Esomeprazole Capsules: Package Insert / Prescribing Info

1.1 Healing of Erosive Esophagitis (EE)

Adults

Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 weeks to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 week to 8 week course of esomeprazole magnesium delayed-release capsules may be considered.

Pediatric Patients 12 Years to 17 Years of Age

Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 weeks to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.

1.2 Maintenance of Healing of EE

Esomeprazole magnesium delayed-release capsules are indicated for the maintenance of healing of EE in adults. Controlled studies do not extend beyond 6 months.

1.3 Treatment of Symptomatic GERD

Adults

Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 weeks to 8 weeks) of heartburn and other symptoms associated with GERD in adults.

Pediatric Patients 12 Years to 17 Years of Age

Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age.

1.4 Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID) Associated Gastric Ulcer

Esomeprazole magnesium delayed-release capsules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in adult patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (60 years and older) and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months.

1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Triple Therapy

Esomeprazole magnesium delayed-release capsules in combination with amoxicillin and clarithromycin is indicated for the treatment of adult patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori.

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 [see Clinical Pharmacology (12.4) and the prescribing information for clarithromycin].

1.6 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.

2.1 Recommended Dosage in Adults by Indication

Table 1 shows the recommended adult dosage of esomeprazole magnesium delayed-release capsules by indication.

The duration of esomeprazole magnesium delayed-release capsules treatment should be based on available safety and efficacy data specific to the defined indication and dosing frequency and individual patient medical needs. Esomeprazole magnesium delayed-release capsules should only be initiated and continued if the benefits outweigh the risks of treatment.

2.2 Recommended Dosage in Pediatric Patients by Indication

Table 2 shows the recommended dosage of esomeprazole magnesium delayed-release capsules in pediatric patients by indication.

2.3 Preparation and Administration Instructions

• Take esomeprazole magnesium delayed-release capsules at least one hour before meals [see Clinical Pharmacology (12.3)].
• Antacids may be used concomitantly with esomeprazole magnesium delayed-release capsules.
• Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time.

Esomeprazole Magnesium Delayed-Release Capsules

Administer esomeprazole magnesium delayed-release capsules orally or via a nasogastric tube, as described below.

Oral Administration

• Swallow esomeprazole magnesium delayed-release capsules whole; do not chew or crush the capsules.
• For patients who have difficulty swallowing capsules, esomeprazole magnesium delayed-release capsules can be opened, and the contents sprinkled on applesauce. Use with other foods has not been evaluated and is not recommended.

1. Add one tablespoon of applesauce to an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.
2. Open the esomeprazole magnesium delayed-release capsule and carefully empty the granules inside the capsule onto the applesauce.
3. Mix the granules with the applesauce.
4. Administer the mixture immediately. Do not chew or crush the granules
5. Discard any remaining mixture. Do not store the mixture for future use.

Administration via Nasogastric Tube

1. Open the esomeprazole magnesium delayed-release capsule and empty the granules into a 60 mL catheter-tipped syringe.
2. Mix the granules with 50 mL of water.
3. Replace the plunger and shake the catheter-tipped syringe vigorously for 15 seconds.
4. Hold the catheter-tipped syringe with the tip up and check for any granules remaining in the tip.
5. Attach the catheter-tipped syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach.
6. After administering the granules, flush the nasogastric tube with additional water.
7. Use the mixture immediately after preparation. Do not administer the granules if they have dissolved or disintegrated.

Esomeprazole Magnesium Delayed-release Capsules USP, 20 mg are white to cream to pale yellow colored pellets filled in size '4' hard gelatin capsules having dark blue opaque cap with '441' in black ink and white opaque body printed with '20 mg' in black ink.

Esomeprazole Magnesium Delayed-release Capsules USP, 40 mg are white to cream to pale yellow colored pellets filled in size '2' hard gelatin capsules having blue opaque cap with '442' in black ink and white opaque body printed with '40 mg' with black ink.

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with esomeprazole magnesium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to nonspecific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue esomeprazole magnesium delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.3 Clostridium difficile-Associated Diarrhea

Published observational studies suggest that PPI therapy like esomeprazole magnesium may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)].

