FDA Analysis of Postmarketing Adverse Events of Omeprazole in Pediatric Patients, Slides of History

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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 Pharmacovigilance Date: April 3, 2018 Safety Evaluator: Kimberley Swank, PharmD Division of Pharmacovigilance-I (DPV-I) Team Leader: Lisa Harinstein, PharmD, BCCCP DPV-I Deputy Division Director: Monica Muñoz, PharmD, MS, BCPS DPV-I Product Name(s): Prilosec (omeprazole magnesium) delayed-release oral suspension Pediatric Labeling Approval Date: February 3, 2016 Application Type/Number: NDA 022056/S-018 Applicant/Sponsor: AstraZeneca OSE RCM #: 2018-2 TABLE OF CONTENTS Executive Summary........................................................................................................................ 3 1 Introduction ............................................................................................................................. 5 1.1 Product Formulations and Indications.............................................................................. 5 1.2 Pediatric Regulatory History, ........................................................................................... 6 1.3 Highlights of Labeled Safety Issues................................................................................. 8 2 Postmarket adverse event Reports .......................................................................................... 8 2.1 Methods and Materials ..................................................................................................... 9 2.1.1 FDA Adverse Event Reporting System (FAERS) Search Strategy.......................... 9 2.2 Results .............................................................................................................................. 9 2.2.1 Total number of FAERS reports by Age .................................................................. 9 2.2.2 Selection of Serious Pediatric Cases in FAERS ....................................................... 9 2.2.3 Characteristics of Pediatric Case Series.................................................................. 11 2.3 Summary of Non-Fatal Pediatric Serious Adverse Event Cases (N=5)......................... 11 2.3.1 Nervous System Disorders (n=3)............................................................................ 12 2.3.2 Psychiatric Disorders (n=1) .................................................................................... 14 2.3.3 Renal and Urinary Disorders (n=1) ........................................................................ 15 3 Discussion ............................................................................................................................. 15 4 Conclusion ............................................................................................................................ 16 5 Recommendations................................................................................................................. 16 6 Appendices............................................................................................................................ 16 6.1 Appendix A FDA Adverse Event Reporting System (FAERS)..................................... 16 6.2 Appendix B. FAERS Case Numbers, FAERS Version Numbers And Manufacturer Control Numbers For The Pediatric Case Series With Drug (N=5) ......................................... 18 7 References............................................................................................................................. 19 1 INTRODUCTION This review evaluated postmarketing adverse event reports with a serious outcome for two omeprazole drug products, Prilosec (omeprazole magnesium; NDA 022056) delayed-release oral suspension and Prilosec (omeprazole; NDA 19810) delayed-release pellets capsule, in pediatric patients. This review was triggered by the pediatric indication for Prilosec (omeprazole magnesium) delayed-release oral suspension. 