Esomeprazole Sodium

Clinical Trials Experience With Intravenous NEXIUM

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 intravenous esomeprazole is based on results from clinical trials conducted in four different populations including patients having symptomatic GERD with or without a history of erosive esophagitis (n=199), patients with erosive esophagitis (n=160), healthy subjects (n=204) and patients with bleeding gastric or duodenal ulcers (n=375).

The data described below reflect exposure to NEXIUM I.V. for Injection in 359 patients. NEXIUM I.V. for Injection was studied only in actively-controlled trials. The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, 28% Other, and had either erosive reflux esophagitis (44%) or GERD (56%). Most patients received doses of either 20 or 40 mg either as an infusion or an injection. Adverse reactions occurring in ≥ 1% of patients treated with intravenous esomeprazole (n=359) in clinical trials are listed below:

Table 2 : Adverse reactions occurring at an incidence ≥ 1% in the NEXIUM I.V. group

Intravenous treatment with esomeprazole 20 and 40 mg administered as an injection or as an infusion was found to have a safety profile similar to that of oral administration of esomeprazole.

Pediatric

A randomized, open-label, multi-national study to evaluate the pharmacokinetics of repeated intravenous doses of once daily esomeprazole in pediatric patients 1 month to 17 years old, inclusive was performed. The safety results are consistent with the known safety profile of esomeprazole and no unexpected safety signals were identified. [See CLINICAL PHARMACOLOGY]

The data described below reflect exposure to NEXIUM I.V. for Injection in 375 patients. NEXIUM I.V. for Injection was studied in a placebo-controlled trial. Patients were randomized to receive NEXIUM I.V. 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 received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for a total treatment duration of 72 hours. After the initial 72-hour period, all patients received oral proton pump inhibitor (PPI) for 27 days.

Table 3 : Incidence (%) of adverse reactions that occurred in greater than 1% of patients within 72 hours after start of treatment*

With the exception of injection site reactions described above, intravenous treatment with esomeprazole administered as an injection or as an infusion was found to have a safety profile similar to that of oral administration of esomeprazole.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NEXIUM. 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.

Postmarketing Reports - There have been spontaneous reports of adverse events with postmarketing use of esomeprazole. These reports occurred rarely and are listed below by body system:

Blood And Lymphatic System Disorders: agranulocytosis, pancytopenia;

Eye Disorders: blurred vision;

Gastrointestinal Disorders: pancreatitis; stomatitis; microscopic colitis;

Hepatobiliary Disorders: hepatic failure, hepatitis with or without jaundice;

Immune System Disorders: anaphylactic reaction/shock;

Infections and Infestations: GI candidiasis;

Metabolism and nutritional disorders: hypomagnesemia;

Musculoskeletal And Connective Tissue Disorders: muscular weakness, myalgia, bone fracture;

Nervous System Disorders: hepatic encephalopathy, taste disturbance;

Psychiatric Disorders: aggression, agitation, depression, hallucination;

Renal and Urinary Disorders: interstitial nephritis;

Reproductive System and Breast Disorders: gynecomastia;

Respiratory, Thoracic and Mediastinal Disorders: bronchospasm;

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

Other adverse events not observed with NEXIUM, but occurring with omeprazole can be found in the omeprazole package insert, ADVERSE REACTIONS section.

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

The effect of intravenous esomeprazole on intragastric pH was determined in two separate studies. In the first study, 20 mg of NEXIUM I.V. 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 NEXIUM I.V. 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.

Table 4 : Effect of NEXIUM I.V. for Injection on Intragastric pH on Day 5

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 – 64.4) and 4.8 % (1.8 – 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 – 60.3) and 15.1 % (9.5 – 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.

In oral studies, the effect of NEXIUM 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 6-12 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.

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]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

Human gastric biopsy specimens have been obtained from more than 3,000 patients 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 NEXIUM (10, 20 or 40 mg/day) up to 6-12 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.

NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of NEXIUM 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

The pharmacokinetic profile of NEXIUM I.V. 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 NEXIUM I.V. for Injection by constant rate over 30 minutes for five days. The results are shown in the following table:

Table 5 : Pharmacokinetic Parameters of NEXIUM Following I.V. Dosing for 5 days

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 (100.5-122.7 μmol*h/L), Cmax 15.0 μmol/L (13.5-16.6 μmol/L), and steady state plasma concentration (Css) 3.9 μmol/L (3.5-4.5 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.

