Esomeprazole (EC) and Domperidone (SR) Capsules 20mg /30mg(PRFACID-DXR); (PROSIUMD)

Esomeprazole (EC) and Domperidone (SR) Capsules 20mg /30mg; 40mg/30mg (PRFACID-DXR); (PROSIUM-D)
Esomeprazole (EC) and Domperidone (SR) Capsules 40mg /30mg; 40mg/30mg (PRFACID-DXR); (PROSIUM-D)

Name of the medicinal product

a) Esomeprazole (EC) and Domperidone (SR) Capsules 20mg/30mg

b) Esomeprazole (EC) and Domperidone (SR) Capsules 40mg/30mg

Composition

a) Each Esomeprazole (EC) and Domperidone (SR) 30mg/20mg capsule contains:

Esomeprazole Magnesium           20 mg

(as enteric-coated pellets)

Domperidone                                30 mg

(as sustained-release pellets)

Excipients q.s.

b) Each Esomeprazole (EC) and Domperidone (SR) 40mg/30mg capsule contains:

Esomeprazole Magnesium          40 mg

(as enteric-coated pellets)

Domperidone                              30 mg

(as sustained-release pellets)

Excipients q.s.

Dosage Form

Capsule for oral use

Description

Esomeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors (PPI?s) that do not exhibit anticholinergic or histamine H₂-receptor antagonist properties but suppress gastric acid secretion by inhibiting the gastric H⁺/K⁺ ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, esomeprazole has been characterized as a gastric PPI. Esomeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, esomeprazole is protonated, accumulates, and is transformed into an active sulfonamide.

Domperidone is a derivative of benzimidazole that possesses both pro-kinetic and anti-emetic properties due to its inhibitory action at dopamine D₂-receptors.

Pharmacology

Pharmacodynamics

Esomeprazole

Mechanism of Action

Esomeprazole is a proton-pump inhibitor (PPI) that suppresses gastric acid secretion by specific inhibition of the H⁺/K⁺-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulfonamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

Anti-Secretory Activity

The effect of esomeprazole on intragastric pH was determined in patients with symptomatic gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, esomeprazole 40 mg and 20 mg capsules were administered over 5 days. The results are shown in the following table:

Effect on Intragastric pH on Day 5 (N=36)

In a second study, the effect on intragastric pH of esomeprazole 40 mg administered once daily over a 5-day period was similar to the first study (% time with pH>4 was 68% or 16.3 hours).

Serum Gastrin Effects

The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6 to 12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within 2 to 3 months of therapy and returned to baseline levels within 4 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like (ECL) cell hyperplasia and increased serum chromogranin A (CgA) levels. The increased CgA levels may cause false-positive results in diagnostic investigations for neuroendocrine tumours.

ECL Cell Effects

Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia or neoplasia has been found in these patients.

In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6 to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia or neoplasia in the gastric mucosa.

Endocrine Effects

Esomeprazole had no effect on thyroid function when given in oral doses of 20 mg or 40 mg for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 mg or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

Domperidone

Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors. Studies in humans have shown oral domperidone to increase lower oesophagal pressure, improve gastroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Pharmacokinetics

Esomeprazole

Absorption

The AUC after administration of a single 40 mg dose of esomeprazole is decreased by 43% to 53% after food intake, compared to fasting conditions. Esomeprazole should be taken at least 1 hour before meals.

The pharmacokinetic profile of esomeprazole was determined in 36 patients with symptomatic gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg capsules of esomeprazole over a period of 5 days. The results are shown in the following table:

Distribution

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 ?mol/L. The apparent volume of distribution at the steady state in healthy volunteers is approximately 16 L.

Metabolism

Esomeprazole is extensively metabolized in the liver by the cytochrome (CY) P450 enzyme system. The metabolites of esomeprazole lack anti-secretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and dimethyl metabolites. The remaining amount is dependent on CYP3A4, which forms the sulfone metabolite. The CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole since some 3% of Caucasians and 15% to 20% of Asians lack CYP2C19 and are termed poor metabolizers. At the steady-state, the ratio of AUC in poor metabolizers to AUC in the rest of the population (extensive metabolizers) is approximately 2. Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer.

