Esomeprazole injection

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Use care if you have risks for soft, brittle bones (osteoporosis). Some of these risks include drinking alcohol, smoking, taking steroids, taking drugs to treat seizures, or having family members with osteoporosis. Talk with your doctor about your risks of osteoporosis.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take esomeprazole injection.
• Call your doctor if you have throat pain, chest pain, very bad belly pain, trouble swallowing, or signs of a bleeding ulcer like black, tarry, or bloody stools, throwing up blood, or throw up that looks like coffee grounds. These may be signs of a worse health problem.
• Take calcium and vitamin D as you were told by your doctor.
• This medicine may raise the chance of hip, spine, and wrist fractures in people with weak bones (osteoporosis). The chance may be higher if you take this medicine in high doses or for longer than a year, or if you are older than 50 years old. Talk with your doctor.
• Low magnesium levels have rarely happened in people taking drugs like this one for at least 3 months. Most of the time, this has happened after 1 year of care. You will need to have your blood work checked if you will be taking esomeprazole injection for a long time or if you take certain other drugs like digoxin or water pills. Talk with your doctor.
• Long-term treatment (for instance longer than 3 years) with drugs like this one has rarely caused low vitamin B-12 levels. Talk with the doctor.
• Lupus has happened with this medicine, as well as lupus that has gotten worse in people who already have it. Tell your doctor if you have lupus. Call your doctor right away if you have signs of lupus like a rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using esomeprazole injection while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.
• Keep taking esomeprazole injection as you have been told by your doctor or other health care provider, even if you feel well.
• Ask your doctor before you take antacids with this medicine.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Feeling sleepy.
• Belly pain.
• Loose stools (diarrhea).
• Hard stools (constipation).
• Gas.
• Dry mouth.
• Upset stomach.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If you need to store esomeprazole injection at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take esomeprazole injection or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to esomeprazole injection. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Treatment of Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis

Esomeprazole sodium for Injection is indicated for the short-term treatment of GERD with erosive esophagitis in adults and pediatric patients 1 month to 17 years, inclusively as an alternative to oral therapy when oral esomeprazole is not possible or appropriate.

Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults

Esomeprazole sodium for Injection is indicated for risk reduction of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers in adults.

Mechanism of Action

Esomeprazole is a proton pump inhibitor 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 sulphenamide. 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.

Pharmacodynamics

Antisecretory Activity

The effect of intravenous esomeprazole on intragastric pH was determined in two separate studies. In the first study, 20 mg of esomeprazole sodium for injection was administered intravenously once daily at constant rate over 30 minutes for 5 days. Twenty-two healthy subjects were included in the study. In the second study, 40 mg of esomeprazole sodium for injection was administered intravenously once daily at constant rate over 30 minutes for 5 days. Thirty-eight healthy subjects were included in the study.

Gastric pH was measured over a 24-hour period

In a study in H. pylori negative healthy Caucasian volunteers (n =24), the % time over 24 hours (95 % CI) when intragastric pH was > 6 and > 7 was 52.3 % (40.3 to 64.4) and 4.8 % (1.8 to 7.8), respectively during administration of esomeprazole as an intravenous infusion of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/h for 23.5 hours.

In a study in H. pylori positive and H. pylori negative healthy Chinese subjects (overall n = 19), the % time over 24 hours (95 % CI) when intragastric pH was > 6 and > 7 was 53% (45.6 to 60.3) and 15.1 % (9.5 to 20.7) in the overall study population during administration of esomeprazole as an intravenous infusion of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/h for 23.5 hours. When comparing H. pylori positive (n =8) vs. negative (n =11) subjects, the percentage of time in a 24 h period with intragastric pH > 6 [59 % vs. 47 %] and with pH > 7 [17 % vs. 11 %] tended to be larger in the H. pylori positive subjects.

Serum Gastrin Effects

In oral studies, 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 two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like 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 CgA levels and consider repeating the test if initial CgA levels are high.

Enterochromaffin-like (ECL) Cell Effects

There are no data available on the effects of intravenous esomeprazole on ECL cells.

In 24-month carcinogenicity studies of oral omeprazole in rats, a dose-related significant occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Nonclinical Toxicology (13.1)] . Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H 2-receptor antagonists.

