Esomeprazole Magnesium 40mg gastro-resistant granules for oral suspension, sachet Taj Pharma

  1. Name of the medicinal product

Esomeprazole Magnesium 10mg gastro-resistant granules for oral suspension, sachet Taj Pharma
Esomeprazole Magnesium 20mg gastro-resistant granules for oral suspension, sachet Taj Pharma
Esomeprazole Magnesium 40mg gastro-resistant granules for oral suspension, sachet Taj Pharma

2.Qualitative and quantitative composition

a) Each packet contains:
Esomeprazole (as magnesium trihydrate)       10mg
Excipients                                                          q.s.

b) Each packet contains:
Esomeprazole (as magnesium trihydrate)      20mg
Excipients                                                        q.s.

c) Each packet contains:
Esomeprazole (as magnesium trihydrate)     40mg
Excipients                                                        q.s.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Gastro-resistant granules for oral suspension, sachet.

  1. Clinical particulars

4.1 Therapeutic indications

Esomeprazole Magnesium oral suspension is primarily indicated for:

Paediatric population

Children 1-11 years old

Gastroesophageal Reflux Disease (GERD)

– treatment of endoscopically proven erosive reflux esophagitis

– symptomatic treatment of gastroesophageal reflux disease (GERD)

Children over 4 years of age

In combination with antibiotics in treatment of duodenal ulcer caused by Helicobacter pylori.

Adults and adolescents from the age of 12 years

For indications in patients from the age of 12 years reference is made to the Esomeprazole Magnesium gastro-resistant tablet SmPC.

Esomeprazole Magnesium oral suspension may also be used by patients having difficulty swallowing dispersed Esomeprazole Magnesium gastro-resistant tablets.

4.2 Posology and method of administration

Posology

Paediatric population

Children 1 – 11 years with a bodyweight of ≥10 kg

Gastroesophageal Reflux Disease (GERD)

– Treatment of endoscopically proven erosive reflux esophagitis
– Weight ≥10 – <20 kg: 10 mg once daily for 8 weeks.
– Weight ≥20 kg: 10 mg or 20 mg once daily for 8 weeks.
– Symptomatic treatment of gastroesophageal reflux disease (GERD)
– 10 mg once daily for up to 8 weeks.

Doses over 1 mg/kg/day have not been studied.

Children over 4 years of age

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 kg Combination with two antibiotics: Esomeprazole Magnesium 10 mg, amoxicillin 25 mg/kg body weight and clarithromycin 7.5 mg/kg body weight are all administered together twice daily for one week.
30 – 40 kg Combination with two antibiotics: Esomeprazole Magnesium 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 Magnesium 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered together twice daily for one week.

Children below the age of 1 year

The experience of treatment with esomeprazole in infants < 1 year is limited and treatment is therefore not recommended (see section 5.1).

Adults and adolescents from the age of 12 years

For posology in patients from the age of 12 years reference is made to the Esomeprazole Magnesium gastro-resistant tablet SmPC.

Special populations

Renal impairment

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).

Hepatic impairment

Dose adjustment is not required in patients with mild to moderate liver impairment. For patients ≥12 years with severe liver impairment, a maximum dose of 20 mg Esomeprazole Magnesium should not be exceeded. For children 1-11 years with severe liver impairment, a maximum dose of 10 mg should not be exceeded (see section 5.2).

Elderly

Dose adjustment is not required in the elderly.

Method of administration

For a 10 mg dose empty the contents of a 10 mg sachet into a glass containing 15 ml water. For a 20 mg dose empty the contents of two 10 mg sachets into a glass containing 30 ml water. Do not use carbonated water. Stir the contents until the granulate has been dispersed and leave for a few minutes to thicken. Stir again and drink within 30 minutes. The granules must not be chewed or crushed. Rinse with 15 ml water to obtain all granules.

For patients who have a nasogastric or gastric tube in place: see section 6.6 for preparation and administration instructions.

4.3 Contraindications

Hypersensitivity to the active substance, to substituted benzimidazoles or to any of the excipients listed in section 6.1.

Esomeprazole should not be used concomitantly 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 Esomeprazole Magnesium may alleviate symptoms and delay diagnosis.