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

Clostridium difficile-associated diarrhea (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 magnesium, refer to Warnings and Precautions section of the corresponding prescribing information.

5.4 Bone Fracture

Several published observational studies suggest that proton pump inhibitor (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, and 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 established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue esomeprazole magnesium at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving esomeprazole magnesium, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Interaction with Clopidogrel

Avoid concomitant use of esomeprazole magnesium with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole magnesium consider alternative anti-platelet therapy [see Drug Interactions (7)].

5.8 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.

5.9 Hypomagnesemia and Mineral Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. 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), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

Consider monitoring magnesium and calcium levels prior to initiation of esomeprazole magnesium and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.10 Interaction with St. John’s Wort or Rifampin

Drugs which induce CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease esomeprazole concentrations [see Drug Interactions (7 )]. Avoid concomitant use of esomeprazole magnesium with St. John's Wort or rifampin.

5.11 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. 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. 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 [see Clinical Pharmacology (12.2)].

5.12 Interaction with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)].

5.13 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

6.1 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 magnesium delayed-release capsules was evaluated in over 15,000 patients (aged 18 years 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 months to 12 months.

The safety in the treatment of healing of EE in adults was assessed in four randomized comparative clinical trials, which included 1,240 patients on esomeprazole magnesium 20 mg, 2,434 patients on esomeprazole magnesium 40 mg, and 3,008 patients on omeprazole 20 mg once daily. The most frequently occurring adverse reactions (at least 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 magnesium or omeprazole.

Less common adverse reactions with an incidence of less than 1% are listed below by body system:

Body as a Whole

Abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal 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

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 relationship to esomeprazole magnesium, were reported in 1% or less 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 [see Clinical Pharmacology (12)]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions include: 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 adverse reactions during 6-month trials for the maintenance of healing of EE with esomeprazole magnesium 20 mg once daily was similar to placebo. There were no differences in types of adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment.

Two placebo-controlled studies were conducted in 710 adults patients for the treatment of symptomatic GERD. adverse reactions that were reported were: diarrhea (4%), headache (4%), and abdominal pain (4%).

Combination Treatment with Esomeprazole Magnesium, Amoxicillin and Clarithromycin

In clinical trials of H. pylori eradication of to reduce duodenal ulcer recurrence, no additional adverse reactions specific to the combination of esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin were observed and were similar to those observed with esomeprazole magnesium, amoxicillin, or clarithromycin alone. The most frequently reported adverse reactions for patients who received esomeprazole magnesiu, amoxicillin and clarithromycin for 10 days were diarrhea (9%), taste perversion (4%), and abdominal pain (4%). No adverse reactions were observed at higher rates with esomeprazole magnesium, amoxicillin and clarithromycin than were observed with esomeprazole magnesium alone.

In clinical trials using of esomeprazole magnesium, amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed.

For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the respective prescribing information.

Pediatrics

1 Year to 17 Years of Age

The safety of esomeprazole magnesium delayed-release capsules was evaluated in 316 pediatric and adolescent patients aged 1 year to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical Studies (14.3)]. In 109 pediatric patients aged 1 year to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (3%), headache (2%) and somnolence (2%). In 149 pediatric patients aged 12 years to 17 years the most frequently reported adverse reactions (at least 2%) were headache (8%), abdominal pain (3%), diarrhea (2%), and nausea (2%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of esomeprazole magnesium. 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;

Eye

Blurred vision;

Gastrointestinal

Pancreatitis; stomatitis; microscopic colitis; fundic gland polyps;

Hepatobiliary

Hepatic failure, hepatitis with or without jaundice;

Immune System

Anaphylactic reaction/shock; systemic lupus erythematosus;

Infections and Infestations

GI candidiasis; Clostridium difficile-associated diarrhea;

Metabolism and nutritional disorders

Hypomagnesemia (may lead to hypocalcemia and/or hypokalemia) [see Warnings and Precautions (5.9)]

Musculoskeletal and Connective Tissue

Muscular weakness, myalgia, bone fracture;

Nervous System

Hepatic encephalopathy, taste disturbance;

Psychiatric

Aggression, agitation, depression, hallucination;

Renal and Urinary

Interstitial nephritis;

Reproductive System and Breast

Gynecomastia, erectile dysfunction;

Respiratory, Thoracic, and Mediastinal

Bronchospasm;

Skin and Subcutaneous Tissue

Alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), cutaneous lupus erythematosus.

