Instructions for Ezolong-40 film-coated tablets 40 mg blister No. 14
Composition
active ingredient: esomeprazole;
1 film-coated tablet contains esomeprazole magnesium trihydrate equivalent to esomeprazole 20 mg or 40 mg;
excipients: microcrystalline cellulose, sodium bicarbonate, colloidal anhydrous silica, crospovidone, povidone (K-30), magnesium stearate, talc, mint flavor, coating (Opadry White 58901), talc, iron oxide yellow (E 172) - available in film-coated tablets, 20 mg, iron oxide red (E 172) - available in film-coated tablets, 40 mg.
Dosage form
Film-coated tablets.
Main physicochemical properties: oval, biconvex tablets, film-coated, light pink (for 40 mg) or light yellow (for 20 mg), with a score line on one side.
Pharmacotherapeutic group
Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Esomeprazole. ATC code A02B C05.
Pharmacological properties
Pharmacodynamics.
Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion by a specifically targeted mechanism of action. It is a specific inhibitor of the proton pump in the parietal cell. The R- and S-isomers of omeprazole have the same pharmacodynamic activity.
Esomeprazole is a weak base, it concentrates and converts to the active form in the highly acidic environment of the secretory tubules of the parietal cell, where it inhibits the enzyme H+K+-ATPase - the acid pump, and also suppresses basal and stimulated acid secretion.
After oral administration of 20 mg and 40 mg esomeprazole, the onset of action is within one hour. After repeated administration of 20 mg esomeprazole once daily for 5 days, the mean peak acid output after pentagastrin stimulation is reduced by 90% when measured 6-7 hours after the dose on day 5.
After 5 days of oral administration of esomeprazole 20 mg and 40 mg, gastric pH was >4 for a mean of 13 and 17 hours, respectively, and >24 hours in patients with symptomatic reflux esophagitis. The proportion of patients with gastric pH >4 for 8, 12, and 16 hours after 20 mg esomeprazole was 76%, 54%, and 24%, respectively. The corresponding proportions for 40 mg esomeprazole were 97%, 92%, and 56%.
When using AUC as an indirect indicator of plasma concentration, the dependence of acid secretion inhibition on drug exposure was shown.
Therapeutic effects of inhibiting hydrochloric acid secretion.
Treatment of reflux esophagitis with esomeprazole 40 mg was successful in approximately 70% of patients after 4 weeks of treatment and in 93% after 8 weeks of treatment.
Esomeprazole 20 mg twice daily for one week, together with appropriate antibiotics, resulted in successful eradication of Helicobacter pylori in approximately 90% of patients. After one week of treatment, no further antisecretory monotherapy was required for successful ulcer healing and symptom relief in uncomplicated duodenal ulcers.
Other effects associated with inhibition of hydrochloric acid secretion.
During the period of use of antisecretory drugs, plasma gastrin concentration increases in response to decreased acid secretion. Chromogranin A (CgA) also increases due to decreased gastric acidity.
It is possible that the increase in the number of ECL cells is associated with an increase in plasma gastrin levels, which has been observed in some patients with long-term use of esomeprazole.
There have been several reports of an increased incidence of gastric granular cysts with long-term use of antisecretory drugs. These phenomena are a physiological consequence of prolonged inhibition of acid secretion and are benign and reversible.
The reduction in gastric acidity caused by any proton pump inhibitor increases the number of bacteria normally present in the gastrointestinal tract in the stomach. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections caused by, for example, Salmonella or Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.
Esomeprazole was more effective than ranitidine in treating stomach ulcers in patients treated with NSAIDs (nonsteroidal anti-inflammatory drugs), including selective COX-2 inhibitors.
Esomeprazole was effective in preventing gastric and duodenal ulcers in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (in patients aged 60 years and over and/or with a history of ulcer).
Pharmacokinetics.
Absorption.
Esomeprazole is rapidly absorbed, with peak plasma concentrations occurring approximately 1-2 hours after dosing. Absolute bioavailability is 64% after a single 40 mg dose and increases to 89% after repeated once-daily dosing. For 20 mg esomeprazole, the corresponding values are 50% and 68%.
Food intake slows down and reduces the absorption of esomeprazole, but does not affect the effect of esomeprazole on gastric acidity.
The volume of distribution in healthy volunteers at steady state is 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.
Metabolism.
Esomeprazole is completely metabolized by the cytochrome P450 (CYP) system. The main part of the metabolism of esomeprazole depends on the polymorphic CYP2C19, which is responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The rest depends on a second specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in blood plasma.
