Esomeprazole 40 Mg Gastro-Resistant Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Esomeprazole 40 mg gastro-resistant tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each gastro-resistant tablet contains 20 mg esomeprazole (as magnesium dihydrate). For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Gastro-resistant tablet
40mg: A pink, oblong, biconvex, film-coated tablet, with “40” engraved on one side and dimensions of approximately 17.2 x 8.7 mm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
Esomeprazole tablets are indicated for:
Gastro-oesophageal Reflux Disease (GORD):
-Treatment of erosive reflux oesophagitis
-Long-term management of patients with healed oesophagitis to prevent relapse -Symptomatic treatment of gastro-oesophageal reflux disease (GORD)
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.
Adolescents from the age of 12 years Gastro-oesophageal Reflux Disease (GORD)
- treatment of erosive reflux oesophagitis
- long-term management of patients with healed oesophagitis to prevent relapse
- symptomatic treatment of gastro-oesophageal reflux disease (GORD)
In combination with antibiotics in treatment of duodenal ulcer caused by Helicobacter pylori
4.2 Posology and method of administration
The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.
For patients who have difficulty in swallowing the tablets can also be dispersed in half a glass of non-carbonated water. No other liquids should be used as the enteric coat may be dissolved. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
For patients who cannot swallow, the tablets can be dispersed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested. For preparation and administration instructions see section 6.6.
Adults and adolescents from the age of 12 years:
Gastro-oesophageal Reflux Disease (GORD):
- Treatment of erosive reflux oesophagitis
40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms.
Long-term management of patients with healed esophagitis to prevent relapse 20 mg once daily.
- Symptomatic treatment of gastro-oesophageal reflux disease (GORD)
20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily. In adults, an on demand regimen taking 20 mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on demand regimen is not recommended.
Adults:
In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori:
- Healing of Helicobacter pylori associated duodenal ulcer
- Prevention of relapse ofpeptic ulcers in patients with Helicobacter pylori associated ulcers
20 mg Esomeprazole with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
Patients requiring continued NSAID therapy
- Healing of gastric ulcers associated with NSAID therapy:
The usual dose is 20 mg once daily. The treatment duration is 4-8 weeks.
- Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk:
20 mg once daily.
Prolonged treatment after i.v. induced prevention of rebleeding of peptic ulcers.
40 mg once daily for 4 weeks after i.v. induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger Ellison Syndrome
The recommended initial dosage is 40 mg Esomeprazole twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80 to 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.
Adolescents from the age of 12 years
Treatment of duodenal ulcer caused by Helicobacter pylori
When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents. The treatment should be supervised by a specialist.
The posology recommendation is:
|
Weight |
Posology |
|
30 - 40 kg |
Combination with two antibiotics: Esomeprazole 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered together twice daily for one week. |
|
> 40 kg |
Combination with two antibiotics: Esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered together twice daily for one week. |
Children below the age of 12 years
This medicinal product should not be used in children younger than 12 years since no data is available.
Impaired renal function
Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section 5.2).
Impaired hepatic function
Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg Esomeprazole should not be exceeded (see section 5.2).
Elderly
Dose adjustment is not required in the elderly.
4.3 Contraindications
Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients listed in section 6.1.
Esomeprazole should not be administered with nelfinavir (see section 4.5).
4.4 Special warnings and precautions for use
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with this medicinal product may alleviate symptoms and delay diagnosis.
Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 1040%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with PPIs like esomeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered(See section
4.5) .
When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).
Co-administration of esomeprazole with atazanavir is not recommended (see section
4.5) . If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.
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.
Interference with laboratory tests
Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be temporarily stopped for at least five days before CgA measurements.
Esomeprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy.
4.5 Interaction with other medicinal products and other forms of interaction Effects of esomeprazole on the pharmacokinetics of other drugs
Medicinal products with pH dependent absorption
The decreased intragastric acidity during treatment with 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 and the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.
Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. 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. The co-administration of omeprazole (20 mg qd) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36-39 % and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%. For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.
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. This should be considered especially when prescribing esomeprazole for on demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg esomeprazole 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) Cmax and AUCr by 15% and 41%, respectively.
Concomitant 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, 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 administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life(t^) 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 (see also section 4.4).
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin, quinidine.
Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.
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.
Effects of other drugs on the pharmacokinetics of esomeprazole
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant 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 AUCr 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.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John’s wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.
4.6 Fertility, Pregnancy and lactation
For esomeprazole, clinical data on exposed pregnancies are insufficient. With the racemic mixture, omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.
It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore this medicinal product should not be used during breast-feeding.
4.7 Effects on ability to drive and use machines
No effects have been observed.