Adverse reactions associated with omeprazole may also be expected to occur with esomeprazole. See the full prescribing information for omeprazole for complete safety information.

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies with esomeprazole in pregnant women. Esomeprazole is the S-isomer of omeprazole. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data). Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person).

Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls.

A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 1999, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.

A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.

A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.

A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.

Animal Data

Omeprazole

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period.

Esomeprazole

No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 41 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at

doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.

A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

8.2 Lactation

Risk Summary

Esomeprazole is the S-isomer of omeprazole and limited data suggest that omeprazole may be present in human milk. There are no clinical data on the effects of esomeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for esomeprazole magnesium and any potential adverse effects on the breastfed infant from esomeprazole magnesium or from the underlying maternal condition.

8.4 Pediatric Use

Healing of EE

Pediatric Patients 1 Year to 17 Years of Age

The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years for short-term treatment (4 weeks to 8 weeks) for healing of EE [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

Symptomatic GERD

Pediatric Patients 1 Year to 17 Years of Age

The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years of age for the short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

Other Conditions

The safety and effectiveness of esomeprazole magensium for the risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence and treatment of pathological hypersecretory conditions have not been established in pediatric patients.

Juvenile Animal Toxicity Studies

In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)].

8.5 Geriatric Use

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

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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh Class C) exposure to esomeprazole substantially increased compared to healthy subjects. Dosage modification of esomeprazole magnesium is recommended for patients with severe hepatic impairment for the healing of EE, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison Syndrome [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

In patients with mild to moderate liver impairment (Child-Pugh Classes A and B), no dosage adjustment is necessary.

The active ingredient in esomeprazole magnesium delayed-release capsules, USP for oral administration is bis (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium dihydrate, a PPI. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is (C17H18N3O3S)2 Mg x 2 H2O with molecular weight of 749.15 as a dihydrate and 713.15 on an anhydrous basis. The structural formula is:

Figure 1

The magnesium salt is a white to creamish colored hygroscopic powder. It contains 2 moles of water of solvation and is slightly soluble in water and methanol, practically in soluble in heptane and soluble in N, N-dimethyl formamide. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.

Each capsule of esomeprazole magnesium delayed-release capsule, USP contains 20 mg, or 40 mg of esomeprazole (present as 21.8 mg and 43.5 mg esomeprazole magnesium dihydrate, respectively), in the form of the enteric-coated pellets. The enteric-coated pellets are composed of following inactive ingredients: FD&C blue 1, hydroxypropyl cellulose, gelatin, magnesium oxide, magnesium stearate, mannitol, methacrylic acid copolymer dispersion, mono- and di-glycerides, povidone, polysorbate 80, sodium lauryl sulfate, starch (source: maize), sucrose, talc, titanium dioxide and triethyl citrate.

Additionally, each 20 mg capsule shell contains: FD&C red 3 and each 40 mg capsule shell contains: D&C red 28.

The capsule shell is printed with black pharmaceutical ink which contains following ingredients: black iron oxide, potassium hydroxide, propylene glycol and shellac.

12.1 Mechanism of Action

Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

12.2 Pharmacodynamics

Antisecretory Activity

Adults

The effect of esomeprazole magnesium on intragastric pH was determined in adult patients with symptomatic GERD in two separate studies. In the first study of 36 patients, esomeprazole magnesium 40 mg and 20 mg delayed-release capsules were administered once daily over 5 days as shown in Table 5.