Long term use

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance. Long-term treatment is indicated in adults and adolescents (12 years and older, see section 4.1).

On demand treatment

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. On demand treatment has not been investigated in children and is therefore not recommended in this patient group.

Helicobacter Pylori eradication:

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 clartithromycin should be considered when triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4, such as cisapride.

Gastrointestinal infections

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

Absorption of vitamin B12

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.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (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 medicinal products that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Risk of fractures

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 10-40%. 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.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Esomeprazole Magnesium. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Combination with other medicinal products

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 medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

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).

Sucrose and glucose

This medicinal product contains sucrose and glucose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

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 CYP2C19.

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%. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended (see section 4.4) and concomitant administration with esomeprazole and nelfinavir is contraindicated (see section 4.3).

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)

Methotrexate

When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.

Tacrolimus

Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Medicinal products with pH dependent absorption

Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib 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.

Medicinal products metabolised by CYP2C19

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on demand therapy.

Diazepam

Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Phenytoin

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.

Voriconazole

Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUC by 15% and 41%, respectively.

Cilostazol

Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Cisapride

In healthy volunteers, concomitant 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(t1/2) 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 (see section 4.4).

Warfarin

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.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic (PK)/ pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o.daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.

When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg +ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups.

Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged.

Investigated medicinal products with no clinically relevant interaction

Amoxicillin and quinidine

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

Naproxen or rofecoxib

Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products which inhibit CYP2C19 and/or CYP3A4

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 AUCt 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. Long-term treatment is indicated in adults and adolescents (12 years and older, see section 4.1).

Medicinal products which induce CYP2C19 and/or CYP3A4

Medicinal products 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Clinical data on exposed pregnancies with Esomeprazole Magnesium 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/foetal 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.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of esomeprazole.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Breast-feeding

It is not known whether esomeprazole is excreted in human breast milk. There is insufficient information on the effects of esomeprazole in newborns/infants. Esomeprazole should not be used during breast-feeding.

Fertility

Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.

4.7 Effects on ability to drive and use machines

Esomeprazole has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) has been reported (see section 4.8). If affected patients should not drive or use machines.

4.8 Undesirable effects

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 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).

System Organ Class Frequency Undesirable Effect
Blood and lymphatic system disorders Rare Leukopenia, thrombocytopenia
Very rare Agranulocytosis, pancytopenia
Immune system disorders Rare Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders Uncommon Peripheral oedema
Rare Hyponatraemia
Not known Hypomagnesaemia (see section 4.4); severe hypomagnesaemia can correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
Psychiatric disorders Uncommon Insomnia
Rare Agitation, confusion, depression
Very rare Aggression, hallucinations
Nervous system disorders Common Headache
Uncommon Dizziness, paraesthesia, somnolence
Rare Taste disturbance
Eye disorders Rare Blurred vision
Ear and labyrinth disorders Uncommon Vertigo
Respiratory, thoracic and mediastinal disorders Rare Bronchospasm
Gastrointestinal disorders Common Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign)
Uncommon Dry mouth
Rare Stomatitis, gastrointestinal candidiasis
Not known Microscopic colitis
Hepatobiliary disorders Uncommon Increased liver enzymes
Rare Hepatitis with or without jaundice
Very rare Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders Uncommon Dermatitis, pruritus, rash, urticaria
Rare Alopecia, photosensitivity
Very rare Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Not known Subacute cutaneous lupus erythematosus (see section 4.4)
Musculoskeletal and connective tissue disorders Uncommon Fracture of the hip, wrist or spine (see section 4.4)
Rare Arthralgia, myalgia
Very rare Muscular weakness
Renal and urinary disorders Very rare Interstitial nephritis; in some patients renal failure has been reported concomitantly.
Reproductive system and breast disorders Very rare Gynaecomastia
General disorders and administration site conditions Rare 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.

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.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitor

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 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.

Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.

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 both children and adults during long term treatment with esomeprazole. The findings are considered to be of no clinical significance.

During long-term treatment with antisecretory medicinal products 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 count of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.