Human gastric biopsy specimens have been obtained from more than 3,000 patients (both children and adults) treated orally 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 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 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 pharmacokinetic profile of esomeprazole sodium for injection 20 mg and 40 mg was determined in 24 healthy volunteers for the 20 mg dose and 38 healthy volunteers for the 40 mg dose following once daily administration of 20 mg and 40 mg of esomeprazole sodium for injection by constant rate over 30 minutes for five days. The results are shown in the following table:

Values represent the geometric mean (95% CI)

During administration of esomeprazole over 24 hours as an intravenous infusion of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/h for 23.5 hours (for a total of 24 hours) in healthy volunteers (n = 24), esomeprazole PK parameters [geometric mean value (95 % CI)] were as follows: AUCt 111.1 µmol*h/L (100.5 to 122.7 µmol*h/L), C max 15.0 µmol/L (13.5 to 16.6 µmol/L), and steady state plasma concentration (C ss) 3.9 µmol/L (3.5 to 4.5 µmol/L ).

In a Caucasian healthy volunteer study evaluating esomeprazole 80 mg over 30 minutes, followed by 8 mg/h over 23.5 h, systemic esomeprazole exposures were modestly higher (~ 17 %) in the CYP2C19 intermediate metabolizers (IM; n = 6 ) compared to extensive metabolizers (EM; n = 17) of CYP2C19. Similar PK differences were noted across these genotypes in a Chinese healthy volunteer study that included 7 EMs and 11 IMs. There is very limited PK information for poor metabolizers (PM) from these studies.

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 steady state in healthy volunteers is approximately 16 L.

Elimination

Metabolism

Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory 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 sulphone metabolite. 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 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

Esomeprazole is excreted as metabolites primarily in urine but also in feces. Less than 1% of parent drug is excreted in the urine. Esomeprazole is completely eliminated from plasma, and there is no accumulation during once daily administration. The plasma elimination half-life of intravenous esomeprazole is approximately 1.1 to 1.4 hours and is prolonged with increasing dose of intravenous esomeprazole. During administration of esomeprazole over 24 hours as an intravenous infusion of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/h for 23.5 hours plasma clearance (CL) is approximately 5.9 to 7.2 L/h.

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 C max and 23% reduction in the AUC of MPA.

Specific Populations

Investigation of age, gender, race, renal, and hepatic impairment and metabolizer status has been made previously with oral esomeprazole. The pharmacokinetics of esomeprazole is not expected to be affected differently by intrinsic or extrinsic factors after intravenous administration compared to oral administration. The same recommendations for dose adjustment in special populations are suggested for intravenous esomeprazole as for oral esomeprazole.

Age: Geriatric Population

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 steady state. Dosage adjustment based on age is not necessary.

Age: Pediatric Population

In a randomized, open-label, multi-national, repeated dose study, esomeprazole PK was evaluated following a once-daily 3-minute injection in a total of 50 pediatric patients 0 to 17 years old, inclusive. Esomeprazole plasma AUC values for 20 mg esomeprazole were 183% and 60% higher in pediatric patients aged 6 to 11 years and 12 to 17 years respectively compared to adults given 20 mg. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 0.5 mg/kg once-daily for pediatric patients 1 to 11 months of age, 10 mg for pediatric patients 1 to 17 years with body weight <55 kg, and 20 mg for pediatric patients 1 to 17 years with body >55 kg would achieve comparable steady-state plasma exposures (AUC 0-24) to those observed in adult patients administered 20 mg of esomeprazole once every 24 hours. Further, increasing the infusion duration from 3 minutes to 10 minutes or 30 minutes was predicted to produce steady-state C max values that were comparable to those observed in adult patients at the 40 mg and 20 mg esomeprazole doses.

Gender

In oral studies, the AUC and C max values were slightly higher (13%) in females than in males at steady state. Similar differences have been seen for intravenous administration of esomeprazole. Dosage adjustment based on gender is not necessary.

Hepatic Impairment

In oral studies, the steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to 4 patients each with mild (Child-Pugh Class 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 insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child-Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child-Pugh Class C) a maximum dose of 20 mg once daily should not be exceeded [see Dosage and Administration (2.2), Use in Specific Populations (8.6)] .

