Public Assessment Report Scientific discussion Esomeprazol “Krka ...

Public Assessment Report 

Scientific discussion 

Esomeprazol “Krka” 

20 mg and 40 mg gastro-resistant capsules, hard 

Esomeprazole magnesium dihydrate 

DK/H/1725/001-002/DC 

This module reflects the scientific discussion for the approval of Esomeprazol “Krka”. The 

procedure was finalised on 20 January 2010. For information on changes after this date please 

refer to the module ‘Update’. 

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I. INTRODUCTION 

Based on the review of the quality, safety and efficacy data, the Member States have granted a 

marketing authorisation for Esomeprazol “Krka” 20 mg and 40 mg gastro-resistant capsules, hard, 

from krka. The date of authorisation in Denmark was on 19 February 2010. The product is indicated 

for: 

• Gastroesophageal Reflux Disease (GERD): 

- Treatment of erosive reflux esophagitis. 

- Long-term management of patients with healed esophagitis to prevent relapse. 

- Symptomatic treatment of gastroesophageal reflux disease (GERD). 

• In combination with appropriate antibacterial therapeutic regimens for the eradication of 

Helicobacter pylori: 

- Healing of Helicobacter pylori associated duodenal ulcer. 

- Prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers. 

• Patients requiring continued NSAID therapy: 

- Healing of gastric ulcers associated with NSAID therapy. 

- Prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk. 

• Prolonged treatment after i.v. induced prevention of rebleeding of peptic ulcers. 

• Treatment of Zollinger Ellison Syndrome. 

The weak base esomeprazole is the S-isomer of omeprazole and is concentrated and converted to the 

active form in the highly acidic environment of the secretory canaliculi of the parietal cell. The 

antisecretory substituted benzimidazole acts as a proton pump inhibitor capable of reducing both the 

basal and stimulated gastric acid secretion by suppressing H+ ion formation by specific inhibition of 

the gastric enzyme system proton pump (H+/K+-ATPase) at the secretory surface of the gastric parietal 

cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity. 

This decentralised procedure concerns a generic application claiming essential similarity with the 

reference product Nexium 20 mg and 40 mg gastro-resistant tablets, which has been registered in 

Sweden by AstraZeneca AB since 2000. 

The reference product marketed in Denmark is Nexium 20 mg and 40 mg gastro-resistant tablets, 

marketed by AstraZeneca A/S since 2000. 

The reference product used for BE studies is Nexium Mups 20 mg and 40 mg gastro-resistant tablets, 

AstraZeneca GmbH, marketed in Germany. 

The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC. 

II. QUALITY ASPECTS 

II.1 Introduction 

Esomeprazol “Krka” 20 mg and 40 mg gastro-resistant capsules, hard contains as active substance 

20 mg esomeprazole (as magnesium dihydrate) and 40 mg esomeprazole (as magnesium dihydrate), 

respectively. 

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The body and the cap of the 20 mg capsules are slightly pink. The content of the 20 mg capsules are 

white to almost white pellets. 

The body and the cap of the 40 mg capsules are off-pink. The content of the 40 mg capsules are white 

to almost white pellets. 

Esomeprazol “Krka” is packed in blister packs (OPA-Al-PE + dessicant/Al + PE foil) in pack sizes of 

7, 14, 15, 28, 30, 50, 56, 60, 90, 98 and 100 gastro-resistant capsules, hard, in a box, and in HDPE 

tablet containers with PP closure with desiccant in pack sizes of 98 gastro-resistant capsules, hard, in a 

box. 

However, not all pack sizes may be marketed. 

The excipients in the capsule core (pellets) are: Sucrose; maize starch, povidone K30; sodium 

laurilsulfate; poly(vinyl alcohol); titanium dioxide (E171); macrogol 3000; macrogol 6000, talc; heavy 

magnesium carbonate; methacrylic acid – ethyl acrylate copolymer (1:1), dispersion 30%; and 

polysorbate 80 

The capsule shell consists of: Gelatin; titanium dioxide (E171); and red iron oxide (E172). 

Compliance with Good Manufacturing Practice 

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 esomeprazole magnesium dihydrate is not described in the European 

Pharmacopoeia; however there is an EP monograph on esomeprazole magnesium trihydrate. 