Breeding.
The parameters listed below mainly reflect pharmacokinetics in individuals with a functional CYP2C19 enzyme (extensive metabolizers).
Total plasma clearance is approximately 17 l/h after a single dose and approximately 9 l/h after repeated dosing. The plasma elimination half-life is approximately 1.3 h after repeated once-daily dosing. Esomeprazole is completely eliminated from plasma between doses without any tendency for accumulation with once-daily dosing.
The main metabolites of esomeprazole do not affect gastric secretion. About 80% of an oral dose of esomeprazole is excreted in the form of metabolites in the urine, the rest in the intestines. Less than 1% of the parent drug is found in the urine.
Special patient groups.
Slow metabolizers.
Approximately 2.9 ± 1.5% of the patient population is deficient in the CYP2C19 enzyme (referred to as poor metabolisers). In these individuals, esomeprazole is predominantly metabolised by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve in poor metabolisers is approximately 100% higher than in subjects with normal CYP2C19 function (extensive metabolisers). The mean peak plasma concentration is increased by approximately 60%. These findings have no impact on the dosage of esomeprazole.
Patients with impaired liver function.
The metabolism of esomeprazole in patients with mild to moderate hepatic dysfunction may be impaired. The rate of metabolism is reduced in patients with severe hepatic impairment, resulting in a 2-fold increase in the area under the plasma concentration-time curve. Therefore, the maximum dose for patients with severe hepatic impairment is 20 mg. Esomeprazole and its metabolites do not tend to accumulate when administered once daily.
Patients with impaired renal function.
Studies in this category of patients have not been conducted. Since the kidneys are responsible for the excretion of esomeprazole metabolites, and not the main parent compound, no changes in metabolism are expected in patients with impaired renal function.
Elderly patients.
The metabolism of esomeprazole does not undergo significant changes in elderly patients (71 to 80 years).
Pediatric patients.
After multiple doses of 20 mg and 40 mg esomeprazole, the overall exposure and time to peak plasma concentrations in children aged 12-18 years were similar to those in adults.
Gender characteristics.
After a single dose of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was 30% higher in women than in men. No gender-related differences were observed with repeated once-daily dosing. These findings do not impact the dosing of esomeprazole.
Indication
Gastroesophageal reflux disease (GERD):
- treatment of erosive reflux esophagitis;
- long-term treatment to prevent relapse;
- symptomatic treatment of gastroesophageal reflux disease.
In combination with antibacterial agents for the eradication of Helicobacter pylori:
- treatment of duodenal ulcers associated with Helicobacter pylori;
- prevention of recurrence of peptic ulcers in patients with ulcers caused by Helicobacter pylori.
Treatment and prevention of ulcers caused by long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs):
- treatment of ulcers caused by NSAID therapy;
- prevention of gastric and duodenal ulcers in patients at risk due to taking NSAIDs.
Prevention of recurrent bleeding of gastric or duodenal ulcers after intravenous treatment with esomeprazole.
Treatment of Zollinger-Ellison syndrome.
Contraindication
Known hypersensitivity to esomeprazole, substituted benzimidazoles or other components of the drug. Concomitant use with atazanavir, nelfinavir.
Interaction with other medicinal products and other types of interactions
Effect of esomeprazole on the pharmacokinetics of other drugs.
Warfarin.
In clinical trials, the use of 40 mg esomeprazole in patients taking warfarin showed that coagulation times were within normal limits. However, after the widespread introduction of the drug into medical practice, there were several reports of a clinically significant increase in coagulation times, therefore, with the simultaneous use of esomeprazole and warfarin (or other coumarin derivatives), coagulation parameters should be monitored.
Omeprazole, like esomeprazole, acts as an inhibitor of CYP 2C19. Co-administration of omeprazole (40 mg once daily) resulted in an increase in Cmax and AUC of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively.
Diazepam.
Concomitant use of 30 mg esomeprazole results in a 45% decrease in the clearance of the CYP2C19 substrate diazepam.
Protease inhibitors.