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

Pediatrics

Serum Gastrin Effects

The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials of oral esomeprazole for up to 8 weeks and in over 1,300 patients for up to 12 months. The mean fasting gastrin level increased in a dose-related manner. The increase in serum gastrin concentrations 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 [see Warnings and Precautions (5.11)].

Enterochromaffin-like (ECL) Cell Effects

Human gastric biopsy specimens have been obtained from more than 3,000 patients (both pediatrics and adults) 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 [see (Nonclinical Pharmacology (13.1)].

In over 1,000 patients treated with oral esomeprazole (10 mg/day, 20 mg/day or 40 mg/day) up 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 in adults when given esomeprazole magnesium 20 mg or 40 mg delayed-release capsules once daily for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed in studies of omeprazole. Oral doses of omeprazole 30 mg or 40 mg once daily for 2 weeks to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.

12.3 Pharmacokinetics

Absorption

Esomeprazole magnesium delayed-release capsules showed similar bioavailability after a single dose (40 mg) administration in 94 healthy male and female subjects under fasting conditions. After oral administration, peak plasma levels (Cmax) of oral esomeprazole occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 micromol*hr/L on Day 1 to 11.2 micromol*hr/L on Day 5 after 40 mg once daily dosing.

The AUC after administration of a single 40 mg dose of esomeprazole magnesium delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration (2.3)]. The pharmacokinetics of esomeprazole in adult patients with symptomatic GERD following repeated once daily administration of 20 mg and 40 mg esomeprazole magnesium delayed-release capsules over a period of five days are shown in Table 6:

Esomeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure increases in a more than dose proportional manner after multiple oral doses of esomeprazole.

Compared to the first dose, the systemic exposure (Cmax and AUC0-24h) at steady state following once a day dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose.

Distribution

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 micromol/L. The apparent volume of distribution at steady state in healthy subjects 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 CYP 2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP 3A4 which forms the sulphone metabolite.

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 Amoxicillin and Clarithromycin

Esomeprazole magnesium delayed-release capsules 40 mg once daily was given in combination with amoxicillin 1,000 mg twice daily and clarithromycin 500 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 combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during coadministration with amoxicillin and clarithromycin is not expected to be clinically relevant.

The pharmacokinetic parameters for amoxicillin and clarithromycin were similar during 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 relevant.

Specific Populations

Geriatric Patients

The AUC and Cmax values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. This increase in exposure is not considered clinically relevant.

Pediatric Patients

12 Years to 17 Years of Age

The pharmacokinetics of esomeprazole magnesium were studied in 28 adolescent patients with GERD aged 12 years to 17 years inclusive, in a single center study. Patients were randomized to receive esomeprazole magnesium 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 magnesium pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD. See Table 9.

Male and Female Patients

The AUC and Cmax values of esomeprazole were slightly higher (13%) in females than in males at steady state when dosed orally. This increase in exposure is not considered clinically relevant.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

The steady state pharmacokinetics of esomeprazole obtained after administration of esomeprazole magnesium delayed-release capsules 40 mg orally once daily to patients with mild (Child-Pugh Class A, n=4), moderate (Child-Pugh Class B, n=4), and severe (Child-Pugh Class C, n=4) hepatic impairment 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 2 to 3 times higher than in the patients with normal liver function [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Esomeprazole/Omeprazole on Other Drugs

In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4.

Antiretrovirals

For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions (7)].

Rilpivirine

Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, Cmax by 40%, and Cmin by 33% for rilpivirine [see Contraindications (4)].

Nelfinavir

Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8.

Atazanavir

Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95 %.

Saquinavir

Following multiple dosing of saquinavir/ritonavir (1,000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. The AUC was increased by 82%, Cmax by 75%, and Cmin by 106%. The mechanism behind this interaction is not fully elucidated.

Clopidogrel

In a crossover study, healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day as the maintenance dosage for 28 days) alone and with esomeprazole (40 mg orally once daily at the same time as clopidogrel) for 29 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period when clopidogrel and esomeprazole were administered together. 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 [see Warnings and Precautions (5.7) and Drug Interactions (7)].

Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days and a single 1,000 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 [see Drug Interactions (7)].