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 220 μmol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.

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 15-20% 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.

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.

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.

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.

In oral studies, the AUC and Cmax 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.

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 NEXIUM IV were 183% and 60% higher in pediatric patients aged 6 – 11 years and 12 –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 1-11 months of age, 10 mg for pediatric patients 1-17 years with body weight < 55 kg, and 20 mg for pediatric patients 1-17 years with body > 55 kg would achieve comparable steady-state plasma exposures (AUC0-24) to those observed in adult patients administered 20 mg of NEXIUM I.V. once every 24 hours. Further, increasing the infusion duration from 3 minutes to 10 minutes or 30 minutes was predicted to produce steady-state Cmax values that were comparable to those observed in adult patients at the 40 mg and 20 mg NEXIUM I.V. doses.

In oral studies, the AUC and Cmax 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.

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, Use In Specific Populations].

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, Use in Specific Populations].

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

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.

Animal Toxicology And/Or Pharmacology

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Pregnancy, Animal Data].

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 57 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg /kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

Clinical Studies

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 NEXIUM 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 22-24 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 6.0 mcg/kg of pentagastrin.

In these studies, after 10 days of once daily administration, the intravenous dosage forms of NEXIUM 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.

Table 6 : Mean (SD) BAO and MAO measured 22-24 hours post-dose following once daily oral and intravenous administration of esomeprazole for 10 days in GERD patients with or without a history of erosive esophagitis

Bleeding Gastric or Duodenal Ulcers

In a randomized, double blind, placebo-controlled clinical study, 764 patients were randomized to receive NEXIUM I.V. 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 72hour 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 NEXIUM I.V. 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 Senantiomer esomeprazole.

• Advise patients to let their healthcare provider know if they are taking, or begin taking other medications, because NEXIUM can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [see DRUG INTERACTIONS].
• Let patients know that antacids may be used while taking NEXIUM.
• Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see WARNINGS AND PRECAUTIONS].
• Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see WARNINGS AND PRECAUTIONS].

Esomeprazole is in a group of drugs called proton pump inhibitors. Esomeprazole decreases the amount of acid produced in the stomach.

Esomeprazole is used to treat symptoms of gastroesophageal reflux disease (GERD) and other conditions involving excessive stomach acid such as Zollinger-Ellison syndrome. Esomeprazole is also used to promote healing of erosive esophagitis (damage to your esophagus caused by stomach acid).

Esomeprazole may also be given to prevent gastric ulcer caused by infection with helicobacter pylori (H. pylori), or by the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Esomeprazole is not for immediate relief of heartburn symptoms.

Esomeprazole may also be used for purposes not listed in this medication guide.

This medication can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking esomeprazole and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

• GERD (Acid Reflux, Heartburn)
• Heartburn
• Peptic Ulcer (Stomach Ulcer)
• Reflux Laryngitis

Contraindications

• Known hypersensitivity to esomeprazole, any ingredient in the formulation, or other substituted benzimidazoles (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole).1 34

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, anaphylactic shock) reported.1 34

Gastric Malignancy

Response to esomeprazole does not preclude presence of occult gastric neoplasm.1 34

Atrophic Gastritis

Atrophic gastritis reported occasionally with long-term omeprazole use.1 34

Clostridium difficile Infection

Proton-pump inhibitors associated with possible increased (1.4–2.75 times) risk of Clostridium difficile infection, including C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis).335 336 339 340 Many patients also had other risk factors for CDAD.335 May be severe; colectomy and, rarely, death reported.335

Use the lowest effective dosage and shortest duration of therapy appropriate for the patient's clinical condition.335

Consider CDAD if persistent diarrhea develops and manage accordingly; initiate supportive therapy (e.g., fluid and electrolyte management), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.335 336

Bone Fracture

Several observational studies suggest that use of proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., ≥1 year), may be associated with increased risk of osteoporosis-related fractures of the hip, wrist, or spine.1 34 35 300 301 302 303 304 305 Magnitude of risk is unclear;35 300 301 302 303 304 305 310 causality not established.305 FDA is continuing to evaluate this safety concern.305

Use the lowest effective dosage and shortest duration of therapy appropriate for the patient’s clinical condition.1 34 35 301 303 305 307