Omeprazole has been reported to interact with some protease inhibitors (antiretroviral drugs). The clinical significance and mechanisms of such interactions are not always known. The increase in gastric pH during omeprazole use may alter the absorption of protease inhibitors. Other mechanisms of interaction may be related to inhibition of CYP 2C19. In the case of some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels of the latter have been observed when administered with omeprazole. Therefore, concomitant use of omeprazole and drugs such as atazanavir and nelfinavir is not recommended. The use of omeprazole (40 mg once daily) with atazanavir 300 mg and ritonavir 100 mg in healthy volunteers resulted in a significant decrease in the exposure of atazanavir (approximately 75% decrease in AUC, Cmax, Cmin). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on the efficacy of atazanavir. Increased plasma levels of other antiretroviral agents, such as saquinavir, have been reported. There are also other antiretroviral agents (darunavir, aprenavir, lopinavir) whose plasma levels were unchanged when co-administered with omeprazole.
Due to the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of esomeprazole with atazanavir is not recommended. The concomitant use of esomeprazole with nelfinavir is contraindicated.
Clopidogrel.
In healthy subjects, a pharmacokinetic/pharmacodynamic interaction was observed between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg daily orally), resulting in a mean 40% decrease in exposure to the active metabolite of clopidogrel and a mean 14% decrease in maximal inhibitory activity (ADP-induced) against platelet aggregation.
In a study in healthy subjects, in which clopidogrel was co-administered with a combination of 20 mg esomeprazole and 81 mg acetylsalicylic acid compared with clopidogrel alone, a decrease in exposure to the active metabolite of clopidogrel by almost 40% was observed. However, the maximum inhibitory activity (ATP-induced) on platelet aggregation in these subjects was the same in the groups receiving clopidogrel alone and clopidogrel + combination (esomeprazole + acetylsalicylic acid), which is probably explained by the concomitant administration of low doses of acetylsalicylic acid.
Several observational and clinical studies on PK/PD interactions have shown conflicting results regarding whether the risk of major cardiovascular events is increased when a patient receives clopidogrel with a PPI. As a precaution, it is recommended that concomitant use of clopidogrel be avoided.
Drugs metabolized by CYP2C19.
Esomeprazole inhibits CYP2C19, the main enzyme that metabolizes esomeprazole. Therefore, when esomeprazole is used in combination with drugs that are metabolized by CYP2C19 (such as diazepam, citalopram, imipramine, clomipramine, phenytoin), the plasma concentrations of these drugs may be increased, and a dose reduction may be necessary. This should be taken into account, especially when prescribing esomeprazole "on an "as needed" basis.
Drugs whose absorption depends on pH.
Reduced gastric acidity during the use of esomeprazole may increase or decrease the absorption of medicinal substances if their absorption depends on the acidity of gastric juice.
As with other drugs that reduce gastric acidity, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced, while the absorption of drugs such as digoxin may be increased during treatment with esomeprazole. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (in two out of ten subjects by 30%). Digoxin toxicity has been reported rarely. However, caution should be exercised when esomeprazole is used in high doses in elderly patients. Increased therapeutic drug monitoring of digoxin should be carried out.
Methotrexate.
Increased blood levels of methotrexate have been reported in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are required, temporary withdrawal of esomeprazole should be considered.
Tacrolimus.
Increased plasma levels of tacrolimus have been reported with concomitant use of esomeprazole. Renal function (creatinine clearance) and tacrolimus plasma levels should be monitored and the dose of tacrolimus adjusted if necessary.
In healthy volunteers, co-administration of 40 mg esomeprazole with cisapride resulted in a 32% increase in area under the concentration-time curve (AUC) and a 31% increase in elimination half-life (t1/2), but no significant increase in peak plasma levels of cisapride. A moderate prolongation of the QT interval was observed after administration of cisapride alone and was not increased by subsequent administration of cisapride in combination with esomeprazole.
Cilostazol.
Omeprazole, like esomeprazole, acts as an inhibitor of CYP 2C19. Administration of omeprazole at a dose of 40 mg to healthy volunteers in a study resulted in an increase in Cmax and area under the concentration-time curve (AUC) for cilostazol by 18% and 26%, respectively, and for one of its active metabolites by 29% and 69%, respectively.
Phenytoin.
Concomitant use of 40 mg esomeprazole results in a 13% increase in phenytoin plasma levels in epileptic patients. It is recommended to monitor phenytoin plasma levels when initiating or discontinuing esomeprazole therapy.
Effect of other drugs on the pharmacokinetics of esomeprazole.
Drugs that inhibit CYP2C19, CYP3A4, or both enzymes.
Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) resulted in a two-fold increase in exposure (AUC) to esomeprazole.
Concomitant use of esomeprazole and a combined CYP2C19 and CYP3A4 inhibitor may result in more than a doubling of esomeprazole exposure. Voriconazole (a CYP2C19 and CYP3A4 inhibitor) increased omeprazole AUC by 280%. In such situations, dose adjustment of esomeprazole is not always necessary. However, dose adjustment should be considered in patients with severe hepatic impairment or in the case of long-term treatment.