INN: Esomeprazole 

Chemical names: 

5-Methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole 

magnesium dihydrate 

5-Methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole 

magnesium salt (2:1), dihydrate 

bis(5-Methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1Hbenzimidazole-1-yl) 

magnesium dihydrate 

Magnesium bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1Hbenzimidazol-1-ide] 

dihydrate 

Other non-proprietary name: Esomeprazole magnesium dihydrate 

Molecular formula: C34H36MgN6O6S2 . 2 H2O 

Molecular mass: 749.15 g/mol 

Esomeprazole is a white to slightly coloured powder, which is slightly soluble in water, soluble in 

methanol and practically insoluble in heptane. 

Esomeprazole is the S-isomer of omeprazole with a chiral center at the sulphur. 

The documentation on the active substance is presented as a European Drug Master File in CTD 

format and satisfactory letters of access are provided. 

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The chemical-pharmaceutical documentation in relation to esomeprazole magnesium dihydrate is of 

sufficient quality in view of the present European regulatory requirements. 

The control tests and specifications for drug substance product are adequately drawn up. 

Stability studies have been performed on pilot scale batches of the drug substance. No significant 

changes in any parameters were observed. A suitable retest period has been set. 

II.3 Medicinal Product 

The product composition is adequately described. The development of the product has been 

satisfactorily performed and explained. The excipients used are commonly employed. The packaging 

materials are adequately described. 

Manufacture of gastro-resistant capsules is a non-standard process. Satisfactorily manufacturing 

process validation has been carried out on production scale batches of pellets and encapsulated 

product. Further data will be performed post-approval. 

The product specifications cover all appropriate parameters for this dosage form. Satisfactory 

validations of the analytical methods have been presented. Batch analysis has been performed on 6 

pilot batches; 3 of each strength. The batch analysis results show that the finished products meet the 

proposed specifications. 

Stability data covering up to 12 months data are provided for pilot scale batches stored in the proposed 

market packagings. The conditions used in the stability studies are according to the ICH stability 

guideline. The control tests and specifications for drug product are adequately drawn up. 

Based on the data submitted, a shelf-life of 2 years has been accepted for both strengths with the 

following storage conditions: 

Blister packs: Store in the original package in order to protect from moisture. 

Tablet containers: Keep the container tightly closed in order to protect from moisture. 

III. NON-CLINICAL ASPECTS 

This product is a generic formulation of Nexium gastro-resistant tablets, which is available on the 

European market. No new preclinical data have been submitted, and therefore the application has not 

undergone preclinical assessment. This is acceptable for this type of application 

Environmental risk assessment 

The product is intended as a substitute for other identical products on the market. The approval of this 

product will not result in an increase in the total quantity of esomeprazole released into the 

environment. It does not contain any component, which results in an additional hazard to the 

environment during storage, distribution, use and disposal. 

IV. CLINICAL ASPECTS 

IV.1 Introduction 

Esomeprazole is a well-known active substance with established efficacy and tolerability. 

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For this generic application, the MAH has submitted 3 bioequivalence studies in which the 

pharmacokinetic profile of the test product Esomeprazol “Krka” gastro-resistant capsules, hard is 

compared with the pharmacokinetic profile of the reference product Nexium Mups gastro-resistant 

tablets, AstraZeneca GmbH, marketed in Germany: 

• Single-dose study under fasting and fed conditions with the 40 mg strength 

• Single-dose study under fasting conditions with the 20 mg strength 

• Multiple-dose study under fasting conditions with the 40 mg strength 

Single-dose study under fasting and fed conditions – 40 mg 

The study was a single dose, randomized, three-way crossover bioavailability study conducted under 

fasting and fed conditions with a wash out period of 7 days between administrations. 40 mg was 

administered in each period. 

Fasting group: Blood samples were collected pre-dosing and at 0.50, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 

2.25, 2.5, 2.75, 3, 3.5, 4.0, 4.5, 5, 6, 8, 10, 12 hours post administration of a single-dose 40 mg gastroresistant 

capsule or tablet with 240 ml of water for the analyses of esomeprazole in plasma. 

Fed group: Blood samples were collected pre-dosing and at 0.50, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4, 4.5, 5, 

5.5, 6, 6.5, 7, 7.5, 8, 10, 12, 14 hours post administration of a single-dose 40 mg gastro-resistant 

capsule or tablet with 240 ml of water for the analyses of esomeprazole in plasma. 

54 healthy Caucasian male subjects (18-55 years) participated in the study. 54 subjects completed the 

study. 1 to18 participated under fasting conditions and 19 to 54 under fed conditions. 

