ESOMAC Tablets / Granules / Pellets (Esomeprazole magnesium)

Table of Content

Of late, there has been a better understanding of the effects of acid disorders on health and related aspects of life. Well-recognized symptoms, such as heartburn and acid regurgitation are perhaps the key pointers to the existence of acidity but not all patients will necessarily present with them. Symptoms such as dysphagia, odynophagia, globus (lump in the throat), sore throat, laryngitis, water brash and cough are other possible symptoms of an acidity problem, but their diagnostic usefulness is uncertain.

Serious sequelae to untreated, long-standing acid-related disorders can be a pre-cancerous Barrett’s esophagus and strong evidence supports the association of gastroesophageal reflux disease and adenocarcinoma of the esophagus. Other complications include severe erosions of the esophagus, bleeding and formation of strictures.

The key to avoid these unpleasant complications lies in acidity control. The higher the level of acid inhibition, the better is the symptom relief and healing experienced by patients. Omeprazole, the first proton pump inhibitor (PPI) ushered in an era of safe, effective and faster relief from acidity problems. However, this agent is effective only as long as it remains in the system and, thus, is limited by its short-term presence and fast metabolism. This problem has led to certain sub groups of patients requiring higher than standard doses of PPIs to relieve their symptoms, observations from these patients pointed to problem of short serum presence of PPIs. Low bioavailability and short half-life may lead to insufficient symptoms control in some patients. In further research done to overcome these drawbacks, it was observed that the S-isomer was responsible for a large part of omeprazole’s efficacy and this led to the isolation and development of esomeprazole.

Esomeprazole (S-isomer of omeprazole),the first single optical isomer proton pump inhibitor, generally provides better acid control than current racemic proton pump inhibitors and has a favorable pharmacokinetic profile relative to omeprazole. After 5 days’ of treatment, the mean AUC for esomeprazole 20mg was approximately two times higher than that for omeprazole 20mg daily, which possibly explains the higher clinical efficacy with esomeprazole as compared to omeprazole.

Esomeprazole has been proven in numerous studies to afford better acidity control than all other PPIs. In fact, evidence has shown that patients with acidity-related disorders were highly satisfied after switching over from treatment with other PPIs to esomeprazole, thereby, attesting to its faster healing and relief, which is well-documented in literature.

Acid related disorders require lifestyle changes by patients that go along with treatment to ensure the best outcome. However it is not always possible for doctors to elaborate on the different measures a patient can take apart from medications to improve their symptoms. With this thought, the pack of ESOMAC (esomeprazole) has been designed to include a patient information leaflet with details of simple steps that can be followed to reduce acid related symptoms.

ESOMAC with this special patient friendly pack will help deliver more patient oriented relief and healing of acidity related disorders in a faster and effective manner as compared to any other PPI.

                                                                                 

Composition

ESOMAC 20 Tablets

Each tablet contains:

Esomeprazole Magnesium ........................... 20 mg

ESOMAC 40 Tablets

Each tablet contains:

Esomeprazole Magnesium ........................... 40 mg

ESOMAC 10 Granules

Each sachet contains

Esomeprazole Magnesium Trihydrate IP

equivalent to esomeprazole ………………… 10 mg

(as enteric coated pellets)

Dosage Form

Tablet for oral use and granules/pellets for oral suspension.

Pharmacology

Pharmacodynamics

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 sulfenamide. 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 (GERD) 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)

Parameter

Esomeprazole
40 mg

Esomeprazole
20 mg

% Time gastric pH >4* (hours)

70%**/*  (16.8 hours)

53%  (12.7 hours)

Coefficient of variation

26%

37%

Median 24-hour pH

4.9**/*

4.1

Coefficient of variation

16%

27%

* Gastric pH was measured over a 24-hour period

**/* p<0.01 Esomeprazole 40 mg versus esomeprazole 20 mg

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 tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CaA levels and consider repeating the test if initial CgA levels are high.

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.  

Pharmacokinetics

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:

Pharmacokinetic Parameters of Esomeprazole on Day 5 Following Oral Dosing for 5 Days

Parameter* (CV)

Esomeprazole 40 mg

Esomeprazole 20 mg

AUC (µmol*h/L)

12.6 (42%)

4.2 (59%)

Cmax (µmol/L)

4.7 (37%)

2.1 (45%)

Tmax (hour)

1.6

1.6

t1/2 (hour)

1.5

1.2

* Values represent the geometric mean, except the Tmax, which is the arithmetic mean CV = Coefficient of variation

Distribution

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 µmol/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 desmethyl 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 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 feces.

Combination Therapy with Antimicrobials

Esomeprazole magnesium 40 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.

The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant.

Concomitant Use with Clopidogrel

Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading 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.

Concomitant Use with Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA.

Special Populations

Geriatric

In oral studies, the AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at the steady state. Dosage adjustment based on age is not necessary.

