Global Medical Cures™ | Nexium- Pediatric PostMarketing Adverse Event Review

Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Surveillance and Epidemiology
Pediatric Postmarketing Adverse Event Review
Date: October 31, 2012
Reviewer(s): Thang La, PharmD, BCPS, Safety Evaluator
Division of Pharmacovigilance (DPV) 1
Ethan D. Hausman, MD, Medical Officer
Team Leader(s): Ann Mackey, RPh, MPH, Safety Evaluator Team
Leader, DPV 1
Division Director(s): Linda Scarazzini, MD, RPh, Director
DPV 1
Product Name(s): Nexium® (esomeprazole IV and delayed-release oral
suspension)
Pediatric
Approval Dates: December 15, 2011 (Nexium® oral suspension) (latest)
April 29, 2011 (Nexium® IV) (latest)
Application Type/Number: 021957 (Nexium® oral suspension)
021689 (Nexium® IV)
Applicant/Sponsor: AstraZeneca
OSE RCM #: 2012-1755 and 2012-1758
Reference ID: 3204251 1

CONTENTS
Executive Summary............................................................................................................ 2
1 Introduction................................................................................................................. 2
1.1 Background......................................................................................................... 2
1.2 Formulations and Indications.............................................................................. 2
1.3 Pediatric filing history......................................................................................... 3
1.4 Pediatric labeling (see appendix A for additional label details) ......................... 3
2 Methods and materials................................................................................................ 5
2.1 AERS Search Strategy........................................................................................ 5
3 Results and discussion ................................................................................................ 5
3.1 Nexium® powder for oral suspension (NDA 021957)....................................... 5
3.2 Nexium® IV (NDA 021689).............................................................................. 8
4 Conclusion ................................................................................................................ 11
5 Recommendations..................................................................................................... 11
6 Appendices................................................................................................................ 12
6.1 Appendix A: Pediatric Product Labeling (selected information from the label -

January 20, 2012 revision)............................................................................................ 12
6.2 Appendix B: Standard Searches....................................................................... 19
6.3 Appendix C: Adverse Event Reporting System (AERS) Database Description

20


EXECUTIVE SUMMARY
In accordance with the Best Pharmaceuticals for Children Act (BPCA), the Division of
Pharmacovigilance (DPV) was asked to summarize post-marketing reports of adverse
events associated with the use of Nexium® IV and delayed-release oral suspension
formulations in pediatric patients (0-16 years of age). The main focus of this review is
pediatric deaths and pediatric reports of serious unlabeled adverse events with these
products.
The active ingredient in Nexium® is esomeprazole, the S-isomer of the proton pump
inhibitor (PPI) omeprazole. It is approved for the treatment of gastroesophageal reflux
disease (GERD) with erosive esophagitis in the pediatric population.
The Adverse Event Reporting System (AERS) database was searched for all reports of
adverse events (serious and non-serious) from the original approval dates up to the data-
lock date of June, 30, 2012. Pediatric reports represent approximately 25% (3 of 12) and
5% (6 of 124) of the total number of reports for the oral suspension and IV formulations,
respectively.
There were no reports of death in children that were attributed to the use of either
formulation. We identified no new serious unlabeled pediatric safety issues.
DPV recommends continued routine pharmacovigilance monitoring.
1 INTRODUCTION
1.1 BACKGROUND
The Division of Pharmacovigilance was asked to perform two safety reviews; one to
summarize post-marketing reports of adverse events associated with the use of Nexium®
IV in pediatric patients (0-16 years of age), and the other to summarize post-marketing
reports of adverse events associated with the use of Nexium® delayed-release oral
suspension formulations in pediatric patients (0-16 years of age). Per agreement with the
Office of Pediatric Therapeutics, this single review of both products fulfills both consult
requests.
1.2 FORMULATIONS AND INDICATIONS
Formulations:
Nexium® oral (esomeprazole magnesium) formulations:
• Delayed-Release oral suspension: 10mg, 20mg, and 40mg
• Delayed-Release capsules: 20mg and 40mg
Nexium® IV (esomeprazole sodium) formulations:
• 20mg and 40mg powder for injection in single-use vials

