated 90% confidence intervals of the ratio of the means for the primary
pharmacokinetic parameters are within the accepted range of 80-125%.
30 mg study – fasting conditions
The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way
crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period
of 7 days between the two administrations. 30 mg was administered in each period.
The test product was compared to Prezal 30 mg capsules, Aventis Pharma B.V., NL.
40 healthy male/female subjects participated in the study. Thirty nine subjects completed the study.
The primary variables for the evaluation of bioequivalence were AUC0-t and Cmax.
90% standard confidence interval for ln-transformed AUC(0-inf), AUC(0-t) and Cmax should be within
80.00% to 125.00% in order for bioequivalence to be concluded.
Results
Table 3. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range)
The 90% confidence intervals for lansoprazole mean test/reference ratios were:
The 90% confidence interval for the ratio between test and reference were within the acceptance criteria
80.00 – 125.00% for AUC0-∞, AUC0-t and Cmax for the test product.
Pharmacokinetic conclusion
Based on the submitted bioequivalence studies, Lansopram 30 mg hard gastro-resistant capsules is
considered bioequivalent with the reference product.
The results of the studies with the 30 mg formulation can be extrapolated to other strengths 15 mg,
according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98
Rev. 1/Corr*, section 4.1.6.
The RMS has been assured that the bioequivalence study has been conducted in accordance with
acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory
Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).
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 Lansopram.
The following summary list of safety concerns with no additional pharmacovigilance measures or risk
minimisation measures has been agreed:
Table 4. Summary table of safety concerns as approved in RMP
V. USER CONSULTATION
A user consultation with target patient groups on the package information leaflet (PIL) has been
performed on the basis of a bridging report making reference to Lansoprazol “Medical Valley”,
DK/H/1910/001-002/DC. The bridging report submitted by the MAH has been found acceptable.
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Lansopram 15 mg and 30 mg hard gastro-resistant capsules, has a proven chemical-pharmaceutical
quality and is a generic form of Lanzo. Lanzo is a well-known medicinal product with an established
favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
Agreement between Member States was reached during a written procedure. There was no discussion
in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that
essential similarity was demonstrated for Lansopram with the reference product, and therefore granted
a marketing authorisation. The decentralised procedure was finalised on 1 October 2013. Lansopram
was authorised in Denmark on 31 January 2014.
PSURs should be submitted in accordance with the requirements set out in the list of Union reference
dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and published on the
European medicines web-portal. According to the EURD list, no routine PSURs need to be submitted.
The date for the first renewal will be: 1 October 2018.
There were no post-approval commitments made during the procedure.
Public Assessment Report
Update
Lansopram
15 mg and 30 mg hard gastro-resistant capsules
(Lansoprazole)
This module reflects the procedural steps and scientific information after the finalisation of the
initial procedure.
Scope Procedure number Product Date of start of the Date of end of Approval/ non approval Assessment report
Information procedure procedure attached
affected
Repeat use with CZ,
PL, RO, SE, SK DK/H/2235/001-002/E/001 N 8 May 2014 5 August 2014 Approval Y, Annex 1
ANNEX 1 – Repeat use procedure (DK/H/2235/001-002/E/001)
The repeat use procedure started on 8 May 2014. There was no discussion in the CMD(h). Agreement
between member states was reached during a written procedure. The concerned member states CZ, PL,
RO, SE and SK on the basis of the data submitted, considered that essential similarity had been
demonstrated for Lansopram 15 mg and 30 mg hard gastro-resistant capsules with the reference product,
and therefore granted a marketing authorisation. The repeat use procedure was finalised on 5 August
2014.
The MAH provided an updated dossier. No variations were filed prior to the repeat use procedure.
The date for the first renewal will be: 1 October 2018.
Commitments made during the repeat use procedure:
A variation to update the CEP to the current one.
E-number for Titanium Dioxide will be include in connection with other changes to this specific
section (3.2.P.1. Description and composition of the medical product).
The heading of section 4.6 ‘Fertility, pregnancy and lactation’, in order to be in line with the
Guideline on SmPC, will be update as soon as other change related to product information takes
place.