4.8 Undesirable effects
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)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
Common |
Uncommon |
Rare |
Very rare |
Not Know | |
|
Blood and lymphatic system disorders |
Leukopenia, thrombocytopenia |
Agranulocytosis, pancytopenia | |||
|
Immune system disorders |
Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock |
Hypomagnesaemia [See Special warnings and precautions for use (4.4)] severe hypomagnesaemia can correlate with hypocalcaemia | |||
|
Metabolism and nutrition disorders |
Peripheral oedema |
Hyponatraemia | |||
|
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, constipation, diarrhoea, flatulence, nausea/vomiting |
Dry mouth |
Stomatitis, gastrointestinal candidiasis | ||
|
Hepatobiliary disorders |
Increased liver enzymes |
Hepatitis with or without jaundice |
Hepatic failure, encephalopathy in patients with preexisting liver disease | ||
|
Skin and subcutaneous tissue disorders |
Dermatitis, pruritus, rash, urticaria |
Alopecia, photosensitivity |
Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) | ||
|
Musculoskeletal and connective tissue disorders |
Fracture of the hip, wrist or spine (see section 4.4) |
Arthralgia, myalgia |
Muscular weakness |
|
Renal and urinary disorders |
Interstitial nephritis | ||||
|
Reproductive system and breast disorders |
Gynaecomastia | ||||
|
General disorders and administration site conditions |
Malaise, increased sweating |
4.9 Overdose
There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg 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 dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD), proton pump inhibitors, ATC code: A02BC05.
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.
Site and 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.
Effect on gastric acid secretion
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 GORD 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.
Therapeutic effects of acid inhibition
Healing of reflux oesophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.
One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients.
After eradication treatment for one week there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomized, double blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterised as Forrest Ia, Ib, Ila or Ilb (9%, 43%, 38% and 10 % respectively) were randomized to receive esomeprazole solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, 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 esomeprazole for 27 days for acid suppression The occurrence of rebleeding within 3 days was 5.9% in the esomeprazole treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the esomeprazole treated versus the placebo treated group 7.7% vs 13.6%.
Other effects related to acid inhibition
During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion.
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.
During long-term treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
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.
In two studies with ranitidine as an active comparator, esomeprazole showed better effect in healing of gastric ulcers in patients using NSAIDs, including COX-2 selective NSAIDs.
In two studies with placebo as comparator, esomeprazole showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs.
5.2 Pharmacokinetic properties Absorption and distribution
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. 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.
Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Biotransformation and elimination
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.
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. 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. 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.
Special patient populations
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 increased by about 60%. These findings have no implications for the posology of esomeprazole.
The metabolism of esomeprazole is not significantly changed in elderly subjects (7180 years of age).
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.
Impaired organ function
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.
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.
Paediatric
Adolescents 12-18 years:
Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration ( tmax) in 12 to18 year-olds was similar to that in adults for both esomeprazole doses.
5.3 Preclinical safety data
Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Mannitol (E421)
Cellulose, Microcrystalline Sodium Laurilsulfate,
Hydroxypropylcellulose Talc (E553b)
Methacrylic Acid-Ethyl Acrylate copolymer 1:1, dispersion 30%,
Propylene Glycol
Triethyl Citrate
Polysorbate 80
Glycerol monostearate 40-55
Silica Colloidal Anhydrous
Hypromellose
Magnesium Stearate
Calcium Hydrogen Phosphate Dihydrate
Crospovidone
Tablet coating:
Hypromellose 15cP (E464)
Titanium Dioxide (E171)
Polydextrose (E1200)
Talc (E553b)
Maltodextrin
Triglycerides, Medium Chain Iron Oxide Yellow (E172)
Iron Oxide Red (E172).
6.2 Incompatibilities
Not applicable
6.3 Shelf life
15 months
6.4 Special precautions for storage
Do not store above 25 °C
6.5 Nature and contents of container
Blister pack (OPA/Aluminium/PVC/Aluminium): 7, 14, 15, 28, 30, 50, 56, 60, 90, 98 and 100 gastro-resistant tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
Administration through gastric tube
1. Put the tablet into an appropriate syringe and fill the syringe with approximately 25 ml water and approximately 5 ml air.
For some tubes, dispersion in 50ml water is needed to prevent the pellets from clogging the tube.
2. Immediately shake the syringe for approximately 2 minutes to disperse the tablet.
3. Hold the syringe with the tip up and check that the tip has not clogged.
4. Attach the syringe to the tube whilst maintaining the above position.
5. Shake the syringe and position it with the tip pointing down. Immediately inject 5 - 10 ml into the tube. Invert the syringe after injection and shake (the syringe must be held with the tip pointing up to avoid clogging of the tip).
6. Turn the syringe with the tip down and immediately inject another 5 - 10 ml into the tube. Repeat this procedure until the syringe is empty.
7. Fill the syringe with 25 ml of water and 5 ml of air and repeat step 5 if necessary to wash down any sediment left in the syringe. For some tubes, 50 ml water is needed.
7 MARKETING AUTHORISATION HOLDER
Specifar S.A.
1, 28 Octovriou str.,
123 51 Ag. Varvara Athens, Greece
8 MARKETING AUTHORISATION NUMBER(S)
PL 20354/0151
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 20/10/2011
10
DATE OF REVISION OF THE TEXT
29/08/2012