Indications:
• Symptomatic treatment of GERD
• Healing and maintenance of healing of erosive esophagitis
• Risk reduction of NSAID-Associated gastric ulcer (oral formulations)
• H. pylori eradication to reduce risk of duodenal ulcer recurrence (oral

formulations)

• Pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
(oral formulations
1.3 PEDIATRIC FILING HISTORY
• April 28, 2006: First pediatric labeling approval for Nexium® capsules for
adolescents 12-17 years of age for short-term treatment of GERD based on
extrapolation from studies in adults, and safety and PK studies in adolescents.
• February 27, 2008: Pediatric label was expanded to include patients 1-11 years
for short-term treatment of GERD based on extrapolation from studies in adults,
and safety and PK studies in pediatric and adolescent patients.
• June 18, 2009: For Nexium® oral suspension, effectiveness for the treatment of
GERD was not supported by data from studies in neonates to 11 months.
• April 29, 2011: Nexium® IV label was expanded for the treatment of erosive
esophagitis due to GERD to include patients 1 month to 17 years based on studies
in adults, and PK and PD studies in pediatric patients.
• December 15, 2011: Nexium® oral suspension label was expanded to include
patients 1 month to < 1 year for short-term treatment (up to 6 weeks) of erosive
esophagitis due to GERD based on studies in adults and safety, PK, PD studies in
pediatric patients. Nexium® was already approved for the treatment of GERD in
adults and children 1 year or older.
1.4 PEDIATRIC LABELING
1
(SEE APPENDIX A FOR ADDITIONAL LABEL DETAILS)
• Indication and Usage: (Pediatric indications only)
Oral suspension:
Symptomatic treatment of GERD in children 1 year or older.
Short-term treatment (4-8 weeks) in healing of erosive esophagitis. An additional
4-8 week course may be considered. In infants 1 month to less than 1 year, short-
term treatment is up to 6 weeks.
IV formulation:
Short-term treatment of GERD with erosive esophagitis in adults and pediatric
patients 1 month to 17 years, as an alternative to oral therapy when oral therapy is
not possible or appropriate.
1
Labels of Axid® capsule/granule for oral suspension (NDA 021957, revision date 1/2012) and IV (NDA
021689, revision date 1/2012)

• Dosage and Administration:
Table 1: Dosage and Administration
ORAL SUSPENSION:
12 to 17 years
Short-term Treatment of
GERD
20mg or 40mg Once Daily for up to 8
Weeks
1 to 11 years (doses over 1mg/kg/day have not been studied)
Symptomatic GERD
10 mg Once Daily for up to 8
Weeks
Healing of Erosive Esophagitis
weight < 20 kg 10 mg Once Daily for 8 Weeks
weight ≥ 20 kg 10 mg or 20 mg Once Daily for 8 Weeks
1 month to < 1 year (doses over 1.33mg/kg/day have not been studied)
Erosive esophagitis due to acid-mediated GERD
weight 3 kg to 5 kg 2.5 mg Once Daily for up to 6
Weeks
weight > 5 kg to 7.5 kg 5 mg Once Daily for up to 6
Weeks
weight >7.5 kg to 12 kg 10 mg Once Daily for up to 6
Weeks
IV FORMULATION (infused over 10 to 30 minutes):
1 year to 17 years
weight < 55 kg: 10 mg n/a
weight >55 kg 20 mg n/a
1 month to 1 year 0.5 mg/kg n/a

2 METHODS AND MATERIALS
2.1 AERS SEARCHSTRATEGY
The Adverse Event Rep01iing System (AERS) database was searched with the su·ategy
described in Table 2 (see Appendix B).
Table 2: AERS Search Strategy for Nexium® powder for oral suspension (NDA
021957)*
Date ofsearch July 20, 2012
Time period October 20, 2006 (Approval date) to June 30, 2012
Dmg Product NDA 021957
AERS Search Strate2)' for Nexium® IV (NDA 021689)*
Date ofsearch July 20, 2012
Time period March 31,2005 (Approval date) to June 30, 2012
Dmg Product NDA 021689
* See Appendix C for description of the AERS database.
3 RESULTS AND DISCUSSION
3.1 NEXIUM® POWDER FOR ORAL SUSPENSION(NDA 021957)