Drop-outs: 1 was excluded before the first dosing due to cigarette smoking. The subject was replaced 

by one of the reserve. 

Bioequivalence was concluded if the 90% geometric confidence intervals of the test/reference ratio of 

least-squares means for ln-transformed AUC0-∞, AUC0-t and Cmax were within the acceptable range of 

80-125%. 

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median 

range)) of esomeprazole under fasting conditions. 

Treatment 

(40 mg) 

N=18 

Test 

Reference 

*Ratio (90% 

CI) 

CV (%) 

AUC0-t 

ng.h/ml 

AUC0-∞ 

ng.h/ml 

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Cmax 

ng/ml 

tmax 

2601.4±1440.7 2619.6±1462.8 1144.0±485.9 2.00 

(1.25-5.00) 

2469.8±1283.2 2483.4±1296.6 1055.8±404.9 2.25 

(1.25-3.00) 

103.66 103.75 107.15 

(94.89-113.24) (94.96-113.35) (97.90-117.28) 

15.3 15.3 15.6 

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity 

AUC0-t area under the plasma concentration-time curve from time zero to t hours 

Cmax maximum plasma concentration 

tmax time for maximum concentration 

t1/2 half-life 

*ln-transformed values 

h 

t1/2 

h 

1.12±0.36 

1.09±0.31 

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, 

range)) of esomeprazole under fed conditions. 

Treatment 

(40 mg) 

AUC0-t 

ng.h/ml 

AUC0-∞ 

ng.h/ml 

Cmax 

ng/ml 

tmax 

h 

t1/2 

h

N=36 

Test 

Reference 

*Ratio (90% 

CI) 

CV (%) 

1954.5±1273.4 1990.9±1302.8 674.7±394.2 5.50 

(2.50-7.50) 

2114.1±1458.3 2134.1±1484.3 698.9±366.7 4.50 

(1.00-6.00) 

94.85 95.79 91.73 

(86.45-104.07) (87.51-104.86) (81.37-103.41) 

23.6 23.0 30.8 







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1.27±0.48 

1.13±0.44 

Single-dose study under fasting conditions – 20 mg 

The study was a randomized, two-period, two-sequence, two-way crossover, single-dose 

bioavailability study conducted under fasting conditions with a wash out period of 7 days between the 

two administrations. 20 mg was administered in each period. 

Blood samples were collected pre-dosing and at 0.50, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3, 

3.5, 4.0, 4.5, 5, 6, 8, 10, 12 hours post administration of a single-dose 20 mg gastro-resistant capsule or 

tablet with 240 ml of water for the analyses of esomeprazole in plasma. 


study. 

Drop-outs: 1 was withdrawn due to illness during the wash-out period. 

The decision about bioequivalence between the test formulation vs. the reference formulation was 

based on the calculated 90% confidence intervals of Cmax, AUC0-t and AUC0-∞ pharmacokinetic 

parameters of esomeprazole, which should be within 80-125% acceptance range. 


range)) of esomeprazole under fasting conditions. 

Treatment 

(20 mg) 

N=35 

Test 

Reference 

*Ratio (90% 

CI) 

CV (%) 

AUC0-t 

ng.h/ml 

AUC0-∞ 

ng.h/ml 

Cmax 

ng/ml 

tmax 

1027.1±612.0 1037.1±621.5 531.5±169.4 1.75 

(1.00-3.50) 

1042.0±629.9 1052.0±641.5 560.3±184.6 1.25 

(0.75-2.50) 

98.62 98.64 94.86 

(92.81-104.79) (92.87-104.77) (87.30-103.08) 

15.1 15.0 20.8 







Steady-state study conducted under fasting conditions – 40 mg 

h 

t1/2 

h 

0.96±0.38 

0.97±0.37

The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way 

crossover, multiple dose bioavailability study (one daily dosage for 7 consecutive days) conducted 

under fasting conditions with no a wash out period between the two administrations phases. 40 mg 

was administered daily in each period. 

Blood samples were collected pre-dosing on days 1, 5, 6, 7, 12, 13, and 14 and at 0.50, 0.75, 1.00, 

1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.0, 12.0 and 24.0 

hours post administration on days 7 and 14 of a single-dose daily of 40 mg capsules with 240 ml of 

water for the analyses of esomeprazole. 


study. 

