AstraZeneca UK Limited

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 of date of revision to 18th July 2011

Section 2

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

Section 4.4

Additional Text

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 Text

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

Additional text and change to very rare

The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole administered orally or intravenously and post-marketing when administered orally. 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).

Very rare: Hypomagnesaemia

Section 6.1

Addition of (for pH adjustment) to Sodium hydroxide

Section 9

Date of first authorisation changed to 10 March 2010

Section 10

Revision date of text: 12th May 2011

This additional information is being implemented as a result of a typographical error that has been identified.

Section 5.2
Additional sentence added at the end of the 5th paragraph. Paragraph now reads as,

"Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol/L. A smaller increase (of approx 30%) can be seen in total exposure after intravenous administration compared to oral administration. 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."

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.

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:

21^st May 2009

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:‘12^th January 2009’

Section 4.5

Effects of esomeprazole on the pharmacokinetics of other drugs

Medicinal products with pH dependent absorption

The decreased intragastric acidity during treatment with Nexium I.V.esomeprazole might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with Nexium I.Vesomeprazole.

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).

Drugs metabolised by CYP2C19
Esomeprazole inhibits CYP2C19, the major esomeprazole-metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC_t by 15% and 41%, respectively.

Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing of oral esomeprazole, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life(t_1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.

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). 

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

Effects of other drugs on the pharmacokinetics of esomeprazole
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. 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. Dose adjustment of esomeprazole is not required.