Excretion

The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of the parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the faeces.

Concomitant Use with Clopidogrel

Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loadings dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite.

Special Populations

Geriatric

In oral studies, the AUC and C_max values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at the steady-state.

Pediatric

1 to 11 Months of Age

The pharmacokinetic parameters following repeated dose administration of 1.0 mg/kg esomeprazole in 1 to 11-month-old infants are summarized in the following table.

Summary of PK parameters in 1 month to < 1-year-Olds with GERD Following 7/8 Days of Once-Daily Oral Esomeprazole Treatment

_{*Geometric mean ** Median}

Subsequent pharmacokinetic simulation analyses showed that a dosage regimen of 2.5 mg once daily for pediatric patients with body weight 3-5 kg, 5.0 mg once-daily for >5 to 7.5 kg and 10 mg once-daily for >7.5 to 12 kg would achieve comparable steady-state plasma exposures (AUC) to that observed after 10 mg in 1 to 11-year-olds, and 20 mg in 12 to 18 year-olds as well as adults.

1 to 11 Years of Age

The pharmacokinetics of esomeprazole were studied in pediatric patients with GERD aged 1 to 11 years. Following once-daily dosing for 5 days, the total exposure (AUC) for the 10 mg dose in patients aged 6 to 11 years was similar to that seen with the 20 mg dose in adults and adolescents aged 12 to 17 years. The total exposure for the 10 mg dose in patients aged 1 to 5 years was approximately 30% higher than the 10 mg dose in patients aged 6 to 11 years. The total exposure for the 20 mg dose in patients aged 6 to 11 years was higher than that observed with the 20 mg dose in 12 to 17-year-olds and adults, but lower than that observed with the 40 mg dose in 12 to 17-year-olds and adults.

Summary of PK Parameters in 1 to 11-Year-Olds with GERD Following 5 Days of Once-Daily Oral Esomeprazole Treatment

12 to 17 Years of Age

The pharmacokinetics of esomeprazole was studied in 28 adolescent patients with GERD, aged 12 to 17 years inclusive, in a single-center study. Patients were randomized to receive esomeprazole 20 mg or 40 mg once daily for 8 days. Mean C_max and AUC values of esomeprazole were not affected by body weight or age, and more than dose-proportional increases in mean C_max and AUC values were observed between the two dose groups in the study. Overall, esomeprazole pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD.

Comparison of Pharmacokinetic Parameters in Adolescents with GERD, Aged 12 to 17 Years, and Adults with Symptomatic GERD Following the Repeated Daily Oral Dose Administration of Esomeprazole*

Gender

The AUC and C_max values were slightly higher (13%) in females than in males at the steady-state. Dosage adjustment based on gender is not necessary.

Hepatic Impairment

The steady-state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to 4 patients each with mild (Child-Pugh A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic impairment, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic impairment, the AUCs were two to three times higher than in patients with normal liver function. No dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment (Child-Pugh Classes A and B). However, in patients with severe hepatic impairment (Child-Pugh Class C), a dose of 20 mg once daily should not be exceeded.

Renal Impairment

The pharmacokinetics of esomeprazole in patients with renal impairment is not expected to be altered relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in the urine.

Domperidone

Absorption

In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to extensive first-pass metabolism in the gut wall and liver. Although domperidone`s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15 to 30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

Distribution

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/ml after 2 weeks of oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose. Domperidone is 91% to 93% bound to plasma proteins. Distribution studies with the radiolabeled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of the drug cross the placenta in rats.

Metabolism

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of CYP450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Excretion

Urinary and faecal excretions amount to 31% and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7 to 9 hours in healthy subjects but is prolonged in patients with severe renal impairment.

Indications

For the treatment of adult patients with GERD (gastroesophageal reflux disease) not responding to esomeprazole alone.

