Zosa Tablets

Esomeprazole Gastro-resistant Tablets IP 40 mg

Each gastro-resistant tablet contains :

Esomeprazole Magnesium Trihydrate IP

equivalent to Esomeprazole 40 mg

Excipients q.s.

Colours : Red Oxide of Iron & Titanium Dioxide IP

Gastro resistant tablet, 40 mg

4.1 Therapeutic indication

Gastroesophageal Reflux Disease (GERD), erosive reflux esophagitis, prevention of relapse of esophagitis & helps in eradication of H.Pylori associated peptic ulcer. It is also indicated for pathological hypersecretory conditions including Zollinger-Ellison syndrome ulcer, risk reduction of NSAID-associated gastric ulcer, and prolonged treatment after IV-induced prevention of rebleeding of peptic ulcer

4.2 Posology and method of administration

The recommended dosages are outlined in the table below. Zosa tablets should be taken at least 1 hour before meals

The duration of PPI administration should be based on available safety and efficacy data specific to the defined indication and dosing frequency, as described in the prescribing information, and individual patient medical needs. PPI treatment should only be initiated and continued if the benefits outweigh the risks of treatment.

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.

Hepatic impairment

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.

Geriatric population

Dose adjustment is not required in the elderly

Pediatric Population

Safety and effectiveness of Zosa in pediatric patients have not been established

Method of Administration

The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.

4.3 Contraindications

• Hypersensitivity to the active substance, to substituted benzimidazoles or to any of the excipients listed in the formulation.
• Esomeprazole should not be used concomitantly with nelfinavir.

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 Tablet 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.

On demand treatment

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character.

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 clarithromycin should be considered when the triple therapy is used in patients concurrently taking other active substances metabolised via CYP3A4 such as cisapride. Gastrointestinal infections

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. 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 drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. Risk of fracture 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 older people 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 gastro-resistant Tablets. 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. 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 esomeprazole. 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. 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 five days before CgA measurements. 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 Drugs interactions

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 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 300 mg atazanavir/100 mg ritonavir 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 400 mg atazanavir/100 mg ritonavir to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with 300 mg atazanavir/100 mg ritonavir qd without 20 mg omeprazole 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 and concomitant administration with esomeprazole and nelfinavir is contraindicated.

For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with 20 mg omeprazole qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with 20 mg esomeprazole qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with 40 mg omeprazole 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 other medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these active substances 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 with diazepam resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Phenytoin

Concomitant administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Voriconazole

Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUC τ 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 resulted in a 32% increase in AUC and a 31% prolongation of elimination half-life (t½) 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.

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

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 AUC to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in doubling the AUC of esomeprazole. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC 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. Medicinal products which induce CYP2C19 and/or CYP3A4 Drugs known to induce CYP2C19, 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 perform in adults.

4.6 Use in special populations

Pregnancy

Clinical data on exposed pregnancies with Esomeprazole gastro-resistant Tablets 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. 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 or use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) has been reported. If affected patients should not drive or use machines

4.8 Undesirable effects

Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most

commonly reported. 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.

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; 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.

Musculoskeletal and connective tissue disorders

Uncommon : Fracture of the hip, wrist or spine.

Rare : Arthralgia, myalgia.

Very rare : Muscular weakness.

Renal and urinary disorders

Very rare : Interstitial nephritis; in some patients renal failure has been reported

concomitantly, Acute Kidney

injury.

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. Healthcare

professionals are

asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this

medicine.

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.

5.1 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.

5.2 Pharmacodynamic properties

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. Healing of reflux esophagitis 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 medicinal products 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, IIa or IIb (9%, 43%, 38% and 10% respectively) were randomized to receive esomeprazole I.V., 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%. 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 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 and, in hospitalized patients, possibly also Clostridium difficile.

5.3 Pharmacokinetic properties

Absorption

Esomeprazole is acid labile and is administered orally as enteric-coated granules in a tablet. 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.

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 (omeprazole) 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.

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.

8.1 Incompatibilities

8.2 Shelf-life

24 Months.

8.3 Packaging information

A strip of 15 tablets.

8.4 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with :

• Hypersensitivity Reactions
• Acute Tubulointerstitial Nephritis
• Clostridium difficile-Associated Diarrhea
• Bone Fracture
• Cutaneous and Systemic Lupus Erythematosus
• Cyanocobalamin (Vitamin B-12) Deficiency
• Hypomagnesemia

Drug Interactions

Advise patients to let you know if they are taking, or begin taking, other medications, because Esomeprazole can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes.

26/08/2021