Nexium

1 INDICATIONS AND USAGE NEXIUM is a proton pump inhibitor (PPI). NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the: • Short-term treatment in the healing of erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years of age. • Maintenance of healing of EE in adults. • Short-term treatment of heartburn and other symptoms associated GERD in adults and pediatric patients 12 years to 17 years of age. • Risk reduction of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults at risk for developing gastric ulcers due to age (60 years and older) and/or documented history of gastric ulcers. • Helicobacter pylori eradication in adult patients to reduce the risk of duodenal ulcer recurrence in combination with amoxicillin and clarithromycin. • Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome in adults. NEXIUM for delayed-release oral suspension is indicated for the: • Short-term treatment in the healing of EE in pediatric patients 1 year to 11 years of age and of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age. • Short-term treatment of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.

1.1Healing of Erosive Esophagitis

(EE) Adults NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the short-term treatment (4 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- to 8- week course of NEXIUM may be considered. Pediatric Patients 12 Years to 17 Years of Age NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.

Pediatric Patients 1 Year to 11 Years of Age NEXIUM for delayed-release oral suspension is indicated for the short-term treatment (8 weeks) for the healing of EE in pediatric patients 1 year to 11 years of age. Pediatric Patients 1 Month to Less Than 1 Year of Age NEXIUM for delayed-release oral suspension is indicated for short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age.

1.2Maintenance of Healing of

EE NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the maintenance of healing of EE in adults. Controlled studies do not extend beyond 6 months.

1.3Treatment of Symptomatic

GERD Adults NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults. Pediatric Patients 12 Years to 17 Years of Age NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension 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. Pediatric Patients 1 Year to 11 Years of Age NEXIUM for delayed-release oral suspension is indicated for short-term treatment (up to 8 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.

1.4Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs

(NSAID)-Associated Gastric Ulcer NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension 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.

1.5Helicobacter

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 NEXIUM delayed-release capsules or NEXIUM for delayed-release oral suspension 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 .

1.6Pathological Hypersecretory Conditions Including Zollinger-Ellison

Syndrome NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.

Population Recommended Adult and Pediatric Dosage Healing of EE (1 year and older) EE due to Acid-Mediated GERD (1 month to less than 1 year) Adults 20 mg or 40 mg A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C). once daily for 4 to 8 weeks; some patients may require an additional 4 to 8 weeks 12 years to 17 years 20 mg or 40 mg once daily for 4 to 8 weeks 1 month to 11 years see full prescribing information for weight-based dosing and duration of treatment Maintenance of Healing of EE Adults 20 mg once daily. Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD Adults 20 mg once daily once daily for 4 weeks some patients may require an additional 4 weeks 12 years to 17 years 20 mg once daily for 4 weeks 1 year to 11 years 10 mg once daily for up to 8 weeks Risk Reduction of NSAID-Associated Gastric Ulcer Adults 20 mg or 40 mg once daily for up to 6 months Controlled studies do not extend beyond 6 months. H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Adults NEXIUM 40 mg once daily for 10 days Amoxicillin 1000 mg twice daily for 10 days Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients. Clarithromycin 500 mg twice daily for 10 days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults Starting dosage is 40 mg twice daily A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C). (varies with the individual patient) as long as clinically indicated. Preparation and Administration Information • Swallow capsules whole; do not crush or chew. For patients who cannot swallow intact capsule, the capsule can be opened, and the contents mixed with applesauce. • Mix packets with water to create an oral suspension. • Opened capsules can be administered through a nasogastric tube and oral suspension can be administered through a nasogastric or gastric tube.

2.1Recommended Dosage in Adults by Indication Table

1 shows the recommended adult dosage of NEXIUM by indication. The duration of NEXIUM treatment should be based on available safety and efficacy data specific to the defined indication and dosing frequency and individual patient medical needs. NEXIUM should only be initiated and continued if the benefits outweigh the risks of treatment.