Cilostazol

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. The Cmax and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above mentioned active metabolite [see Drug Interactions (7)].

Diazepam

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance.

Digoxin

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions (7)].

Other Drugs

Concomitant administration of esomeprazole and either naproxen (non-selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of these NSAIDs.

Effect of Other Drugs on Esomeprazole/Omeprazole

St. John's Wort

In a cross-over 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 both decreased by 38%) and extensive metabolizers (Cmax and AUC decreased by 50% and 44%, respectively) [see Drug Interactions (7)].

Voriconazole

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state Cmax and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions (7)].

Other Drugs

Co-administration of esomeprazole with oral contraceptives, diazepam, phenytoin, quinidine, naproxen (non-selective NSAID) did not seem to change the pharmacokinetic profile of esomeprazole.

12.4 Microbiology

Esomeprazole magnesium, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections [see Indications and Usage (1) and Clinical Studies (14)].

Helicobacter pylori

Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.

Pretreatment Resistance

Clarithromycin pretreatment resistance rate (MIC ≥ 1 mcg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates that were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes

The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in Table 10:

Patients not eradicated of H. pylori following triple therapy with esomeprazole magnesium, amoxicillin and clarithromycin will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In patients treated with esomeprazole magnesium, amoxicillin and clarithromycin in clinical trials, 83% (176/212) of the patients who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.

Susceptibility Test for Helicobacter pylori

For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

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 PPIs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

12.5 Pharmacogenomics

CYP2C19, a polymorphic enzyme, is involved in the metabolism of esomeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. The systemic exposure to esomeprazole varies with a patient's metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.

Systemic esomeprazole exposures were modestly higher (approximately 17%) in CYP2C19 intermediate metabolizers (IM; n=6) compared to extensive metabolizers (EM; n=17) of CYP2C19. Similar pharmacokinetic differences were noted across these genotypes in a study of Chinese healthy subjects that included 7 EMs and 11 IMs. There is very limited pharmacokinetic information for poor metabolizers (PM) from these studies.

At steady state following once daily administration of esomeprazole 40 mg, the ratio of AUC in poor metabolizers to AUC in the rest of the population (EMs) is approximately 1.5. This change in exposure is not considered clinically meaningful.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of esomeprazole magnesium was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24 month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg/day on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78 week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.

Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

13.2 Animal Toxicology and/or Pharmacology

Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 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 42 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 Use in Specific Populations (8.1)].

Juvenile Animal Study

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 68 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.

14.1 Healing of EE in Adults

The healing rates of esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium delayed-release capsules 20 mg, and omeprazole delayed-release capsules 20 mg (the approved dose for this indication) once daily were evaluated in adult patients with endoscopically diagnosed EE in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 11:

In these same studies of patients with EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in Table 12:

In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for esomeprazole magnesium 40 mg, 7 to 8 days for esomeprazole magnesium 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of esomeprazole magnesium with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of EE.

14.2 Maintenance of Healing of EE in Adults

Two multicenter, randomized, double-blind placebo-controlled 4-arm studies were conducted in adult patients with endoscopically confirmed, healed EE to evaluate esomeprazole magnesium delayed-release capsules 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with esomeprazole magnesium 40 mg over esomeprazole magnesium 20 mg. Esomeprazole magnesium 40 mg once daily is not a recommended regimen for the maintenance of healing of EE in adults.

The percentages of patients that maintained healing of EE at the various time points are shown in the Figures 2 and 3:

Figure 2

Maintenance of Healing Rates of EE in Adults by Month (Study 177)

s= scheduled visit

Figure 3

Maintenance of Healing Rates by Month (Study 178)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of EE was significantly less in patients treated with esomeprazole magnesium compared to placebo.

In both studies, the proportion of patients on esomeprazole magnesium who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with esomeprazole magnesium 40 mg, the percentage of patients that maintained healing of EE was 93.7% for six months and 89.4% for one year.

14.3 Symptomatic GERD in Adults

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 adult patients comparing four weeks of treatment with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had at least a 6 month history of heartburn episodes, no EE by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.