Table 3: Cm de cmmts1
of AERS Rep01ts for Nexium® powder for oral suspension (NDA
021957)
From October 20, 2006 (Approval Date) to June 30, 2012
All rep01ts
cusi
Serious3
(US) Death (US)
Adults(? 17 yrs.) 2 (2) 1 (1) 0 (0)
Pediatrics (0-16 yrs.) 3 (1) 2 (0)4
0 (0)
Age lmknown (Null values) 7 (7) 1 (1)
5
0 (0)
Total 12 (10) 4 (2) 0 (0)
1
May include duplicates
2
US counts in parentheses
3
Serious adverse dmg experiences per regulat01y definition (CFR 314.80) include
outcomes of death, life-threatening, hospitalization (initial or prolonged), disability,
congenital anomaly, and other serious important medical events.
4
See Figure 1
5
No pediatric cases identified
The rep01ts with the age not reported describing death outcomes or non-fatal serious
outcomes included inadequate infonnation to determine age.
Figure 1 below summarizes the specific selection of cases for Nexium® powder for oral
suspension (NDA 021957)

Total Serious Pediatr ic Reports (n= 2)
Pediatric (0-16 years) Serious Outcomes Cmde Reports (n = 2)0
Pediatric deaths (n= 0)0
I

(
~
) l
~
J
Duplicate Repmts (n = 0) Unduplicated Repmts (n = 2)
II
+

Excluded cases
(n=O)
+

Pediatric Case Selies
(n= 2)
The AERS database search did not identify any previously lmlabeled serious safety issues
for Nexium® powder for oral suspension.
Deaths: No death cases were found. The two serious cases are summarized below
(unlabeled tenns are in bold font).
Non-fatal Serious Adverse Events:
Case #7694034, foreign: A 4-month-old male baby with a hist01y ofreflux previously
treated with lansoprazole, ranitidine, and domperidone began esomeprazole 1Omg daily
for reflux esophagitis sometime in November 2010. The baby was rep01ied to develop
hypersomnia (closely related to the labeled te1m 'somnolence') with armmd 20 hours of
sleep a day at an undete1mined time after first exposure. Esomeprazole was the only dmg
taken. No other infonnation was provided. Reviewer's comment: Hypersomnia is
closely related to the labeled te1m somnolence. Additionally, the administered dose
could not be dete1mined.
Case #7016971, foreign: A 5-year-old female with a medical hist01y ofceliac disease,
asthma, anemia, and cow's milk protein intolerance experienced recunent of dianhea
while on Nexium® treatment. Her medications included esomeprazole (stmi date May
30, 2009), liquid iron (unknown stmi date), montelukast (unknown stmi date),
prednisone, and other minerals/vitamins/atnino acids supplements. The symptoms were
ascribed to ongoing celiac issues; however, diatThea reportedly resolved after
discontinuation of iron and Nexium®. Reviewer's comment: Since diatThea is a core
symptom ofceliac disease and since multiple medicines were stmied and discontinued
around the time ofthe event, a causal relationship with Nexium® cannot be established.