Paediatric population

GERD – 1 to 11 Years of Age

In a multicentre, parallel-group study, 109 paediatric patients with endoscopically proven GERD (1 to 11 years of age) were treated with Esomeprazole Magnesium once daily for up to 8 weeks to evaluate safety and tolerability. Dosing by patient weight was as follows:

Weight <20 kg: once daily treatment with esomeprazole 5 mg or 10 mg

Weight ≥20 kg: once daily treatment with esomeprazole 10 mg or 20 mg

Patients were endoscopically characterised as to the presence or absence of erosive esophagitis. Fifty-three patients had erosive esophagitis at baseline. Of the 45 patients who had follow-up endoscopy, 42 (93.3%) of these patients had their erosive esophagitis resolved (88.9%) or improved (4.4%) after 8 weeks of treatment.

GERD – 0 to 11 months of age

In a placebo-controlled study (98 patients aged 1-11 months) efficacy and safety in patients with signs and symptoms of GERD were evaluated. Esomeprazole 1 mg/kg once daily was given for 2 weeks (open-label phase) and 80 patients were included for an additional 4 weeks (double blind, treatment-withdrawal phase). There was no significant difference between esomeprazole and placebo for the primary endpoint time to discontinuation due to symptom worsening.

In a placebo-controlled study (52 patients aged <1 month) efficacy and safety in patients with symptoms of GERD were evaluated. Esomeprazole 0.5 mg/kg once daily was given for a minimum of 10 days. There was no significant difference between esomeprazole and placebo in the primary endpoint, change from baseline of number of occurrences of symptoms of GERD.

Results from the paediatric studies further show that 0.5 mg/kg and 1.0 mg/kg esomeprazole in <1 month old and 1 to 11 month old infants, respectively, reduced the mean percentage of time with intra-esophageal pH < 4.

The safety profile appeared to be similar to that seen in adults.

In a study in paediatric GERD patients (<1 to 17 years of age) receiving long-term PPI treatment, 61% of the children developed minor degrees of ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumours.

5.2 Pharmacokinetic properties

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 increased by about 60%. These findings have no implications for the posology of esomeprazole.

Gender

Following a single dose of 40 mg esomeprazole the mean area 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

The metabolism of esomeprazole is not significantly changed in elderly subjects (71–80 years of age).

Paediatric population

Adolescents 12-18 years:

Following repeated dose administration of 20 mg and 40 mg esomeprazole in adolescents 12-18 years of age, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) was similar to that in adults.

Children 1 – 11 years:

Following repeated dose administration of 10 mg esomeprazole, the total exposure (AUC) was similar within the age range 1 to 11 years and the exposure was similar to the exposure seen with the 20 mg dose in adolescents and adults. Following repeated dose administration of 20 mg esomeprazole, the total exposure (AUC) was higher in 6 to 11 year-olds compared to the same dose in adolescents and adults.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, 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. No new or unexpected toxicity findings were observed in juvenile rats and dogs, after administration of esomeprazole for up to 3 months, as compared to the adult animals.

  1. Pharmaceutical particulars

6.1 List of excipients

Esomeprazole granules:

Glycerol monostearate,  Hydroxypropyl cellulose, Hypromellose, Magnesium stearate, Methacrylic acid –ethyl acrylate copolymer (1:1) dispersion, Polysorbate, Sugar spheres (sucrose and maize starch), Talc

Triethyl citrate.

Excipient granules:

Citric acid anhydrous (for pH adjustment), Crospovidone, Glucose, Hydroxypropyl cellulose, Yellow iron oxide, Xanthan gum.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

To be used within 30 minutes after reconstitution.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Carton containing 28 or 30 sachets. Not all pack sizes may be marketed.

Sachets (containing granules): Laminate consisting of three layers: polyethylene terephthalate (PET), aluminium, low density polyethylene (LDPE) which protects the granules against moisture.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

For patients who have a nasogastric or gastric tube in place

  1. For a 10 mg dose, add the contents of a 10 mg sachet into 15 ml of water.
  2. For a 20 mg dose add the contents of two 10 mg sachets into 30 ml of water.
  3. For a 40 mg dose add the contents of two 10 mg sachets into 60 ml of water
  4. Stir.
  5. Leave for a few minutes to thicken.
  6. Stir again.
  7. Draw the suspension into a syringe.
  8. Inject through the enteric tube, French size 6 or larger, into the stomach within 30 minutes after reconstitution.
  9. Refill the syringe with 15 ml water for a 10 mg dose and 30 ml for a 20 mg dose.
  10. Shake and flush any remaining contents from the enteric tube into the stomach.