Pediatric

1 to 11 month 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

 

1 month to <1 year

Parameter

1.0 mg/kg

AUC (μmol*h/L) (n=7)*

3.51

Css,max (μmol/L) (n=15)*

0.87

t½ (hours) (n=8)*

0.93

tmax (hours) (n=15)**

3.0

*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

 

1 to 5 Year Olds

6 to 11 Year Olds

Parameter

10 mg (N=8)

10 mg (N=7)

20 mg (N=6)

AUC (µmol.h/L) *

4.83

3.70

6.28

Cmax (µmol/L) *

2.98

1.77

3.73

tmax (h)**/*

1.44

1.79

1.75

t½(lambda)z (h)*

0.74

0.88

0.73

Cl/F (L/h) *

5.99

7.84

9.22

* Geometric mean

**/* Arithmetic mean

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 Cmax and AUC values of esomeprazole were not affected by body weight or age, and more than dose-proportional increases in mean Cmax 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*
 

Parameter

12 to 17 Years (N=28)

Adults (N=36)

 

20 mg

40 mg

20 mg

40 mg

AUC (µmol.h/L)

3.65

13.86

4.2

12.6

Cmax (µmol/L)

1.45

5.13

2.1

4.7

tmax (h)

2.00

1.75

1.6

1.6

t1/2(lambda)z (h)

0.82

1.22

1.2

1.5

Data presented are geometric means for AUC, Cmax and t1/2(lambda)z, and median value for tmax.

* Duration of treatment for adolescents aged 12 to 17 years and adults were 8 days and 5 days, respectively. Data were obtained from two independent studies.

Gender

The AUC and Cmax 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 the patients with normal liver function.

Renal Impairment

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

Other pharmacokinetic observations

Co-administration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.

Studies evaluating concomitant administration of esomeprazole and either naproxen (nonselective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs.

Indications

Treatment of GERD

a.    Healing of Erosive Esophagitis

ESOMAC Tablets/Granules are indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4- to 8-week course of ESOMAC Tablets/Granules may be considered.

In infants 1 month to less than 1 year, ESOMAC Granules is indicated for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.

b.    Maintenance of Healing of Erosive Esophagitis

ESOMAC Tablets/Granules are indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months.

c.    Symptomatic GERD

ESOMAC Tablets/Granules are indicated for the short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults and children, 1 year or older.

Risk Reduction of NSAID-Associated Gastric Ulcer

ESOMAC Tablets/Granules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (≥60 years) and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months.

1.    H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy (ESOMAC Tablets/Granules plus amoxicillin and clarithromycin): This triple combination is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.

2.    Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

ESOMAC Tablets/Granules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

Dosage and Administration

The recommended dosages are outlined in the table below. ESOMAC Tablets/Granules 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.

Recommended Dosage Schedule of ESOMAC Tablets/Granules

Indication

Dose

Frequency

GERD

Healing of Erosive Esophagitis

20 mg or 40 mg

Once daily for 4 to 8 weeks*

Maintenance of Healing of Erosive Esophagitis

20 mg

Once daily**

Symptomatic GERD

20 mg

Once daily for 4 weeks^

Pediatric GERD

12 to 17 Years of Age

Healing of Erosive Esophagitis

 

20 mg or 40 mg

 

Once daily for 4 to 8 weeks

Symptomatic GERD

20 mg

Once daily for 4 weeks

1 to 11 Years of Age §

Short-term treatment of Symptomatic GERD

 

10 mg

 

Once daily for up to 8 weeks

Healing of Erosive Esophagitis

  Weight <20 kg

  Weight ≥20 kg

 

 

10 mg

10 mg or 20 mg

 

 

Once daily for 8 weeks

Once daily for 8 weeks

1 month to < 1 year of

 age ‡‡‡

Erosive esophagitis due to acid mediated GERD

Weight 3 kg to 5 kg

Weight >5 kg to 7.5 kg

weight >7.5 kg to 12 kg

 

 

 

 

2.5 mg

5 mg

10 mg

 

 

 

 

Once daily for up to 6 weeks

Once daily for up to 6 Weeks

Once daily for up to 6 Weeks

Risk Reduction of NSAID-Associated Gastric Ulcer

20 mg or 40 mg

Once daily for up to 6 months**

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy

ESOMAC Tablets

Amoxicillin

Clarithromycin

 

40 mg

1000 mg

500 mg

 

Once daily for 10 days

Twice daily for 10 days

Twice daily for 10 days

Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

40 mg

Twice daily#

* The majority of patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be considered.

** Controlled studies did not extend beyond 6 months.

^ If symptoms do not resolve completely after 4 weeks, an additional 4 weeks of treatment may be considered.

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

The dosage of ESOMAC Tablets/Granules in patients with pathological hypersecretory conditions varies with the individual patient. Dosage regimens should be adjusted to individual patient needs.

# Doses up to 240 mg daily have been administered.

‡‡‡ Doses over 1.33 mg/kg/day have not been studied.

         

Contraindications

Esomeprazole is contraindicated in patients with a known hypersensitivity to any component of the formulation or to substituted benzimidazoles. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria.

Warnings and Precautions

General

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 diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea 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 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.

Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue esomeprazole if acute interstitial nephritis develops.

Cyanocobalamin (vitamin B-12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

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. 