3.2 NEXIUM® IV (NDA 021689)

Table: Cmde cmmts1
of AERS Rep01ts for Nexium ® IV (NDA 021689)
From March 31, 2005 (Approval Date to June 30, 2012
All rep01ts Serious3
(US) Death (US)
(US)2
Adults(? 17 yrs.) 95 (17) 86(9) 11(1)
4
Pediatrics (0-16 yrs.) 6 (0) 2(0)6 (0)
Age unknown (Null values) 23(15) 0(0)9 (1i
124(32) 101 (10) 13(1)Total
1
May include duplicates
2 US cmmts in parentheses
3
Serious adverse dmg experiences per regulat01y definition (CFR 314.80) include outcomes
of death, life-threatening, hospitalization (initial or prolonged), disability, congenital
anomaly, and other serious imp01tant medical events.
4
See Figure 2 and 3
5
No pediau·ic cases identified.
Figure 2. Total Number of Pediatric Reports (including serious and non-serious)
for Nexium® IV, by year of FDA receipt (from March 31, 2005 [Approval Date] to
June 30, 2012 (n=6)
These numbers include data where age (0-16 years) is known and may contain duplicate
rep01ts.
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The rep01is with the age not reported describing death outcomes or non-fatal serious
outcomes included inadequate infonnation to determine age.
Figure 3 below summarizes the specific selection of cases for Nexium® IV (NDA
021689)
Total Serious Pediatric Reports (n= 6)
0 Pediatric (0-16 years) Serious Outcomes Cmde Reports (n = 6)
(Includes 2 deaths)
I
~ ~
Duplicate Repmts (n = 0) Unduplicated Repmts (n = 6)
( ) l J
I
't 't
Excluded Repmt s
(n = 0)
Pediatric Case Selies

(n = 6)

Includes 2 deaths

The AERS database search did not identify any major safety issues for Nexium® IV.
Overall, the case cmmts are low. Unlabeled events are in bold.
Deaths: Two deaths were rep01ied, one of which appeared attributable to complications
of intentional poly-phrumaceutical overdose rather than Nexium® administration, and the
second of which apperu·ed to be due to complications of pneumonia in a patient with HIV
infection. These cases ru·e summru·ized below.
Case #7966813, foreign: A 16-year-old male with a medical hist01y of heroin and
cocaine addiction was admitted on (bH
6
> for multiple drug intoxication and
overdose including colchicine, paracetamol (acetaminophen), roxithromycin (a macrolide
antibiotic not available in the US), oxazepam, opium, and caffeine. He experienced
worsening pulmonruy complications, deterioration of hepatic ftmction, and hematological
abn01malities despite multiple supp01i ive interventions including esomeprazole IV. His
condition worsened and he eventually died of vasoplegic shock. Reviewer's comment:
The patient appeared to die of multi-organ failm e due to intentional polyphannaceutical
overdose.
Case #8409876, foreign: A 've1y weak', 8-year-old girl with HIV infection was admitted
for aspiration pneumonia. She 'could not eat' and had 'blood in her stools'. No other
prior medical and phrumacotherapy information was available. Esomeprazole IV was