Individuals at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D; assess and manage these patients’ bone health according to current standards of care.1 34 35 303 305 307

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, reported rarely in patients receiving long-term therapy (≥3 months or, in most cases, >1 year) with proton-pump inhibitors, including esomeprazole.1 34 317 318 319 320 321 322 323 324 325 326 327 328 329 330 Serious adverse effects include tetany, seizures, tremors, carpopedal spasm, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia), and abnormal QT interval.1 34 318 319 321 322 323 325 327 328 329 Paresthesia, muscle weakness, muscle cramps, lethargy, fatigue, and unsteadiness may occur.319 320 321 325 330 Most patients required magnesium replacement and discontinuance of the proton-pump inhibitor.1 34 317 319 321 322 323 324 325 326 327 330 Hypomagnesemia resolved within 1 week (median) following discontinuance and recurred within 2 weeks (median) of rechallenge.327

In patients expected to receive long-term proton-pump inhibitor therapy or in patients currently receiving digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), consider measuring serum magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1 34 319 326 327 328 330

Cardiovascular Effects

Preliminary safety data from 2 long-term clinical trials comparing esomeprazole or omeprazole with antireflux surgery in patients with severe GERD raised concerns about a potential increased risk of cardiac events (e.g., MI, heart failure, sudden death) in patients receiving these drugs.36 37 38 After reviewing data from these and other studies, FDA has concluded that long-term use of these drugs is not likely to be associated with an increased risk of such cardiac events.36 37 38 FDA recommends that clinicians continue to prescribe and patients continue to use these drugs in the manner described in the manufacturers’ labelings.36 37 38

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).29 30

Use of Fixed Combinations

When used in fixed combination with naproxen, consider the cautions, precautions, and contraindications associated with naproxen.342

Specific Populations

Category B.1 34

Not known whether esomeprazole is distributed into milk, but omeprazole is distributed into milk.1 34 Discontinue nursing or the drug.1 34

Safety and efficacy of oral esomeprazole for short-term (4–8 weeks) treatment of GERD established in pediatric patients 1–17 years of age.1 Adverse effects and pharmacokinetics in children and adolescents similar to those reported in adults.1

Safety and efficacy of oral esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD established in infants 1 month to <1 year of age.1 Oral esomeprazole was not more effective than placebo in a randomized, controlled, treatment-withdrawal study in infants 1–11 months of age with symptomatic GERD.1 Common adverse effects include irritability and vomiting.1

Efficacy of oral esomeprazole not established in infants <1 month of age.1

Safety and efficacy of IV esomeprazole for short-term treatment of GERD with erosive esophagitis established in pediatric patients 1 month to 17 years of age.34 Adverse effects consistent with the drug's known safety profile.34

Safety and efficacy of IV esomeprazole in neonates <1 month of age not established.34

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 34

Use with caution in patients with severe hepatic impairment.1 20 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Oral: Headache, diarrhea, nausea, flatulence, abdominal pain, constipation, dry mouth.1 19

IV: Similar adverse effects as oral esomeprazole; also injection site reaction, dizziness/vertigo, pruritus.34

• Importance of swallowing capsule intact, without crushing or chewing.1

• Importance of taking 1 hour before a meal.1

• If capsule contents are mixed with applesauce for administration, importance of applesauce being soft enough to swallow without chewing.1 Importance of not using hot applesauce.1 Importance of immediately swallowing mixture without crushing or chewing;1 do not store for later use.1

• If oral suspension is used, importance of mixing packet contents with an appropriate amount of water, allowing mixture to thicken for 2–3 minutes, and then drinking mixture (without crushing or chewing the granules) within 30 minutes of preparation.1

• Importance of advising patients that use of multiple daily doses of the drug for an extended period of time may increase the risk of fractures of the hip, wrist, or spine.1 305

• Risk of hypomagnesemia; importance of immediately reporting and seeking care for any cardiovascular or neurologic manifestations (e.g., palpitations, dizziness, seizures, tetany).1

• Possible increased risk of Clostridium difficile infection; importance of contacting a clinician if persistent watery stools, abdominal pain, and fever occur.335

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Antacids may be used concomitantly as needed for pain relief.1

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 34

• Importance of informing patients of other important precautionary information. (See Cautions.)