Dosage and Administration

One capsule once daily

Contraindications

PREVACID-XDR Capsule is contraindicated in patients with a known hypersensitivity to esomeprazole, domperidone or to substituted benzimidazoles or to any excipients used in the formulation. Hypersensitivity reactions, e.g., angioedema and anaphylactic shock, have been reported with esomeprazole use. This product should not be used whenever stimulation of gastric motility is to be avoided or could be harmful, e.g., in the presence of gastrointestinal haemorrhage, obstruction or perforation.

It is also contraindicated in patients with a prolactin-releasing pituitary tumour (prolactinoma), hepatic and renal impairment.

Warnings and Precautions

Esomeprazole

Concurrent Gastric Malignancy

Symptomatic response to therapy with esomeprazole does not preclude the presence of gastric malignancy.

Clostridium difficile Associated Diarrhea

Published observational studies suggest that proton pump inhibitor (PPI) therapy like esomeprazole may be associated with an increased risk of Clostridium difficile associated diarrhoea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhoea that does not improve.

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

CDAD has been reported with the use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with esomeprazole, refer to package inserts of those antibacterial agents.

Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically thereafter.

Interaction with Clopidogrel

Avoid concomitant use of esomeprazole/omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole/omeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole/omeprazole, consider alternative anti-platelet therapy.

Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose (defined as multiple daily doses), long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines.

Interactions with Diagnostic Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false-positive results in diagnostic investigations for neuroendocrine tumours. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

Drug Interactions

Interference with Antiretroviral Therapy

Concomitant use of atazanavir and nelfinavir with PPIs is not recommended. Co-administration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with PPIs is expected to increase saquinavir concentrations, which may increase the toxicity and require dose reduction.

Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19.

Reduced Concentrations of Atazanavir and Nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1,250 mg twice daily) and omeprazole (40 mg daily), the AUC was decreased by 36% and 92%, the C_max by 37% and 89% and the C_min by 39% and 75%, respectively, for nelfinavir and M8. Following multiple doses of atazanavir (400 mg daily) and omeprazole (40 mg daily, 2 hours before atazanavir), the AUC was decreased by 94%, the C_max by 96% and the C_min by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is, therefore, not recommended.

Increased Concentrations of Saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in the AUC by 82%, in the C_max by 75% and in the C_min by 106%, following multiple dosing of saquinavir/ritonavir (1,000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered on days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with esomeprazole. A dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs for which unchanged serum levels have been reported when given with omeprazole.

Voriconazole

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.

Concomitant Use of Esomeprazole with St John?s wort or Rifampin

Drugs which induce CYP2C19 or CYP3A4 or both (such as St John?s wort or rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St John?s wort, an inducer of CYP3A4. In a crossover study in 12 healthy male subjects, St John?s wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_max and AUC decreased by 37.5% and

37.9%, respectively) and extensive metabolizers (C_max and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of esomeprazole with St John?s wort or rifampin.

Concomitant Use of Esomeprazole with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

Drugs for Which Gastric pH Can Affect Bioavailability

Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, atazanavir, iron salts and digoxin). Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in 2 subjects). Esomeprazole is an enantiomer of omeprazole. Co-administration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.

Effects on Hepatic Metabolism/CYP450 Pathways

Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYP1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.

However, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in the International Normalized Ratio (INR) and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in the INR and prothrombin time.

Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole/omeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of esomeprazole/omeprazole with clopidogrel. When using esomeprazole/omeprazole, consider use of alternative anti-platelet therapy.

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for 1 week to 20 healthy subjects in a crossover study, increased the C_max and AUC of cilostazol by 18% and 26%, respectively. The C_max and AUC of one of its active metabolites, 3,4-dihydro cilostazol, which has four to seven times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore, a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison?s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St John?s wort, an inducer of CYP3A4. In a crossover study in 12 healthy male subjects, St John?s wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_max and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St John?s wort or rifampin with esomeprazole.

Tacrolimus

Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.

Combination Therapy with Clarithromycin

Co-administration of esomeprazole, clarithromycin and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin.

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine is contraindicated.

Methotrexate

Case reports published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Domperidone

Drug Interactions

Concomitant administration of anticholinergic drugs may antagonize the anti-dyspeptic effect of domperidone.