Any unused suspension should be discarded.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Esomeprazole Magnesium  gastro-resistant granules for oral suspension, sachet 10mg/20mg/40mg Taj Pharma

Package leaflet: Information for the patient

(Esomeprazole Magnesium)

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Esomeprazole Magnesium is and what it is used for
2. What you need to know before you take Esomeprazole Magnesium
3. How to take Esomeprazole Magnesium
4. Possible side effects
5. How to store Esomeprazole Magnesium
6. Contents of the pack and other information

  1. What Esomeprazole Magnesium is and what it is used for

Esomeprazole Magnesium  contains a substance called esomeprazole. This belongs to a group of medicines called proton pump inhibitors. These work by reducing the amount of acid that your stomach produces.

Esomeprazole Magnesium  is used to treat the following conditions:

Children over 1 year of age

Esomeprazole Magnesium  is used to treat a condition called “gastroesophageal reflux disease” (GERD).

  • This is where acid from the stomach escapes into the gullet (esophagus) causing pain, inflammation and heartburn. Heartburn is a burning feeling rising from the stomach or lower chest up towards the neck.
  • In children, the symptoms of the condition can include the return of stomach contents into the mouth (regurgitation), being sick (vomiting) and poor weight gain.

Children over 4 years of age

  • Ulcers which are infected with bacteria called ‘Helicobacter pylori’. If your child has this condition, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.
  1. What you need to know before you take Esomeprazole Magnesium

Do not take Esomeprazole Magnesium :

  • If you are allergic to esomeprazole or other similar proton pump inhibitors (e.g. pantoprazole, lansoprazole, rabeprazole, omeprazole), or any other ingredients of this medicine (listed in section 6).
  • If you are taking a medicine containing nelfinavir (used to treat HIV infection).

Do not take Esomeprazole Magnesium  if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Esomeprazole Magnesium .

Warnings and precautions

Talk to your doctor or pharmacist before taking Esomeprazole Magnesium :

  • If you have severe liver problems.
  • If you have severe kidney problems.
  • If you have ever had a skin reaction after treatment with a medicine similar to Esomeprazole Magnesium  that reduces stomach acid.
  • If you are due to have a specific blood test (Chromogranin A).

Esomeprazole Magnesium  may hide the symptoms of other diseases.

Therefore, if any of the following happen to you while you are taking Esomeprazole Magnesium , you should talk to your doctor immediately:

  • You lose a lot of weight for no reason.
  • You get stomach pain or indigestion.
  • You begin to vomit repeatedly.
  • You have problems swallowing.
  • You vomit blood or pass black (blood-stained) motions (faeces).

If you have been prescribed Esomeprazole Magnesium  “on demand” you should contact your doctor if the symptoms are persistent or change character. “On demand” treatment has not been investigated in children and is therefore not recommended in this patient group.

Taking a proton pump inhibitor like Esomeprazole Magnesium , especially over a period of more than one year, may slightly increase your risk of fracture in the hip, wrist or spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids (which can increase the risk of osteoporosis).

If you get a rash on your skin, especially in areas exposed to the sun tell your doctor as soon as you can, as you may need to stop your treatment with Esomeprazole Magnesium . Remember to also mention any other ill-effects like pain in your joints.

Other medicines and Esomeprazole Magnesium

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines that you buy without a prescription. This is because Esomeprazole Magnesium  can affect the way some medicines work and some medicines can have an effect on Esomeprazole Magnesium .

Do not take Esomeprazole Magnesium  if you are taking nelfinavir (used to treat HIV infection).

Tell your doctor or pharmacist if you are taking any of the following medicines:

  • Atazanavir (used to treat HIV infection).
  • Clopidogrel (used to prevent blood clots).
  • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus).
  • Erlotinib (used to treat cancer).
  • Diazepam (used to treat anxiety or relax muscles).
  • Citalopram, imipramine or clomipramine (used to treat depression).
  • Phenytoin (used in epilepsy).
  • Warfarin or coumarin (medicines called anticoagulants that are used to thin your blood).
  • Cilostazol (used to treat intermittent claudication – a pain in your legs when you walk which is caused by an insufficient blood supply).
  • Cisapride (used for indigestion and heartburn).
  • Digoxin (used for heart problems).
  • Methotrexate (a chemotherapy medicine used in high doses to treat cancer) – if you are taking a high dose of methotrexate, your doctor may temporarily stop your Esomeprazole Magnesium  treatment.
  • Tacrolimus (organ transplantation).
  • Rifampicin (used for treatment of tuberculosis).
  • St. John’s wort (Hypericum perforatum) (used to treat depression).