provided for ‘one day.’ The patient later died of unknown causes; however, the time
course from Nexium® exposure to death cannot be determined. Reviewer’s comment:
The patient may have died due to complications of pneumonia; however there insufficient
clinical information to assess causality.
Non-fatal Serious Cases:
Case #6317786, foreign: A 10-month-old2
female with a history of severe GERD and
anastomotic stricture after surgical repair of esophageal atresia, experienced severe
pulmonary deterioration ‘immediately after’ esomeprazole was administered. A
similar event reportedly occurred approximately 6 months earlier when she experienced
mild facial edema and worsening respiratory distress (chess retraction, tachypnea,
wheezing) within 30-60 minutes of omeprazole administration. Supportive treatment
was provided and symptoms resolved after discontinuation of PPIs. There was no
reported treatment with corticosteroid or epinephrine. Reviewer’s comment: The events
described in this report appear to represent repeated PPI-related
hypersensitivity/anaphylactic reactions. Anaphylactic reaction, bronchospasm, dyspnea,
larynx edema, and facial edema are currently described in the Contraindications and
Adverse Reactions section of labeling
Case #7677779, foreign: A 10-month-old male patient was admitted on
for fever and purpura, which progressed to septic shock. He received hemodynamic
support with saline and dopamine, and was ventilated and sedated with sufentanil and
(b) (6)
ketamine. He was treated with ceftriaxone, then cefotaxime for possible meningococcal
meningitis. The next day esomeprazole IV was started, followed by furosemide IV and
bumetanide IV on the next day. During this time, his skin lesions ‘spread’ and stabilized
with around 22% body skin detachment. He was diagnosed with bullous epidermolysis.
All drugs, except sufentanil, ketamine, dobutamine, and noradrenaline were discontinued.
At the time of the report, he was improved but not fully recovered. Reviewer’s comment:
This patient’s skin lesions were present prior to first administration of esomeprazole
making this an unlikely drug event combination in this case.
Case #7125606, foreign: A 16-year-old male with acute myeloid leukemia developed
neurological events including cytotoxic edema, hemiplegia, facial palsy, and epileptic
fit after administration of chemotherapy including intrathecal methotrexate and
aracythine (cytarabine) as well as intravenous mitoxantrone. He also received multiple
other supportive drugs including analgesics, corticosteroids, antibiotics, and antifungal
drugs. Esomeprazole appears to have been provided as a cytoprotectant for the preceding
therapies. He recovered from the neurological events. Events resolved with supportive
care. Reviewer’s comment: Causality assessment is confounded by the underlying
medical condition and intrathecal administration of chemotherapy.
Case #8006883, foreign: A 6-year-old male received esomeprazole IV from February 2,
2011 for stress-induced peptic ulcer protection after a traumatic surgery for unknown
issue. On February 17, 2012, hemorrhagic gastritis was discovered during endoscopy.
2
Incorrectly reported and coded as 4-month-old at the time of report submission to AERS although the
narrative described a second exposure adverse event which occured 6 months after first exposure to PPI at
4 months of age.

The reporter believed it was due to lack of esomeprazole efficacy. Reviewer’s comment:
Lack of efficacy is a risk with all drugs. There is insufficient clinical information (for
example, lack of surgical indication) to further assess causality.
4 CONCLUSION
This current DPV review of AERS reports do not identify any new clinically meaningful
pediatric safety concerns involving Nexium® IV (NDA 021689) and powder for oral
suspension (NDA 021957). The AERS searches were performed using the approval
dates rather than the later pediatric labeling dates to capture any prior potential off-label
pediatric use. To date the number of reports for Nexium® IV and powder for oral
suspension remains low and the adverse events captured are sufficiently described in the
label.
The previous review from DPV for the Pediatric Advisory Committee for PPIs in June of
2010 did not find any pediatric case for Nexium® powder for oral suspension (NDA
021957) and did not identify any unique or new pediatric safety issues for Nexium®
delayed-release capsule (NDA 021153).3
5 RECOMMENDATIONS
DPV identified no new clinically meaningful safety signals. DPV will continue routine
pharmacovigilance monitoring for Nexium® IV (NDA 021689) and powder for oral
suspension (NDA 021957).
3
Mackey A. Pediatric Post-marketing Adverse Event Review. DPV Review April 29, 2010. RCM# 2010
306

6 APPENDICES
6.1 APPENDIX A: PEDIATRIC PRODUCT LABELING (SELECTED INFORMATION FROM
THE LABEL - JANUARY 20, 2012 REVISION)
Indications and Usage: (section 1 of the label)
Oral suspension:
Treatment of Gastroesophageal Reflux Disease (GERD):
“Healing of Erosive Esophagitis
NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and
symptomatic resolution of diagnostically confirmed erosive esophagitis. For those
patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week
course of NEXIUM may be considered.
In infants 1 month to less than 1 year, NEXIUM is indicated for short-term treatment (up
to 6 weeks) of erosive esophagitis due to acid-mediated GERD.
Maintenance of Healing of Erosive Esophagitis
NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis.
Controlled studies do not extend beyond 6 months.
Symptomatic Gastroesophageal Reflux Disease
NEXIUM is indicated for short-term treatment (4 to 8 weeks) of heartburn and other
symptoms associated with GERD in adults and children 1 year or older.”
Risk Reduction of NSAID-Associated Gastric Ulcer:
“NEXIUM is indicated for the reduction in the occurrence of gastric ulcers associated
with continuous NSAID therapy in patients at risk for developing gastric ulcers. Patients
are considered to be at risk due to their age (≥ 60) and/or documented history of gastric
ulcers. Controlled studies do not extend beyond 6 months.”
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence:
“Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, in
combination with amoxicillin and clarithromycin, is indicated for the treatment of
patients with H. pylori infection and duodenal ulcer disease (active or history of within
the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce
the risk of duodenal ulcer recurrence.
In patients who fail therapy, susceptibility testing should be done. If resistance to
clarithromycin is demonstrated or susceptibility testing is not possible, alternative
antimicrobial therapy should be instituted.”
Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome:

