Approval of Type II variation to include information regarding AGEP and DRESS

Approval of Type II variation to include information regarding AGEP and DRESS

Marketing authorisation transferred to Grunenthal Pharma Ltd., Ireland and associated product licence number change

Marketing authorisation transferred to Grunenthal Pharma Ltd., Ireland and associated product licence number change

Removal of Malta adverse event reporting details and update to revision date

Section 7 – Marketing Authorisation Holder details updated

Section 8 – Marketing Authorisation numbers updated

Section 10 – date of revision updated

Section 4.2- Method of administration instructions updated

Section 4.8- ‘fundic gland polyps (benign)’ has been added as an Undesirable Effect

Section 6.2- Minor editorial update

Section 6.6- Minor editorial update

Section 10- Date of revision updated

Section 4.4: Additional information on PPI’s has been added under sub-section ‘Interference with laboratory tests’.

Section 5.1: Additional information on recommendation of Chromogranin A and PPI:S has been added.

Section 10: Date of revision of the text has been revised.

Change to section 4.2 – minor editorial changes to bring in line with QRD

Change to section 4.4 – Inclusion of paragraph regarding Subacute cutaneous lupus erythematosus (SCLE)

Change to section 4.8 – inclusion of the side effect SCLE

Change to section 5.2 – minor editorial changes to bring in line with QRD

Change to Section 10 – update to date of revision of text.

 Multiple changes throughout the SmPC due to updating SmPC in line with QRD template.
section 10 - updated date of revision

- Section 10 date of revision  
- Section 4.8 addition of hypokalaemia to section under Metabolism and nutrition disorders

Section 4.4 - Input of Chromogranin A

Section 4.5 - Input of pharmacokinetic (PK)/ pharmacodynamic (PD) interaction between clopidogrel and esomeprazole and interaction with Tacromilus

Section 4.8 - Renal and urinary disorders, renal failure added

Section 5.1 - More detail on interaction of Chromogranin A and tumours
Section 10 - Updated date of revision

Last revision date modified to reflect IMB issued SmPC.

Section 4.4

PhVWP wording included regarding hypomagnesaemia and risk of fracture.


Section 4.8

Frequency of hypomagnesaemia changed from “very rare” to “not known” and fracture of the hip, wrist or spine added as uncommon, as per PhVWP wording.

Section 10

Updated to 10th October 2012.

Section 4.4

Addition of information about vitamin B12 absorption.

Section 4.5

Revision of information about ‘gastric acid suppression (initial paragraph).

Addition of information under sub-heading ‘Unknown mechanism’ – related to methotrexate.

Section 4.8

Further information provided about ADR hypomagnesaemia – under ‘Metabolism and nutrition disorders’.

Addition of ADR microscopic colitis – under ‘Gastrointestinal disorders’.  

Section 5.1

Addition of information about paediatric GORD patients receiving long-term PPI treatment.

Section 10

Date of revision updated to 20^th June 2012

Section 4.5

Addition of information about about esomeprazole interaction with cilostazol.

Section 5.1

Addition of information about risk of Clostridium difficile infection in hospitalised patients.

Section 10

Date of revision changed to 11^th May 2012.

Section 4.4 - Information added re about ‘Interference with laboratory tests’

Section 4.5 - Information added about interaction with St John’s wort, rifampicin and digoxin

Section 5.1 - Information added about the increased levels of Chromogranin A

Section 4.1: New GORD Paediatric Indication

Section 4.2: New GORD Paediatric Indication posology

Section 4.5: Addition of statement to indicate that interaction studies have been performed in Adults only

Section 4.8: Details added for Paediatric population

Section 5.1: Pharmacodynamic properties updated to reflect addition of Paediatric population

Section 5.1: Pharmacokinetic properties updated to reflect addition of Paediatric population

 Section 6.5: Revision of Litres abbreviation from L to l

Section 6.6: Revision of reconstitution details

Section 10: Change to date of revision to 18th July 2011 

Nexium IV 40mg Powder for inj/inf

Section 2

Now reads as,

” Each vial contains esomeprazole 40 mg (as sodium salt).

Each vial contains <1 mmol sodium.

For a full list of excipients see section 6.1.”

Section 4.4

Additional last paragraph added, reads as,

” Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.”

Section 4.5

Additional eighth paragraph, reads as,

“In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.”

Section 4.8

Text changes to first paragraph, now reads as,

“The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and post-marketing. None was found to be dose-related. The reactions are classified according to frequency very common > 1/10; common >1/100 to <1/10; uncommon >1/1,000 to <1/100; rare >1/10,000 to <1/1,000; very rare <1/10,000; not known (cannot be estimated from the available data).”