Drugs that induce CYP2C19, CYP3A4, or both enzymes.
Drugs that induce CYP2C19, CYP3A4 or both enzymes (such as rifampicin or St. John's wort) may lead to decreased plasma levels of esomeprazole by accelerating its metabolism.
Esomeprazole did not demonstrate a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.
No clinically significant pharmacokinetic interactions were observed with short-term concomitant use of esomeprazole and naproxen or rofecoxib.
Application features
In the presence of warning symptoms (such as significant weight loss, nausea, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as the use of esomeprazole may alter symptoms and delay the correct diagnosis.
Patients who use the drug for a long time (especially those who take it for more than a year) should be under regular supervision.
Patients who use the drug "as needed" should inform their doctor if the nature of their symptoms changes.
When prescribing esomeprazole for the eradication of Helicobacter pylori, the potential drug interactions of all components of the triple therapy should be considered. Clarithromycin is a potent CYP3A4 inhibitor, and its contraindications and interactions should be considered (if triple therapy is used in patients taking other drugs metabolized by CYP3A4, such as cisapride, concomitantly with esomeprazole).
The use of proton pump inhibitors may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter.
The use of esomeprazole, as with all drugs that inhibit acid secretion, may lead to reduced absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with reduced body stores or risk factors for reduced absorption of vitamin B12 during long-term therapy.
Severe hypomagnesaemia has been reported with proton pump inhibitors (PPIs) (including esomeprazole) in patients taking them for at least 3 months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias may occur. However, the latter may have an abrupt and insidious onset. Hypomagnesaemia has resolved after magnesium replacement therapy and discontinuation of the PPI. In patients who are to be treated for a long period of time or who are taking PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), plasma magnesium levels should be monitored before starting PPI treatment and periodically during treatment.
The concomitant use of esomeprazole and atazanavir is not recommended. If the combination of atazanavir with proton pump inhibitors cannot be avoided, careful monitoring of the patient in a hospital setting is recommended, as well as an increase in the dose of atazanavir to 400 mg with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.
Esomeprazole is an inhibitor of CYP2C19. When initiating or ending treatment with esomeprazole, the potential for interactions with drugs metabolised by CYP2C19 should be considered. An interaction has been observed between clopidogrel and esomeprazole. The clinical significance of this interaction is uncertain. As a precautionary measure, it is recommended to avoid the concomitant use of this combination.
When prescribing esomeprazole, it is necessary to take into account its interaction with other drugs that may affect the concentration of esomeprazole in the blood plasma.
Elevated chromogranin A (CgA) levels may interfere with testing for neuroendocrine tumors. To avoid false results, esomeprazole treatment should be discontinued at least 5 days before CgA measurement.
Use during pregnancy or breastfeeding
Pregnancy period.
Clinical data on the use of esomeprazole in pregnant women are limited. The results of studies on a large number of pregnant women who took the racemic mixture of omeprazole indicate the absence of malformative (fetal development disorders) and fetotoxic effects. Animal studies with esomeprazole did not show direct or indirect negative effects on embryonal/fetal development. Animal studies with the racemic mixture did not show direct or indirect negative effects on pregnancy, childbirth and postnatal development. The drug should be prescribed with caution during pregnancy.
Breastfeeding period.
No studies have been conducted in breast-feeding women. It is not known whether esomeprazole is excreted in breast milk. Therefore, esomeprazole should not be used during breast-feeding.
Fertility.
Animal studies of the racemic mixture of omeprazole have not shown any effect on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug does not affect the reaction rate when driving or operating other mechanisms. If dizziness and/or blurred vision develop during treatment, you should refrain from driving or operating other mechanisms.
Method of administration and doses
The drug is intended for oral use in adults and children over 12 years of age. The tablets should be taken whole 1 hour before meals and washed down with sufficient water. The tablets should not be chewed or crushed. The duration of the course of treatment is usually determined by the doctor.
Adults and children aged 12 and over.
GERD:
Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks are recommended for patients whose esophagitis has not been cured or whose symptoms persist.
Long-term treatment to prevent relapse: 20 mg once a day.
Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily in patients without esophagitis. If symptom control is not achieved within 4 weeks of treatment, the patient should be evaluated. Once symptoms have resolved, further control can be achieved with 20 mg once daily. An “as needed” regimen of 20 mg once daily may be used in adults. In patients who have used NSAIDs and are at risk of developing gastric or duodenal ulcers, further symptom control using the “as needed” regimen is not recommended.