If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Esomeprazole Magnesium  to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking.

Esomeprazole Magnesium  gastro-resistant granules with food and drink

Esomeprazole Magnesium  gastro-resistant granules can be taken with or without food.

Pregnancy, breast-feeding and fertility

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will decide whether you can take Esomeprazole Magnesium  during this time.

It is not known if Esomeprazole Magnesium  passes into breast milk. Therefore you should not take Esomeprazole Magnesium  if you are breast-feeding.

Driving and using machines

Esomeprazole Magnesium  is not likely to affect you being able to drive or use tools or machines. However, side effects such as dizziness and blurred vision may uncommonly or rarely occur (see section 4). If affected, you should not drive or use machines.

Esomeprazole Magnesium  contains sucrose and glucose

Esomeprazole Magnesium  contains sucrose and glucose which are both types of sugars. Careful oral hygiene and regular tooth brushing are therefore important. If you have been told by your doctor, that you have an intolerance to some sugars, contact your doctor before taking Esomeprazole Magnesium .

  1. How to take Esomeprazole Magnesium

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Your medicine comes as granules in individual sachets. Each sachet contains 10 mg of esomeprazole. Your doctor will tell you how many sachets to take each day. He or she will also tell you how long you should take them for.

  • Empty the contents of the sachet or sachets into a glass containing some water. Do not use fizzy (carbonated) water. The amount of water depends on the number of sachets that your doctor has told you to take at one time.
  • Use 15 millilitres (ml) of water (3 teaspoonfuls) for each sachet. This means that you will need 15 ml for one sachet and 30 ml for two sachets.
  • Stir the granules in the water.
  • Leave the mixture for a few minutes until it has thickened.
  • Stir again and drink the mixture. The granules must not be chewed or crushed. Do not leave the mixture to stand for more than 30 minutes before you drink it.
  • If anything remains in the glass, add some more water, stir and drink it immediately.

Esomeprazole Magnesium  gastro-resistant granules can be taken with or without food.

If you are being fed using a feeding (gastric) tube, your doctor or nurse can give you Esomeprazole Magnesium  through your tube. Information for your doctor or nurse is provided at the end of this leaflet.

The recommended doses are given below:

Use in children aged 1 to 11 years

  • Esomeprazole Magnesium  is not recommended for children younger than 1 year.

To treat gastroesophageal reflux disease (GERD)

  • The recommended dose is one sachet (10 mg) or two sachets (20 mg) once daily. The dose for children is based on the child’s weight and the doctor will decide the correct dose.

Use in children aged 4 years and older

To treat ulcers caused by Helicobacter pylori infection and to stop them coming back.

  • The dose for children is based on the child’s weight and your doctor will decide the correct dose. The doctor will also prescribe two antibiotics for your child.

Use in adults and adolescents

Esomeprazole Magnesium  oral suspension may also be used by patients having difficulty swallowing dispersed Esomeprazole Magnesium  gastro-resistant tablets. Information on dosing for patients from the age of 12 years is in Esomeprazole Magnesium  gastro-resistant tablet product information (ask your doctor or pharmacist if you require further information).

Elderly

There is no need to alter the dose if you are elderly.

People with liver problems

  • For people with severe liver problems, the maximum daily dose of Esomeprazole Magnesium  is two sachets (20 mg). For children 1-11 years with severe liver problems, a maximum dose of 10 mg should not be exceeded.

People with kidney problems

  • There are no special dosage restrictions for people with kidney problems. However, if you have severe kidney problems your doctor may decide to carry out regular tests.

If you take more Esomeprazole Magnesium  than you should

If you have taken more Esomeprazole Magnesium  than prescribed by your doctor, seek medical advice.