Change to Metabolism and nutrition disorders, now reads as,

” Metabolism and nutrition disorders

Uncommon: Peripheral oedema

Rare: Hyponatraemia

Very rare: Hypomagnesaemia”


Section 6.1

Text change, now reads as,

” Disodium edetate

Sodium hydroxide (for pH adjustment)”

Section 9

Now reads as,

“Date of first authorisation: 10 March 2005

Date of latest renewal: 10 March 2010”

Section 10

25 February 2011

Section 4.1

Change to text after last bullet point:

prevention of rebleeding following therapeutic endoscopy for actue bleeding gastric or duodenal ulcers.

Section 4.2

Addition of heading:

Gastric antisecretory treatment when the oral route is not possible.

Addition of paragraph:

Prevention of rebleeding of gastric and duodenal ulcers.
Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers, 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous intravenous infusion of 8 mg/h given over 3 days (72 hours).

Change of sentence at end of section to:

The parenteral treatment period should be followed by oral acid-suppression therapy.

Addition of paragraph under heading ‘Infusion’:

80 mg bolus dose

The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.

8 mg/h dose

The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours (calculated rate of infusion of 8 mg/h. See section 6.3 for shelf-life of the reconstituted solution).

Addition of paragraph under heading ‘Impaired hepatic function’:

Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, following an initial bolus dose of 80 mg Nexium for infusion, a continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient (see section 5.2).

Section 4.4

Addition of paragraph:

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Section 4.5

Addition of paragraph:

No in vivo interaction studies have been performed with the high dose IV regimen (80 mg + 8 mg/h). The effect of esomeprazole on drugs metabolised by CYP2C19 may be more pronounced during this regimen, and patients should be monitored closely for adverse effects during the 3-day IV treatment period.

Section 4.8

Addition of side effect under ‘Skin and subcutaneous tissue disorders’:

Common: Administration site reactions*

*Administration site reactions have mainly been observed in a study with high-dose exposure over 3 days (72 hours). See section 5.3.

Deletion of paragraph:

In the non-clinical program for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted.  The non-clinical findings somewhat indicated that the clinical tissue irritation was concentration related.

Section 4.9

Change of sentence to:

Single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg esomeprazole over 24 hours were uneventful.

Section 5.1

Addition of paragraph:

During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours and 11-13 hours, respectively, over 24 hours in healthy subjects.

Addition of paragraph:

In a randomised, double blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterised as Forrest Ia, Ib, IIa or IIb (9%, 43%, 38% and 10% respectively) were randomised to receive Nexium solution for infusion (n=375) or placebo (n=389). Following endoscopic haemostasis, patients received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hours. After the initial 72 hour period, all patients received open-label 40 mg oral Nexium for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the Nexium treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the Nexium treated versus the placebo treated group was 7.7% vs 13.6%

Section 5.2

Addition of paragraph:

There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) over 23.5 hours.

Change of percentage under ‘Special Patient Populations’ to:

Approximately 2.9 ±1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers.

Addition of text in penultimate paragraph:

For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient.

Section 5.3

Addition of text at end of section:

In the non-clinical program for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted. See section 4.8.

Section 6.6

Addition of paragraph at end of section:

Infusion 80 mg

A solution for infusion is prepared by dissolving the content of two vials of esomeprazole 40 mg in up to 100 ml of 0.9% sodium chloride for intravenous use.

Section 10:

Change of date:

Section 4.4

Addition of paragraph 6:

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Section 5.1

Addition of paragraph 4 under heading Other effects related to acid inhibition:

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter

Section 5.2

Change of text in paragraph 3 under heading Special patient populations to:

Approximately 2.9 1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers.

Section 10

Change of date:

Section 4.5

Following new sub heading added to 1^st paragraph:

Medicinal products with pH dependent absorption

Also in 1^st paragraph Nexium IV changed to esomeprazole

Following new text added as 2^nd paragraph:

Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, C_max and C_min). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. PPIs including esomeprazole should not be co-administered with atazanavir (see section 4.3).

Following new sub heading added to 3rd paragraph:

Drugs metabolised by CYP2C19

And following new sentence added to end of paragraph 3: Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC_t by 15% and 41%, respectively.

Following text deleted 6^th paragraph:

Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. PPIs, including esomeprazole, should not be co-administered with atazanavir (see section 4.3). 

Following new text added to last paragraph in section 4.5:

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC_t  by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Also following last sentence deleted:

Dose adjustment of esomeprazole is not required.

Section 10

Date changed to 30^th July 2007

Section 4.1

The following sentence was removed: “Nexium for injection and infusion is indicated as an alternative to oral therapy when oral intake is not appropriate.” And replaced with the following new text: “Nexium for injection and infusion is indicated for gastric antisecretory treatment when the oral route is not possible, such as:”

Also the word “for” was deleted from the beginning of each bullet point.

Section 4.5

End of paragraph 3 the text “Concomitant treatment” was deleted and replaced with: “Concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives”

Section 10