Adults.
Treatment of duodenal ulcer associated with Helicobacter pylori: 20 mg esomeprazole with 1 g amoxicillin and 500 mg clarithromycin 2 times daily for 7 days.
Prevention of recurrence of peptic ulcers in patients with ulcers caused by Helicobacter pylori: 20 mg esomeprazole with 1 g amoxicillin and 500 mg clarithromycin 2 times a day for 7 days.
Treatment of gastric ulcers associated with NSAID therapy: The recommended dose is 20 mg once daily. The duration of treatment is 4-8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID treatment in patients at risk: the recommended dose is 20 mg once daily.
Prevention of recurrent bleeding from gastric or duodenal ulcers after intravenous treatment with esomeprazole: 40 mg once daily for 4 weeks. The period of oral esomeprazole should be preceded by acid suppression therapy, which consists of the use of esomeprazole as a solution for infusion.
Treatment of Zollinger-Ellison syndrome: 40 mg 2 times a day. The dosage should be selected individually, the duration of treatment is determined by clinical indications. According to the obtained clinical data, in most patients the disease can be controlled by taking 80 to 160 mg of esomeprazole per day. If the dose exceeds 80 mg/day, it should be divided into two doses.
Patients with impaired renal function.
There is no need to adjust the dosage regimen. Due to the lack of experience with the use of esomeprazole in patients with severe renal insufficiency, the drug should be prescribed with caution.
There is no need to adjust the dosage regimen in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the maximum dose of esomeprazole should not exceed 20 mg.
Elderly patients
There is no need to adjust the dosage regimen.
Children
The drug should be used in children over 12 years of age.
Overdose
Data on overdose are limited. Gastrointestinal symptoms and weakness have been described after taking 280 mg of esomeprazole. A single dose of 80 mg of esomeprazole does not cause serious side effects. No specific antidote is known. Esomeprazole is highly bound to plasma proteins and is therefore not dialysable.
Treatment: symptomatic and supportive therapy.
Adverse reactions
The following adverse reactions have been reported during clinical trials and after the introduction of esomeprazole into widespread medical practice. No dose-related effects were observed. Adverse reactions are classified according to frequency: common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000) and very rare (<1/10000).
Blood and lymphatic system disorders:
rarely: leukopenia, thrombocytopenia;
very rare: agranulocytosis, pancytopenia.
On the part of the immune system:
Rare: hypersensitivity reactions including fever, angioedema, anaphylactic reactions/shock.
From the side of metabolism and nutrition:
uncommon: peripheral edema;
rarely: hyponatremia;
Very rare: hypomagnesemia; severe hypomagnesemia may lead to hypocalcemia.
Mental disorders:
uncommon: insomnia;
Rare: agitation, depression, confusion;
very rare: aggression, hallucinations.
From the nervous system:
common: headache;
infrequently: dizziness, weakness, paresthesia, drowsiness;
Rare: taste disturbance.
On the part of the organs of vision:
Rare: blurred vision.
Hearing and labyrinth disorders:
uncommon: vertigo.
From the respiratory system, chest organs and mediastinum:
Rare: bronchospasm.
From the digestive tract:
often: abdominal pain, constipation, diarrhea, bloating, nausea, vomiting;
uncommon: dry mouth;
rarely: stomatitis, gastrointestinal candidiasis;
very rare: microscopic colitis.
From the hepatobiliary system:
uncommon: increased liver enzymes;
Rare: hepatitis with or without jaundice;
very rare: hepatic failure, encephalopathy in patients with liver disease.
Skin and subcutaneous tissue disorders:
infrequently: dermatitis, itching, urticaria, rash;
Rare: alopecia, photosensitivity;
very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:
uncommon: fracture of the hip, wrist or spine (see section "Special warnings and precautions for use");
Rare: arthralgia, myalgia;
very rare: muscle weakness.
From the kidneys and urinary system:
very rare: interstitial nephritis (in some patients - simultaneously with renal failure).
From the reproductive system and mammary glands:
very rare: gynecomastia.
General disorders and administration site conditions:
Rare: weakness, increased sweating.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
7 tablets in an aluminum blister, 1 or 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Optimus Generics Limited.
Location of the manufacturer and its business address
Plot No S-8, S-9, S-13 & S-14, APIIC, Pharma Sez, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, In-509 301, India.