“NEXIUM is indicated for the long-term treatment of pathological hypersecretory
conditions, including Zollinger-Ellison Syndrome.”
IV formulation:
“NEXIUM I.V. for Injection is indicated for the short-term treatment of GERD with
erosive esophagitis in adults and pediatric patients 1 month to 17 years, inclusively as an
alternative to oral therapy when oral NEXIUM is not possible or appropriate.”
Dosage and Administration: (section 2 of the label)
Oral suspension:
“NEXIUM is supplied as delayed-release capsules for oral administration or in packets
for preparation of delayed-release oral suspensions. The recommended dosages are
outlined in Table 1. NEXIUM should be taken at least one hour before meals.”
12 to 17 years
Short-term Treatment
of GERD
20 mg or 40 mg Once Daily for up to 8 Weeks
1 to 11 years (doses over 1mg/kg/day have not been studied)
Symptomatic GERD
10 mg Once Daily for up to 8
Weeks
Healing of Erosive Esophagitis
weight < 20 kg 10 mg Once Daily for 8 Weeks
weight ≥ 20 kg 10 mg or 20
mg
Once Daily for 8 Weeks
1 month to < 1 year (doses over 1.33mg/kg/day have not been studied)
Erosive esophagitis due to acid-
mediated GERD
weight 3 kg to 5 kg 2.5 mg Once Daily for up to 6 Weeks
weight > 5 kg to 7.5 kg 5 mg Once Daily for up to 6 Weeks

weight >7.5 kg to 12 kg 10 mg Once Daily for up to 6 Weeks
“NEXIUM for Delayed-Release Oral Suspension should be administered as follows:

Empty the contents of a 2.5 mg or 5 mg 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.

Stir.
Leave 2 to 3 minutes to thicken.
Stir and drink within 30 minutes.
If any medicine remains after drinking, add more water, stir, and drink immediately.

In cases where there is a need to use two packets, they may be mixed in a similar way by

adding twice the required amount of water or follow the mixing instructions provided by

your pharmacist or doctor.
For patients who have a nasogastric or gastric tube in place, NEXIUM For Delayed-

Release Oral Suspension can be administered as follows:

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 strengths, the volume of water in

the syringe should be 15 mL. It is important to only use a catheter tipped syringe when

administering NEXIUM through a nasogastric tube or gastric tube.

Immediately shake the syringe and leave 2 to 3 minutes to thicken.

Shake the syringe and inject through the nasogastric or gastric tube, French size 6 or

larger, into the stomach within 30 minutes.

Refill the syringe with an equal amount of water (5 mL or 15 mL).

Shake and flush any remaining contents from the nasogastric or gastric tube into the

stomach.”
IV formulation: infuse over 10 to 30 minutes
1 year to 17 years:
Body weight less than 55 kg: 10 mg
Body weight 55 kg or greater: 20 mg
1 month to less than 1 year of age: 0.5 mg/kg
“NEXIUM I.V. for Injection should not be administered concomitantly with any other
medications through the same intravenous site and or tubing. The intravenous line should
always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s
Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of
NEXIUM I.V. for Injection.
The admixture should be stored at room temperature up to 30°C (86°F) and should be
administered within the designated time period as listed in the Table 1 below. No
refrigeration is required.