Table 1: Recommended Dosage of NEXIUM in Adults by Indication Adult Indication Recommended Dosage of NEXIUM d elayed-release capsules and NEXIUM for delayed-release oral suspension Treatment Duration Healing of EE 20 mg or 40 mg A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C) . once daily 4 to 8 weeks Most patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be required to achieve healing . Maintenance of Healing of EE 20 mg once daily Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD 20 mg once daily 4 weeks; if symptoms do not resolve completely, consider an additional 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg once daily Controlled studies do not extend beyond 6 months H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (Triple Therapy) NEXIUM 40 mg once daily 10 days Amoxicillin 1000 mg twice daily Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients. 10 days Clarithromycin 500 mg twice daily 10 days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Starting dosage is 40 mg twice daily A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C) . ; individualize the regimen to patient needs. Dosages of up to 240 mg/day have been administered . As long as clinically indicated

2.2Recommended Dosage in Pediatric Patients by Indication

Table 2 shows the recommended dosage of NEXIUM in pediatric patients by indication. Table 2: Recommended Dosage of NEXIUM in Pediatric Patients by Indication Indication Patient Age Recommended Dosage Duration Healing of EE 12 years to 17 years NEXIUM delayed-release capsules or NEXIUM for delayed-release oral suspension: 20 mg or 40 mg once daily 4 to 8 Weeks 1 year to 11 years Dosages over 1 mg/kg/day have not been studied NEXIUM for delayed-release oral suspension: Less than 20 kg 10 mg once daily 20 kg and greater 10 mg or 20 mg once daily 8 weeks Treatment of EE due to Acid-Mediated GERD 1 month to less than 1 year Dosages over 1.33 mg/kg/day have not been studied NEXIUM for delayed-release oral suspension: 3 kg to 5 kg 2.5 mg once daily Greater than 5 kg to 7.5 kg 5 mg once daily Greater than 7.5 kg to 12 kg 10 mg once daily Up to 6 weeks Treatment of Symptomatic GERD 12 years to 17 years NEXIUM delayed-release capsules or NEXIUM for delayed-release oral suspension: 20 mg once daily 4 weeks 1 year to 11 years NEXIUM for delayed-release oral suspension: 10 mg once daily 1 Up to 8 weeks

2.3Preparation and Administration Instructions

• Take NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension at least one hour before meals . • Antacids may be used concomitantly with NEXIUM. • 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.

NEXIUM Delayed-Release Capsules Administer NEXIUM delayed-release capsules orally or via a nasogastric tube, as described below. Oral Administration • Swallow NEXIUM delayed-release capsules whole; do not chew or crush the capsules. • For patients who have difficulty swallowing capsules, NEXIUM 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 NEXIUM 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 NEXIUM 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. NEXIUM For Delayed-Release Oral Suspension Administer NEXIUM for delayed-release oral suspension orally or via a nasogastric or gastric tube, as described below.

Oral Administration 1. Empty the contents of a 2.5 mg or 5 mg NEXIUM packet into a container containing 5 mL of water. For the 10 mg, 20 mg, and 40 mg strengths, the contents of a packet should be emptied into a container containing 15 mL of water. If two packets are needed, mix in a similar way add twice the required amount of water. 2.

Stir the packet contents into the water. 3. Leave 2 to 3 minutes to thicken. 4. Stir and drink within 30 minutes. 5. If any of the contents remain after drinking, add more water, stir, and drink immediately. Administration via Nasogastric or Gastric Tube 1. Add 5 mL of water to a catheter-tipped syringe and then add the contents of a 2.5 mg or 5 mg NEXIUM packet.

For the 10 mg, 20 mg, and 40 mg packet strengths, add at least 15 mL of water to the catheter-tipped syringe. 2. Immediately shake the catheter-tipped syringe and leave 2 to 3 minutes to thicken. 3. Shake the catheter-tipped syringe and inject through the nasogastric or gastric tube, French size 6 or larger, into the stomach within 30 minutes. 4.

Refill the catheter-tipped syringe with an equal amount of water (5 mL or 15 mL). 5. Shake and flush any remaining contents from the nasogastric or gastric tube into the stomach.

5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. • Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. • Clostridium difficile- Associated Diarrhea: PPI therapy may be associated with increased risk. • Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. • Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. • Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue NEXIUM and refer to specialist for evaluation. • Interaction with Clopidogrel: Avoid concomitant use of NEXIUM. • Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. • Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs. • Interaction with St. John’s Wort or Rifampin: Avoid concomitant use of NEXIUM. (5.10 , 7 ) • Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors, temporarily stop NEXIUM at least 14 days before assessing CgA levels. (5.11 , 12.2) • Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider temporary withdrawal of NEXIUM. (5.12 , 7) • Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy.