Bioequivalence was concluded if the 90% intervals of the ratios of LSM derived from analysis on the 

ln-transformed PK parameters AUC0-t, AUCinf and Cmax for esomeprazole in plasma were within the 

80-125% acceptance range. 


range)) of esomeprazole under fasting conditions in steady state. 

Treatment 

(40 mg) 

N=36 

Test 

Reference 

*Ratio (90% 

CI) 

CV (%) 

AUC0-t 

ng.h/ml 

AUC0-∞ 

ng.h/ml 

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Cmax 

ng/ml 

tmax 

4280.2±1492.6 4325.1±1537.2 1649.6±447.6 1.75 

(1.00-3.50) 

4337.8±1451.8 4389.0±1492.3 1484.9±305.5 1.75 

(0.75-3.00) 

98.43 98.27 109.61 

(94.52-102.51) (94.39-102.32) (102.92- 

116.73) 

10.2 10.1 15.9 







h 

t1/2 

h 

1.48±0.46 

1.48±0.42 

The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are within the bioequivalence 

acceptance range of 0.80 – 1.25. 

Based on the submitted bioequivalence studies Esomeprazol “Krka” gastro-resistant capsules, hard are 

considered bioequivalent with Nexium Mups gastro-resistant tablets by AstraZeneca under fed and 

fasting conditions. 

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.2 Risk management plan & Pharmacovigilance system 

Esomeprazole was first approved in 2000, and there is now extensive experience with the active 

substance. The safety profile of esomeprazole can be considered to be well established and no product 

specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately 

covered by the current SPC. Additional risk minimisation activities have not been identified for the

eference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is 

based on the current European legislation. 

The Pharmacovigilance system described fulfils the requirements and provides adequate evidence that 

the applicant has the services of a qualified person responsible for pharmacovigilance and has the 

necessary means for the identification and notification of any a potential risks occurring either in the 

Community or in a third country. 

V. PRODUCT INFORMATION 

SmPC and Package leaflet 

The content of the SmPC and package leaflet approved during the decentralised procedure is in 

accordance with that accepted for the reference product Nexium marketed by AstraZeneca. 

Readability test 

The package leaflet has been evaluated via a user consultation study in accordance with the 

requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose 

of user testing the package leaflet was English. The test consisted of a pilot test with 2 participants, 

followed by two rounds with 10 participants each. The questions covered the following areas 

sufficiently: traceability, comprehensibility and applicability. The readability test has been sufficiently 

performed. 

The results show that the package leaflet meets the criteria for readability as set out in the Guideline 

on the readability of the label and package leaflet of medicinal products for human use. 

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND 

RECOMMENDATION 

Esomeprazol “Krka” 20 mg and 40 mg gastro-resistant capsules, hard has a proven chemicalpharmaceutical 

quality and is a generic form of Nexium gastro-resistant tablets. Nexium is a wellknown 

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. 

The MAH has provided written confirmation that systems and services are in place to ensure 

compliance with their pharmacovigilance obligations. 

The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other 

esomeprazole containing products. 

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 has been demonstrated for Esomeprazol “Krka” with the reference product, and 

have therefore granted a marketing authorisation. The decentralised procedure was finished on 20 

January 2010. Esomeprazol “Krka” was authorised in Denmark on 19 February 2010. 

A European harmonised birth date has been allocated (2000-03-10) and subsequently the first data 

lock point for esomeprazole is 2006-03. The first PSUR will be submitted with the DLP of 2011-03, 

after which the PSUR submission cycle is 3 years. 

The date for the first renewal will be: 20 January 2015. 

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The following post-approval commitments have been made during the procedure: 

• The sampling point (45 minutes) for dissolution at pH 6.8 in the finished product specifications 

should be reviewed when more experience is gained from data collected after 30 minutes. 

• The enclosed stability studies for both active substance (2 years) and finished products (2 years) 

will be continued. Results from these studies will be submitted to the RMS and CMS when 

finalised. 

• The certificates for the third production batch of each strength (20 mg and 40 mg) will be added 

as soon as the batch is manufactured. 

• Third production scale batch of maximum batch size (pellets and capsules) will be validated 

when manufactured. 

• The first 3 production batches of each strength will be put on stability and tested according to 

the stability protocol as presented in section P.8.1. 

• Updated pages of module 3.2.S.2.3 in the Restricted part of the EDMF should be provided no 

later than 1 April 2010. 

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Public Assessment Report Scientific discussion Esomeprazol “Krka ...

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