Table 1
Diluent Administer within:
0.9% Sodium Chloride Injection, USP 12 hours
Lactated Ringer’s Injection, USP 12 hours
5% Dextrose Injection, USP 6 hours
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
As soon as oral therapy is possible or appropriate, intravenous therapy with NEXIUM
I.V. for Injection should be discontinued and the therapy should be continued orally.”
Warnings and Precautions: (section 5 of the label)
Risk of Concomitant Gastric Malignancy
“Symptomatic response to therapy with NEXIUM does not preclude the presence of
gastric malignancy.”
Atrophic Gastritis
“Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients
treated long-term with omeprazole, of which esomeprazole is an enantiomer.”
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
and Adverse Reactions]
Hypomagnesemia
“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. 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]
Concomitant use of NEXIUM 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]. Avoid
concomitant use of NEXIUM with St John’s Wort or rifampin.”
Interactions with Investigations for Neuroendocrine Tumors
“Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in
gastric acidity. The increased CgA level may cause false positive results in diagnostic
investigations for neuroendocrine tumors. Providers should temporarily stop
esomeprazole treatment 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.”
Concomitant use of NEXIUM 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]”
Adverse Reactions: (section 6 of the label)
Clinial Trials Experience with IV Nexium®:
“Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
Adults
The safety of intravenous esomeprazole is based on results from clinical trials conducted
in three different populations including patients having symptomatic GERD with or
without a history of erosive esophagitis (n=199), patients with erosive esophagitis
(n=160), and healthy subjects (n=204). Adverse experiences occurring in >1% of
patients treated with intravenous esomeprazole (n=359) in trials are listed below by body
system:
Symptomatic GERD and Erosive Esophagitis Trials
The data described below reflect exposure to NEXIUM I.V for Injection in 359 patients.
NEXIUM I.V. for Injection was studied only in actively-controlled trials. The population
was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, 28% Other,
and had either erosive reflux esophagitis (44%) or GERD (56%). Most patients received
doses of either 20 or 40 mg either as an infusion or an injection.
Table 2
Adverse reactions occurring at an incidence ≥ 1% in the NEXIUM I.V. group

Adverse Reactions
% of patients
Esomeprazole
Intravenous
(n=359)
Headache 10.9
Flatulence 10.3
Nausea 6.4
Abdominal pain 5.8
Diarrhea 3.9
Mouth dry 3.9
Dizziness/vertigo 2.8
Constipation 2.5
Injection site reaction 1.7
Pruritus 1.1
Intravenous treatment with esomeprazole 20 and 40 mg administered as an injection or as
an infusion was found to have a safety profile similar to that of oral administration of
esomeprazole.
Pediatric
In a randomized, open-label, multi-national study to evaluate the pharmacokinetics of
repeated intravenous doses of once daily esomeprazole, esomeprazole was well tolerated
in pediatric patients 1 month to 17 years old, inclusive. The safety results are consistent
with the known safety profile of esomeprazole and no unexpected safety signals were
identified.”
Clinial Trials Experience with Oral Nexium®:
Adult
“The safety of oral NEXIUM 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 6-12 months. In general, NEXIUM was well tolerated in both short and
long-term clinical trials.
The safety in the treatment of healing of erosive esophagitis was assessed in four
randomized comparative clinical trials, which included 1,240 patients on NEXIUM 20
mg, 2,434 patients on NEXIUM 40 mg, and 3,008 patients on omeprazole 20 mg daily.
The most frequently occurring adverse events (≥1%) in all three groups were headache
(5.5, 5.0, 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.
Additional adverse events that were reported as possibly or probably related to NEXIUM
with an incidence <1% are listed below by body system:
Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain,
chest pain substernal, 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.
Endoscopic findings that were reported as adverse events 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 treatment-related adverse events during 6- month maintenance treatment
was similar to placebo. There were no differences in types of related adverse events seen
during maintenance treatment up to 12 months compared to short-term treatment.
Two placebo-controlled studies were conducted in 710 patients for the treatment of
symptomatic gastroesophageal reflux disease. The most common adverse events that
were reported as possibly or probably related to NEXIUM were diarrhea (4.3%),
headache (3.8%), and abdominal pain (3.8%).
The following potentially clinically significant laboratory changes in clinical trials,
irrespective of relationship to NEXIUM, were reported in ≤ 1% of patients: increased
creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white
blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid
stimulating hormone [see Clinical Pharmacology, Endocrine Effects for further