5.1Presence of Gastric Malignancy In

adults, symptomatic response to therapy with NEXIUM 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.

5.2Acute 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 non-specific 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 NEXIUM and evaluate patients with suspected acute TIN .

5.3Clostridium

difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like NEXIUM 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 . 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 NEXIUM, refer to Warnings and Precautions section of the corresponding prescribing information.

5.4Bone 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 .

5.5Severe 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 . Discontinue NEXIUM at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6Cutaneous 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 NEXIUM, 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.

5.7Interaction with Clopidogrel Avoid

concomitant use of NEXIUM 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 NEXIUM consider alternative anti-platelet therapy .

5.8Cyanocobalamin

(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.

5.9Hypomagnesemia 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 . Consider monitoring magnesium and calcium levels prior to initiation of NEXIUM 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.

5.10Interaction 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 . Avoid concomitant use of NEXIUM with St. John’s Wort or rifampin.

5.11Interactions 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 .

5.12Interaction 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 .

5.13Fundic 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.

4 CONTRAINDICATIONS • NEXIUM is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria . • For information about contraindications of amoxicillin and clarithromycin, indicated in combination with NEXIUM for H. pylori eradication to reduce the risk of duodenal ulcer recurrence, refer to the Contraindications section of the respective prescribing information. • Proton pump inhibitors (PPIs), including NEXIUM, are contraindicated in patients receiving rilpivirine-containing products . • Known hypersensitivity to substituted benzimidazoles or any component of the formulation. • Patients receiving rilpivirine-containing products. ( 4 , 7 ) • Refer to the Contraindications section of the prescribing information for amoxicillin and clarithromycin, when administered in combination with NEXIUM.

8.1Pregnancy 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 . 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 . 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 H 2 -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.

The following serious adverse reactions are described below and elsewhere in labeling: • Acute Tubulointerstitial Nephritis • Clostridium difficile-Associated Diarrhea • Bone Fracture • Severe Cutaneous Adverse Reactions • Cutaneous and Systemic Lupus Erythematosus • Cyanocobalamin (Vitamin B-12) Deficiency • Hypomagnesemia and Mineral Metabolism • Fundic Gland Polyps Most common adverse reactions : • Adults (≥ 18 years) ( > 1%) are: headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. • Pediatrics (1 to 17 years) ( > 2%) are: headache, diarrhea, abdominal pain, nausea, and somnolence. • Pediatrics (1 month to less than 1 year) (>1%) are: abdominal pain, regurgitation, tachypnea, and increased ALT. To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 NEXIUM delayed-release capsules was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6 to 12 months.

The safety in the treatment of healing of EE in adults was assessed in four randomized comparative clinical trials, which included 1,240 patients who received NEXIUM 20 mg once daily, 2,434 patients on NEXIUM 40 mg once daily, 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 NEXIUM 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 NEXIUM, 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 . 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 NEXIUM 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 adult patients for the treatment of symptomatic GERD. The most common adverse reactions that were reported were: diarrhea (4%), headache (4%), and abdominal pain (4%).

Combination Treatment with NEXIUM, 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 NEXIUM delayed-release capsules, amoxicillin and clarithromycin were observed and were similar to those observed with NEXIUM, amoxicillin, or clarithromycin alone. The most frequently reported adverse reactions for patients who received NEXIUM, 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 NEXIUM, amoxicillin and clarithromycin than were observed with NEXIUM alone.

In clinical trials using of NEXIUM, 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 NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension was evaluated in 316 pediatric and adolescent patients aged 1 year to 17 years in four clinical trials for the treatment of symptomatic GERD . 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%). 1 Month to Less Than 1 Year of Age The safety of esomeprazole magnesium was evaluated in 167 infants from 1 month to less than 1 year of age with GERD in three clinical trials . In a study that included 43 pediatric patients, the most frequently reported adverse reactions (at least 5%) with esomeprazole magnesium were irritability and vomiting. In a study that included 98 pediatric patients, administered esomeprazole magnesium for up to 6 weeks (including 39 patients randomized to the withdrawal phase), reported adverse reactions were: abdominal pain (1%), regurgitation (1%), tachypnea (1%), and increased ALT (1%).

6.2Postmarketing Experience The

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