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



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  • 1. 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
  • 2. 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 Reference ID: 3204251 1
  • 3. 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 Reference ID: 3204251 2
  • 4. 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) Reference ID: 3204251 3
  • 5. • 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) Short-term Treatment of 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 Reference ID: 3204251 4
  • 6. 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) Reference ID: 3204251 5
  • 7. 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) Reference ID: 3204251 6
  • 8. 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. Reference ID: 3204251 7
  • 9. 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. 2 .~ ... - 1/) .~­'0 ... Q) 0 a.. g. 1 -o:::0 ... en G>O::: ..cw Ec:s: ::::s z Reference ID: 3204251 .••••••••••••••••••••••••••••••••••••••••,. ••••••••• .•••.••••••••••,. It) 0 0 N <D 0 0 N "0 0 N co 0 0 N en 0 0 N 0 ..... 0 N N ..... 0 N FDA Received Year 8 •••••••• -- ••.. • . ...-..
  • 10. 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 Reference ID: 3204251 9
  • 11. 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. Reference ID: 3204251 10
  • 12. 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 Reference ID: 3204251 11
  • 13. 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: Reference ID: 3204251 12
  • 14. “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) Short-term Treatment of 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 Reference ID: 3204251 13
  • 15. 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. Reference ID: 3204251 14
  • 16. 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 Reference ID: 3204251 15
  • 17. “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 Reference ID: 3204251 16
  • 18. 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). Reference ID: 3204251 17
  • 19. 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 Reference ID: 3204251 18
  • 20. 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 Reference ID: 3204251 19
  • 21. 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. Reference ID: 3204251 20
  • 22. --------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------- ---------------------------------------------------- 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