information on thyroid effects]. Decreases were seen in hemoglobin, white blood cell
count,platelets, potassium, sodium, and thyroxine.”
Pediatric
“The safety of oral NEXIUM was evaluated in 316 pediatric and adolescent patients aged
1 to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical
Studies]. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at
least 1%) treatment-related adverse reactions in these patients were diarrhea (2.8%),
headache (1.9%) and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years
the most frequently reported (at least 2%) treatment-related adverse reactions in these
patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%), and nausea (2%).
No new safety concerns were identified in pediatric patients.”
Postmarketing Experience:
“The following adverse reactions have been identified during post-approval use of
NEXIUM. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Postmarketing Reports - There have been spontaneous reports of adverse events with
postmarketing use of esomeprazole. These reports occurred rarely and are listed below by
body system:
Blood And Lymphatic System Disorders: agranulocytosis, pancytopenia; Eye Disorders:
blurred vision; Gastrointestinal Disorders: pancreatitis; stomatitis; microscopic colitis;
Hepatobiliary Disorders: hepatic failure, hepatitis with or without jaundice; Immune
System Disorders: anaphylactic reaction/shock; Infections and Infestations: GI
candidiasis; Metabolism and nutritional disorders: hypomagnesemia; Musculoskeletal
And Connective Tissue Disorders: muscular weakness, myalgia, bone fracture; Nervous
System Disorders: hepatic encephalopathy, taste disturbance; Psychiatric Disorders:
aggression, agitation, depression, hallucination; Renal and Urinary Disorders: interstitial
nephritis; Reproductive System and Breast Disorders: gynecomastia; Respiratory,
Thoracic and Mediastinal Disorders: bronchospasm; Skin and Subcutaneous Tissue
Disorders: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-
Johnson syndrome, toxic epidermal necrolysis (TEN, some fatal).
Other adverse events not observed with NEXIUM, but occurring with omeprazole can be
found in the omeprazole package insert, ADVERSE REACTIONS section.”
***** Please review the full labels of Nexium® IV and oral suspension for more details,
including information on pediatric studies*****
6.2 APPENDIX B: STANDARD SEARCHES
A. Adults (17 yrs and above)
1. All outcomes from approval date (no set criteria)
2. Serious outcomes from approval date
3. Death as an outcome from approval date

B. Ages 0-16 yrs ONLY
1. Same as above 1-3
2. Retrieve case reports for hands-on review
6.3 APPENDIX C: ADVERSE EVENT REPORTING SYSTEM (AERS) DATABASE
DESCRIPTION
The Adverse Event Reporting System (AERS) is a computerized information database
designed to support the FDA's post-marketing safety surveillance program for drug and
therapeutic biologic products. The FDA uses AERS to monitor adverse events and
medication errors that might occur with these marketed products. The structure of AERS
complies with the international safety reporting guidance (ICH E2B) issued by the
International Conference on Harmonization. Adverse events in AERS are coded to terms
in the Medical Dictionary for Regulatory Activities terminology (MedDRA).
AERS data do have limitations. First, there is no certainty that the reported event was
actually due to the product. FDA does not require that a causal relationship between a
product and event be proven, and reports do not always contain enough detail to properly
evaluate an event. Further, FDA does not receive all adverse event reports that occur with
a product. Many factors can influence whether or not an event will be reported, such as
the time a product has been marketed and publicity about an event. Therefore, AERS
cannot be used to calculate the incidence of an adverse event in the U.S. population.

---------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------
----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
THANG X LA
10/31/2012
ETHAN D HAUSMAN
10/31/2012
ANN MACKEY
10/31/2012
LINDA J SCARAZZINI
11/01/2012
Reference ID: 3204251

Global Medical Cures™ | Nexium- Pediatric PostMarketing Adverse Event Review

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