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Separate in vivo interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone’s CYP3A4-mediated first-pass metabolism by these drugs.

With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the C_max and AUC of domperidone at the steady-state were increased approximately three-fold in each of these interaction studies. In these studies, domperidone monotherapy at 10 mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Use with Potent CYP3A4 Inhibitors

Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided.

Cardiovascular Effects

Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. The risk may be higher in patients older than 60 years or at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration the dosing frequency of domperidone should be reduced to once or twice daily, depending on the severity of the impairment, and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly.

Hepatic Impairment

Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see Contraindications). In subjects with mild hepatic impairment (Pugh score 5 to 6, Child-Pugh rating A), limited data indicate that the pharmacokinetics of domperidone is not significantly altered. In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC, C_max and terminal elimination half-life of domperidone were substantially increased; the unbound fraction of domperidone was increased by 25%. Subjects with severe hepatic impairment were not studied.

Pregnancy

There are limited post-marketing data on the use of domperidone in pregnant women. Domperidone is not recommended in pregnancy.

Lactation

Studies have shown that domperidone enters breast milk. It is not known whether this is harmful to the newborn. Therefore, breastfeeding is not recommended for mothers who are taking domperidone.

Pediatric Use

Neurological side effects are rare. Since metabolic functions and the blood-brain barrier are not fully developed in the first months of life, the risk of neurological side effects is higher in young children. Overdosing may cause extra-pyramidal symptoms in children, but other causes should be taken into consideration.

ESOMAC-D Capsules in Special Populations

Renal Impairment

ESOMAC-D Capsules should be used with caution in patients with renal impairment or in those at risk of fluid retention. Patients on prolonged therapy should be reviewed regularly.

Hepatic Impairment

Since domperidone is highly metabolized in the liver, ESOMAC-D Capsules should be not be used in patients with hepatic impairment.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation

Since many drugs are excreted in human milk, caution should be exercised when this drug is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of this product in pediatric patients has not been established.

Undesirable Effects

Esomeprazole

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug ca Overdosage

 not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The safety of esomeprazole was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide, including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6 to 12 months. In general, esomeprazole was well tolerated in both short- and long-term clinical trials.

The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on esomeprazole 20 mg, 2,434 patients on esomeprazole 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse reactions (?1%) in all three groups were headache (5.5, 5, and 3.8, respectively) and diarrhoea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking esomeprazole or omeprazole.

Additional adverse reactions that were reported as possibly or probably related to esomeprazole with an incidence <1% are listed below by body system:

Body as a Whole: Abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial oedema, peripheral oedema, hot flushes, fatigue, fever, flu-like disorder, generalized oedema, leg oedema, malaise, pain, rigours.

Cardiovascular: Flushing, hypertension, tachycardia.

Endocrine: Goiter.

Gastrointestinal (GI): Bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, oesophagal disorder, frequent stools, gastroenteritis, GI haemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue oedema, ulcerative stomatitis, vomiting.

Hearing: Earache, tinnitus.

Hematologic: Anemia, anaemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia.

Hepatic: Bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased.

Metabolic/Nutritional: Glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease. Musculoskeletal: Arthralgia, arthritis aggravated arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica.

Nervous System/Psychiatric: Anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect.

Reproductive: Dysmenorrhea, menstrual disorder, vaginitis.

Respiratory: Asthma aggravated, coughing, dyspnea, larynx oedema, pharyngitis, rhinitis, sinusitis.

Skin and Appendages: Acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculopapular, skin inflammation, sweating increased, urticaria. Special Senses: Otitis media, parosmia, taste loss, taste perversion.

Urogenital: Abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria.

Visual: Conjunctivitis, vision abnormal.

The following potentially clinically significant laboratory changes in clinical trials, irrespective of a relationship to esomeprazole, were reported in ?1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, haemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid-stimulating hormone. Decreases were seen in haemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions included the following: duodenitis, esophagitis, oesophagal stricture, oesophagal ulceration, oesophagal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett?s oesophagus, and mucosal discolouration.