If you forget to take Esomeprazole Magnesium

If you forget to take a dose, take it as soon as you remember. If it is almost time to take the next dose, wait until then. Do not take a double dose to make up for the forgotten dose.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions

A severe allergic reaction (anaphylaxis) is a rare side effect, affecting less than 1 in 1,000 people taking Esomeprazole Magnesium . You may notice sudden wheezing, swelling of your face or body, rash, fainting or difficulties in swallowing.

If this happens to you, stop taking Esomeprazole Magnesium  and contact a doctor immediately.

Other side effects include:

Common (may affect up to 1 in 10 people)

  • Headache.
  • Effects on your stomach or gut: diarrhoea, stomach pain, constipation, wind (flatulence).
  • Feeling sick (nausea) or being sick (vomiting).
  • Benign polyps in the stomach.

Uncommon (may affect up to 1 in 100 people)

  • Swelling of the feet and ankles.
  • Disturbed sleep (insomnia).
  • Dizziness, tingling feelings such as “pins and needles”, feeling sleepy.
  • Spinning feeling (vertigo).
  • Dry mouth.
  • Changes in blood tests that check how the liver is working.
  • Skin rash, lumpy rash (hives) and itchy skin.
  • Fracture of the hip, wrist or spine (if Esomeprazole Magnesium  is used in high doses and over long duration).

Rare (may affect up to 1 in 1,000 people)

  • Blood problems such as a reduced number of white cells or platelets.
  • Low levels of sodium in the blood.
  • Feeling agitated, confused or depressed.
  • Taste changes.
  • Eyesight problems such as blurred vision.
  • Suddenly feeling wheezy or short of breath (bronchospasm).
  • An inflammation of the inside of the mouth.
  • An infection called “thrush” which can affect the gut and is caused by a fungus.
  • Hepatitis with our without jaundice
  • Hair loss (alopecia).
  • Skin rash on exposure to sunshine.
  • Joint pains (arthralgia) or muscle pains (myalgia).
  • Generally feeling unwell and lacking energy.
  • Increased sweating.

Very rare (may affect up to 1 in 10,000 people)

  • Changes in blood count including agranulocytosis (lack of white blood cells)
  • Aggression.
  • Seeing, feeling or hearing things that are not there (hallucinations).
  • Severe liver problems leading to liver failure and inflammation of the brain.
  • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).
  • Muscle weakness.
  • Severe kidney problems.
  • Enlarged breasts in men.

Not known (frequency cannot be estimated from the available data)

  • If you are on Esomeprazole Magnesium  for more than three months it is possible that the levels of magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness or increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of magnesium.
  • Inflammation in the gut (leading to diarrhoea).
  • Rash, possibly with pain in the joints.

Esomeprazole Magnesium  may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medication at this time.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

  1. How to store Esomeprazole Magnesium

This medicinal product does not require any special storage conditions.

  • Keep out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the carton and sachet after EXP. The expiry date refers to the last day of that month.
  • The reconstituted suspension should be used within 30 minutes.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

  1. Contents of the pack and other information

What Esomeprazole Magnesium  gastro-resistant granules for oral suspension contains

The active substance is esomeprazole.

a) Each packet contains:
Esomeprazole (as magnesium trihydrate)   10mg
Excipients                                                      q.s.

b) Each packet contains:
Esomeprazole (as magnesium trihydrate)   20mg
Excipients                                                     q.s.

c) Each packet contains:
Esomeprazole (as magnesium trihydrate)   40mg
Excipients                                                     q.s.

The other ingredients are:

Esomeprazole granules:

Glycerol monostearate, Hydroxypropyl cellulose, Hypromellose, Magnesium stearate, Methacrylic acid – ethyl acrylate copolymer (1:1) 30% dispersion, Polysorbate, Sugar spheres (sucrose and maize starch), Talc, Triethyl citrate

Excipient granules:

Citric acid anhydrous (for pH adjustment), Crospovidone, Glucose, Hydroxypropyl cellulose, Yellow iron oxide, Xanthan gum.

What Esomeprazole Magnesium  looks like and contents of the pack

Each sachet of Esomeprazole Magnesium  contains fine granules.

Each carton contains 28 or 30 sachets. Not all pack sizes may be marketed.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

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