There are no pharmacokinetic data available for esomeprazole administered as continuous intravenous administration in patients with liver impairment. The pharmacokinetics of omeprazole 80 mg over 30 minutes, followed by 8 mg/h over 47.5 hours in patients with mild (Child-Pugh Class A; n=5), moderate (Child-Pugh Class B; n=4) and severe (Child-Pugh Class C; n=3) liver impairment were compared to those obtained in 24 male and female healthy volunteers.In patients with mild and moderate liver impairment, omeprazole clearance and steady state plasma concentration was approximately 35% lower and 50% higher, respectively, than in healthy volunteers. In patients with severe liver impairment, the omeprazole clearance was 50% of that in healthy volunteers and the steady state plasma concentration was double that in healthy volunteers.

For adult patients with bleeding gastric or duodenal ulcers and liver impairment, no dosage adjustment of the initial esomeprazole 80 mg infusion is necessary. For adult patients with mild to moderate liver impairment (Child -Pugh Classes A and B), a maximum continuous infusion of esomeprazole 6 mg/h should not be exceeded. For adult patients with severe liver impairment (Child -Pugh Class C), a maximum continuous infusion of 4 mg/h should not be exceeded [see Dosage and Administration (2.2), Use in Specific Populations (8.6)] .

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.

Microbiology

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile.

Acid Suppression in Gastroesophageal Reflux Disease (GERD)

Four multicenter, open-label, two-period crossover studies were conducted to compare the pharmacodynamic efficacy of the intravenous formulation of esomeprazole (20 mg and 40 mg) to that of esomeprazole delayed-release capsules at corresponding doses in patients with symptoms of GERD, with or without erosive esophagitis. The patients (n=206, 18 to 72 years old; 112 female; 110 Caucasian, 50 Black, 10 Asian, and 36 Other Race) were randomized to receive either 20 or 40 mg of intravenous or oral esomeprazole once daily for 10 days (Period 1), and then were switched in Period 2 to the other formulation for 10 days, matching their respective dose level from Period 1. The intravenous formulation was administered as a 3-minute injection in two of the studies, and as a 15-minute infusion in the other two studies. Basal acid output (BAO) and maximal acid output (MAO) were determined 22 to 24 hours post-dose on Period 1, Day 11; on Period 2, Day 3; and on Period 2, Day 11. BAO and MAO were estimated from 1-hour continuous collections of gastric contents prior to and following (respectively) subcutaneous injection of 6 mcg/kg of pentagastrin.

In these studies, after 10 days of once daily administration, the intravenous dosage forms of esomeprazole 20 mg and 40 mg were similar to the corresponding oral dosage forms in their ability to suppress BAO and MAO in these GERD patients (see table below).

There were no major changes in acid suppression when switching between intravenous and oral dosage forms.

Bleeding Gastric or Duodenal Ulcers

In a randomized, double blind, placebo-controlled clinical study, 764 patients were randomized to receive esomeprazole sodium for injection (n=375) or placebo (n=389). The population was 18 to 98 years old; 68% Male, 87% Caucasian, 1% Black, 7% Asian, 4% Other, who presented with endoscopically confirmed gastric or duodenal ulcer bleeding. Following endoscopic hemostasis, patients were randomized to either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour for a total of 72 hours or to placebo for 72 hours. After the initial 72-hour period, all patients received oral proton pump inhibitor (PPI) for 27 days. The occurrence of rebleeding within 3 days of randomization was 5.9% in the esomeprazole sodium for injection treated group compared to 10.3% for the placebo group (treatment difference -4.4%; 95% confidence interval: -8.3%, -0.6%; p=0.03). This treatment difference was similar to that observed at Day 7 and Day 30, during which all patients were receiving an oral PPI.

A randomized, double blind, placebo-controlled single-center study conducted in Hong Kong also demonstrated a reduction compared to placebo in the risk of rebleeding within 72 hours in patients with bleeding gastric or duodenal ulcers who received racemic omeprazole, 50% of which is the S-enantiomer esomeprazole.