The incidence of treatment-related adverse reactions during a 6-month maintenance treatment was similar to placebo. There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment.

Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse reactions that were reported as possibly or probably related to esomeprazole were diarrhoea (4.3%), headache (3.8%), and abdominal pain (3.8%).

Pediatric

The safety of esomeprazole was evaluated in 316 pediatric and adolescent patients, aged 1 to 17 years, in four clinical trials for the treatment of symptomatic GERD. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhoea (2.8%), headache (1.9%), and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years, the most frequently reported (at least 2%) treatment-related adverse reactions in these patients were headache (8.1%), abdominal pain (2.7%), diarrhoea (2%), and nausea (2%).

The safety of esomeprazole was evaluated in 167 pediatric patients from birth to <1 year of age in three clinical trials. In a study that included 26 pediatric patients from birth to 1 month of age, there were no treatment-related adverse reactions. In a study that included 43 pediatric patients aged 1 to 11 months, the most frequently reported (at least 5%) adverse reactions, irrespective of causality, were irritability and vomiting. In a study that included 98 pediatric patients aged 1 to 11 months, inclusively exposed to esomeprazole for up to 6 weeks (including 39 patients randomized to the withdrawal phase), there were four treatment-related adverse reactions: abdominal pain (1%), regurgitation (1%), tachypnea (1%), and increased ALT (1%).

No new safety concerns were identified in pediatric patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:

Blood and Lymphatic: Agranulocytosis, pancytopenia.

Eyes: Blurred vision.

GI: Pancreatitis; stomatitis; microscopic colitis.

Hepatobiliary: Hepatic failure, hepatitis with or without jaundice.

Immune System: Anaphylactic reaction/shock.

Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhoea.

Metabolism and Nutritional Disorders: Hypomagnesemia.

Musculoskeletal and Connective Tissue: Muscular weakness, myalgia, bone fracture.

Nervous System: Hepatic encephalopathy, taste disturbance.

Psychiatric: Aggression, agitation, depression, hallucination.

Renal and Urinary: Interstitial nephritis.

Reproductive System and Breast: Gynecomastia.

Respiratory, Thoracic and Mediastinal: Bronchospasm.

Skin and Subcutaneous Tissue: Alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).

Domperidone

The safety of domperidone was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies.

All patients were at least 15 years old and received at least one dose of domperidone (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and the median duration of exposure was 28 days (range 1 to 28 days).

Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied: very common (?1/10), common (?1/100 to <1/10), uncommon (?1/1000 to <1/100), rare (?1/10,000 to <1/1000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as ?Not known?.

Postmarketing experience

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.

The extrapyramidal disorder occurs primarily in neonates and infants.

Other central nervous system-related effects of convulsion and agitation also are primarily reported in infants and children.

Additionally, the following side effects have also been noted:

GI Disorders: Diarrhea, GI disorders, including very rare, transient intestinal cramps.

Cardiac Disorders: Ventricular arrhythmias, QTc prolongation, sudden cardiac death.

Overdosage

Esomeprazole

A single oral dose of esomeprazole at 510 mg/kg (about 103 times the human dose on a body surface area basis) was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions.

The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of esomeprazole were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth and other adverse reactions similar to those seen in normal clinical experience.

No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein-bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.

Domperidone

Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.

There is no specific antidote to domperidone; but in the event of overdose, gastric lavage, as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy are recommended. Anticholinergic, antiparkinson drugs may be helpful in controlling extrapyramidal reactions.

Storage and Handling Instructions

Store in a cool and dry place. Protect from light.

Packaging Information

ESOMEPRAZOLE (EC) AND DOMPERIDONE (SR) 20MG /30MG Capsules ??.. Strip pack of 10 capsules
ESOMEPRAZOLE (EC) AND DOMPERIDONE (SR) 30MG /40MG Capsules ??.. Strip pack of 10 capsules

Last updated: November 2013.
Last reviewed: December 2016.

Manufactured in India By:
TAJ LIFE SCIENCES PVT. LTD.
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at: Ahmedabad- Gujarat, INDIA.
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Toll Free Phone: (1800-222-434 / 1800-222825)