There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg esomeprazole were gastrointestinal symptoms and weakness. Single doses of 80 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialysable. Treatment should be symptomatic and general supportive measures should be utilised.
3 years
Not applicable.
Glycerol monostearate 40-55,
hyprolose,
hypromellose,
iron oxide (reddish-brown) (E 172),
iron oxide (yellow) (E 172),
magnesium stearate,
methacrylic acid ethylacrylate copolymer (I:I) dispersion 30 per cent,
cellulose microcrystalline,
synthetic paraffin,
macrogol 6000,
polysorbate 80,
crospovidone (Type A),
sodium stearyl fumarate,
sugar spheres (sucrose),
talc,
titanium dioxide (E 171),
triethyl citrate.
Summary of the safety profile
Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose-related adverse reactions have been identified.
Tabulated list of adverse reactions
The following adverse reactions have been identified or suspected in the clinical trials programme for esomeprazole and post-marketing. The reactions are classified according to MedDRA frequency convention: very common > 1/10; common >1/100 to <1/10; uncommon >1/1000 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).
|
Common |
Uncommon |
Rare |
Very rare |
Not known | |
|
Blood and lymphatic system disorders |
leukopenia, thrombocytopenia |
agranulocytosis, pancytopenia | |||
|
Immune system disorders |
hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock | ||||
|
Metabolism and nutrition disorders |
peripheral oedema |
hyponatraemia |
hypomagne-saemia; severe hypomagne-saemia can correlate with hypocalcaemia; hypomagne-saemia may also result in hypokalaemia | ||
|
Psychiatric disorders |
insomnia |
agitation, confusion, depression |
aggression, hallucinations | ||
|
Nervous system disorders |
headache |
dizziness, paraesthesia, somnolence |
taste disturbance | ||
|
Eye disorders |
blurred vision | ||||
|
Ear and labyrinth disorders |
vertigo | ||||
|
Respiratory, thoracic and mediastinal disorders |
bronchospasm | ||||
|
Gastrointestinal disorders |
abdominal pain, constipa-tion, diarrhoea, flatulence, nausea/ vomiting, fundic gland polyps (benign) |
dry mouth |
stomatitis, gastrointestinal candidiasis |
microscopic colitis | |
|
Hepatobiliary disorders |
increased liver enzymes |
hepatitis with or without jaundice |
hepatic failure, hepatic encephalopathy in patients with pre-existing liver disease | ||
|
Skin and subcutaneous tissue disorders |
dermatitis, pruritus, rash urticaria |
alopecia, photosensitivity |
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) |
Subacute cutaneous lupus erythematosus. | |
|
Musculoskeletal and connective tissue disorders |
arthralgia, myalgia |
muscular weakness | |||
|
Renal and urinary disorders |
Interstitial nephritis | ||||
|
Reproductive system and breast disorders |
gynaecomastia | ||||
|
General disorders and administration site disorders |
malaise, increased sweating |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system in the United Kingdom: Yellow Card Scheme Website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: [email protected]
In Malta: ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal
Non-clinical data reveal no particular hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and development.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.
Pharmacotherapeutic group: Drugs for acid related disorders, proton pump inhibitors,
ATC code: A02B C05.
Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.
Mechanism of action
Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase (the acid pump) and inhibits both basal and stimulated acid secretion.
Pharmacodynamic effects
After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6-7 hours after dosing on day five.
After five days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic gastroesophageal reflux disease (GERD) patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term treatment with esomeprazole.
Decreased gastric acidity due to any means including PPIs, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with PPIs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and in hospitalised patients, also possibly Clostridium difficile.
Clinical efficacy
Esomeprazole 20 mg has been demonstrated to effectively treat frequent heartburn in subjects receiving one dose per 24 hours over 2 weeks. In two multicenter, randomized, double-blind, placebo-controlled pivotal studies 234 subjects with a recent history of frequent heartburn were treated with 20 mg esomeprazole for 4 weeks. Symptoms associated with acid reflux (such as heartburn and acid regurgitation) were evaluated retrospectively over a 24 hour period. In both studies esomeprazole 20 mg was significantly better compared to placebo for the primary endpoint, complete resolution of heartburn, defined as no heartburn episodes during the last 7 days prior to the final visit (33.9% - 41.6% vs. placebo 11.9 - 13.7%, (p<0.001). The secondary endpoint of complete resolution of heartburn, defined as no heartburn on the patient's diary card for 7 consecutive days, was statistically significant at both week 1 (10.0% - 15.2% vs placebo 0.9% - 2.4%, p = 0.014, p<0.001) and week 2 (25.2% - 35.7% vs placebo 3.4% - 9.0%, p<0.001).
Other secondary endpoints were supportive of the primary endpoint, including relief of heartburn at week 1 and week 2, percentage of 24 hour days without heartburn at week 1 and week 2, mean heartburn severity at week 1 and week 2, and time to initial and sustained resolution of heartburn over a 24 hour period and during the night compared to placebo. Approximately 78% of the subjects on 20 mg esomeprazole reported first resolution of heartburn within the first week of treatment compared to 52 - 58% for placebo. Time to sustained resolution of heartburn, defined as when 7 consecutive days of no heartburn was first recorded, was significantly shorter in the esomeprazole 20 mg group (39.7% - 48.7% by day 14 vs placebo 11.0% - 20.2%). The median time to first resolution of night-time heartburn was 1 day, statistically significant compared to placebo in one study (p=0.048) and approaching significance in the other (p=0.069). About 80% of nights were heartburn free during all time periods and 90% of nights were heartburn free by week 2 of each trial, compared to 72.4 - 78.3% for placebo. The investigators' assessments of heartburn resolution were consistent with the subjects' assessments, showing statistically significant differences between esomeprazole (34.7% - 41.8%) compared to placebo (8.0% - 11.4%). The investigators also found esomeprazole to be significantly more effective than placebo in resolving acid regurgitation (58.5% - 63.6% vs placebo 28.3% - 37.4%) during the week 2 evaluation.
Following Overall Treatment Evaluation (OTE) of patients at week 2, 78.0-80.7% of patients on esomeprazole 20 mg, compared to 72.4 - 78.3% for placebo, reported their condition as improved. The majority of these rated the importance of this change to be Important to Extremely Important in performing their activities of daily living (79 - 86% at week 2).
Absorption
Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For 20 mg esomeprazole the corresponding values are 50% and 68% respectively. Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Distribution
The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% plasma protein bound.
Biotransformation
Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
Elimination
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 l/h after a single dose and about 9 l/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Linearity/non-linearity
The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg b.i.d. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC after repeated administration. This time and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.
Special patient populations
Poor metabolisers
Approximately 2.9±1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were 60% higher.
These findings have no implications for the posology of esomeprazole.
Gender
Following a single dose of 40 mg esomeprazole the mean are under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the posology of esomeprazole.
Hepatic impairment
The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
Renal impairment
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Elderly patients (>65 years old)
The metabolism of esomeprazole is not significantly changed in elderly patients (71-80 years of age).
01 November 2017
Pfizer Consumer Healthcare Ltd
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom
Do not store above 30°C
Store in the original package in order to protect from moisture.
Aluminium blister. Pack sizes of 7 and 14 tablets.
Not all pack sizes may be marketed.
EU/1/13/860/001
EU/1/13/860/002
Esomeprazole has minor influence on the ability to drive or use machines. Adverse reactions such as dizziness and visual disturbances are uncommon. If affected, patients should not drive or use machines.
No special requirements.
Date of first authorisation: 26 August 2013