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 tumors. Providers should temporarily stop esomeprazole treatment atleast 14 days 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 Cmax by 37% and 89% and the Cmin 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 Cmax by 96% and the Cmin 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 Cmax by 75% and in the Cmin 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. 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.

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 hydroxymethotrexate, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Drugs for Which Gastric pH Can Affect Bioavailability

Due to its effects on gastric acid secretion, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Esomeprazole is an enantiomer of omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). 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.

Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use esomeprazole with caution in transplant patients receiving MMF.

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, postmarketing 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.

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 Cmax and AUC of cilostazol by 18% and 26%, respectively. The Cmax and AUC of one of its active metabolites, 3, 4-dihydrocilostazol, 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 (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St John’s Wort or rifampin with esomeprazole.

Interaction with Clopidogrel

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

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 as drug interactions can lead to serious adverse reactions.

Hepatic Impairment

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.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of esomeprazole use in pregnancy. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use.  Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, esomeprazole tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Esomeprazole is likely present in human milk. Esomeprazole is an s-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk. Caution should be exercised when esomeprazole is administered to nursing women.

Pediatric Use

The safety and effectiveness of esomeprazole have been established in pediatric patients 1 to 17 years of age for short-term treatment (up to eight weeks) of GERD. The safety and effectiveness of esomeprazole have been established in pediatric patients 1 month to less than 1 year for short term treatment (up to six weeks) for erosive esophagitis due to acid-mediated GERD. However, safety and efficacy have not been established in patients less than 1 month of age.

1 to 17 Years of Age

Use of esomeprazole in pediatric and adolescent patients, 1 to 17 years of age, for short-term treatment (up to 8 weeks) of GERD is supported by extrapolation of results, from adequate and well-controlled studies in adults and safety and pharmacokinetic studies performed in pediatric and adolescents.

Erosive esophagitis due to acid mediated GERD in infants 1 month to less than one year of age

Use of esomeprazole in pediatric patients 1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid mediated GERD is supported by extrapolation of results, from adequate and well-controlled studies in adults and safety, pharmacokinetic and pharmacodynamic studies performed in pediatric patients.

Symptomatic GERD in infants 1 month to less than one year of age

A multicenter, randomized, double-blind, controlled, treatment-withdrawal study of 98 patients (aged 1 to 11 months) showed that there was no statistically significant difference between esomeprazole and placebo in the rate of discontinuation due to symptom worsening. Patients were enrolled if they had either a clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven GERD. Twenty of 98 enrolled patients underwent endoscopy, and 6 patients were found to have erosive esophagitis on endoscopy at baseline. All patients received esomeprazole granules/pellets once daily during a two-week, open-label phase of the study.

There were 80 patients who attained a pre-specified level of symptom improvement and who entered the double-blind phase, in which they were randomized in equal proportions to receive esomeprazole or placebo for the next four weeks. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week, treatment-withdrawal phase.

The following pharmacokinetic and pharmacodynamic information was obtained in pediatric patients with GERD aged birth to less than one year of age. In infants (1 to 11 months old, inclusive) given esomeprazole 1mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults. Apparent clearance (CL/F) increases with age in pediatric patients from birth to 2 years of age.

Neonates 0 to 1 month of age

Following administration of oral esomeprazole in neonates the geometric mean (range) for the apparent clearance (CL/F) was 0.55 L/h/kg (0.25-1.6 L/h/kg).

The safety and effectiveness of esomeprazole in neonates have not been established.

Geriatric Use

Of the total number of patients who received esomeprazole in clinical trials, 1,459 were 65 to 74 years of age, and 354 patients were ≥75 years of age.

No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but the greater sensitivity of some elderly individuals cannot be ruled out.

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot 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 diarrhea (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, sub-sternal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors.

Cardiovascular: Flushing, hypertension, tachycardia.

Endocrine: Goiter.

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

Hearing: Earache, tinnitus.

Hematologic: Anemia, anemia 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 edema, pharyngitis, rhinitis, sinusitis.

Skin and Appendages: Acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, 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, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid-stimulating hormone. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions included the following: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

The incidence of treatment-related adverse reactions during 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 diarrhea (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 diarrhea (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%), diarrhea (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.

Combination Treatment with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with esomeprazole plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using esomeprazole, amoxicillin or clarithromycin alone.

The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with esomeprazole alone.

For more information on adverse reactions with amoxicillin or clarithromycin, refer to their package inserts.

In clinical trials using combination therapy with esomeprazole plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed.

For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts.

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 diarrhea

Metabolism and Nutritional Disorders: Hypomagnesemia, with or without hypocalcaemia and/or hypokalaemia

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: Gynaecomastia.

Respiratory, Thoracic and Mediastinal: Bronchospasm.

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

Overdosage

A single oral dose of esomeprazole at 510 mg/kg (about 124 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.

Shelf-Life

24 months from the date of manufacture.

Storage and Handling Instructions

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

Packaging Information

ESOMAC Tablets 20 mg …….. Strip pack of 10 tablets
ESOMAC Tablets 40 mg …….. Strip pack of 10 tablets
ESOMAC 10……………………...Box containing 7 sachets

Last updated: April 2016.
Last reviewed: December 2016.