The percentage of patients that were symptom-free of heartburn was significantly higher in the esomeprazole magnesium groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

No additional clinical benefit was seen with esomeprazole magnesium 40 mg over esomeprazole magnesium 20 mg. Esomeprazole magnesium 40 mg once daily is not a recommended regimen for the treatment of symptomatic GERD in adults.

The percent of patients symptom-free of heartburn by day are shown in the Figures 4 and 5:

Figure 4

Percent of Patients Symptom-Free of Heartburn by Day (Study 225)

Figure 5

Percent of Patients Symptom-Free of Heartburn by Day (Study 226)

In three European symptomatic GERD trials, esomeprazole magnesium 20 mg and 40 mg and omeprazole 20 mg were evaluated. No significant treatment related differences were seen.

14.4 Pediatric GERD

12 Years to 17 Years of Age

In a multicenter, randomized, double-blind, parallel-group study, 149 adolescent patients

(12 to 17 years of age; 89 female; 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD were treated with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily for up to 8 weeks to evaluate safety and tolerability. Patients were not endoscopically characterized as to the presence or absence of EE.

14.5 Risk Reduction of NSAID-Associated Gastric Ulcer

Two multicenter, double-blind, placebo-controlled studies were conducted in adult patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs. A total of 1,429 patients were randomized across the 2 studies. Patients ranged in age from 19 to 89 (median age 66 years) with 71% female, 29% male, 83% Caucasian, 5.5% Black, 4% Asian, and 8% Others. At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (at least 60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients receiving NSAIDs and treated with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. See Table 13. No additional benefit was seen with esomeprazole magnesium 40 mg over esomeprazole magnesium 20 mg. Esomeprazole magnesium 40 mg once daily is not a recommended regimen for the risk reduction of NSAID-associated gastric ulcer in adults. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence.

The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the esomeprazole magnesium plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis).

14.6 H. pylori Eradication in Adult Patients with Duodenal Ulcer Disease

Two multicenter, randomized, double-blind studies were conducted in adult patients using a 10 day treatment regimen of triple therapy (esomeprazole magnesium, amoxicillin and clarithromycin). The first study (191) compared esomeprazole magnesium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared esomeprazole magnesium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily.

H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest®, histology and/or culture, at 4 weeks post-therapy were significantly higher in the esomeprazole magnesium, amoxicillin and clarithromycin group than in the esomeprazole magnesium and clarithromycin group or the esomeprazole magnesium alone group. The results are shown in Table 14:

14.7 Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome, in Adults

In a multicenter, open-label dose-escalation study of 21 patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, esomeprazole magnesium significantly inhibited gastric acid secretion. Initial dose was 40 mg twice daily in 19/21 patients and 80 mg twice daily in 2/21 patients. Total daily doses ranging from 80 mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0.17 mmol/hr). Of the 18 patients evaluated with a starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit. See Table 13.

Esomeprazole Magnesium Delayed-release Capsules USP, 20 mg are white to cream to pale yellow colored pellets filled in size '4' hard gelatin capsules having dark blue opaque cap with '441' in black ink and white opaque body printed with '20 mg' in black ink and are supplied as follows:

NDC 68382-441-06 bottles of 30 capsules with child-resistant closure

NDC 68382-441-16 bottles of 90 capsules with child-resistant closure

NDC 68382-441-10 bottles of 1,000 capsules

Esomeprazole Magnesium Delayed-release Capsules USP, 40 mg are white to cream to pale yellow colored pellets filled in size '2' hard gelatin capsules having blue opaque cap with '442' in black ink and white opaque body printed with '40 mg' with black ink and are supplied as follows:

NDC 68382-442-06 bottles of 30 capsules with child-resistant closure

NDC 68382-442-16 bottles of 90 capsules with child-resistant closure

NDC 68382-442-10 bottles of 1,000 capsules

Storage

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

Keep Esomeprazole magnesium delayed-release capsules container tightly closed. Dispense in a tight container if the Esomeprazole magnesium delayed-release capsules product package is subdivided.