1.1 PRODUCT FORMULATIONS AND INDICATIONS Omeprazole is a proton pump inhibitor (PPI) approved in the United States (U.S.) on September 14, 1989 and is available as a prescription and over-the-counter (OTC) product (see Table 1.1.1 for omeprazole formulations and U.S. approval information). Table 1.1.1 Omeprazole Single-Ingredient Product Formulations and U.S. Approval Information Formulations Prescription or OTC Status NDA/ANDA Initial U.S. Approval Dates Approved Indications Approved Population for Use Delayed-release Prescription NDA 022056 3/20/2008 Treatment of active duodenal Adults oral suspension ulcer Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence Treatment of active benign gastric ulcer Treatment of symptomatic gastroesophageal reflux disease (GERD) Treatment of erosive esophagitis (EE) due to acid- mediated GERD Maintenance of healing of EE due to acid-mediated GERD Pathologic hypersensitivity conditions Adults Adults Children 1 year of age and older Children 1 month of age and older Children 1 year of age and older Adults Delayed-release Prescription NDA 019810 9/14/1989 Treatment of active duodenal Adults pellets capsule (discontinued) ANDA 075347, 075576, 075757, ulcer 5 075785, 075876, 076048, 076515, 078490, 091352, 091672, 202384, 203270, 203481, 204661 Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence Treatment of active benign gastric ulcer Treatment of symptomatic GERD Treatment of EE due to acid- mediated GERD Maintenance of healing of EE due to acid-mediated GERD Pathologic hypersensitivity conditions Adults Adults Children 1 year of age and older Children 1 month of age and older Children 1 year of age and older Adults Delayed-release oral disintegrating tablet OTC NDA 209400 7/5/2017 Treatment of frequent heartburn (occurs 2 or more days a week) for 14 days Adults Delayed-release tablet OTC NDA 021229 NDA 022032 ANDA 204152 6/20/2003 Treatment of frequent heartburn (occurs 2 or more days a week) for 14 days Adults Delayed-release capsule OTC ANDA 078878 6/5/2009 Treatment of frequent heartburn (occurs 2 or more days a week) for 14 days Adults 1.2 PEDIATRIC REGULATORY HISTORY1,3 Prilosec (omeprazole; NDA 19810) delayed-release pellets capsule was originally approved as a delayed-release oral capsule on September 14, 1989. Pediatric labeling for the delayed-release pellets capsule was approved for patients 2 to 16 years of age for the treatment of symptomatic gastroesophageal reflux disease (GERD), healing of erosive esophagitis (EE), and maintenance of healing of EE on July 12, 2002. On March 20, 2008, Prilosec (omeprazole magnesium; NDA 022056) delayed-release oral suspension was approved for the short-term treatment of symptomatic GERD and healing of EE in pediatric patients 1 to 2 years old. NDA 022056 was submitted to fulfill the Phase IV commitment made upon approval of NDA 19810 to develop an age appropriate formulation for young children. A postmarketing requirement (PMR) under the Pediatric Research Equity Act 6 (PREA) was issued to the Sponsor, AstraZeneca, to conduct a pediatric study in pediatric patients 1 month to < 1 year of age for the treatment of GERD. On April 29, 2010, the Office of Surveillance and Epidemiology (OSE) completed a review of pediatric postmarketing adverse events for all PPIs, including omeprazole delayed-release oral suspension, in preparation for a June 2010 Pediatric Advisory Committee (PAC) meeting.2 Postmarketing pediatric adverse events in the Adverse Event Reporting System (AERS) database were reviewed for omeprazole from approval date (March 20, 2008) through April 20, 2009. No safety concerns were identified from the OSE review. The Committee recommended to return to standard safety monitoring for all adverse events. The Committee also discussed the need for additional data to evaluate efficacy, dosing regimens, and bone fractures related to PPI use. Additional data on pediatric PPI use was presented at the May 7, 2012 PAC meeting, which did not identify any PPI-related safety signals. On October 10, 2013, FDA released AstraZeneca from part of the above mentioned PMR and replaced it with a new PMR to evaluate the pharmacokinetics, pharmacodynamics, and safety of omeprazole in patients 1 month to 11 months with EE. On June 20, 2013, based on a feasibility analysis, additional concerns were raised by the Sponsor about completing the revised PMR and proposed to use available pharmacokinetic, pharmacodynamic, and safety data from previous omeprazole studies in children to fulfil the PMR. In February 2014, FDA agreed to the Sponsor’s proposal. The following regulatory history was reproduced from Dr. Marjorie Dannis (Medical Officer in the Division of Gastroenterology and Inborn Errors Products (DGIEP)) clinical review of the pediatric supplement to extend the indication to patients 1 month to less than 1 year of age with EE due to acid-mediated GERD.3 There were no new efficacy data submitted with this sNDA (NDA 022056/S-018) submission. Acid-mediated GERD with EE has the same disease definition and similar endoscopic presentation in adults, older children, and infants. In all age groups, the treatment is targeted to reduce pH and heal acid-injury. Therefore, extrapolation of efficacy based on well-controlled adult trials is appropriate for pediatric patients 1-11 months of age. Based on the Clinical Pharmacology and Pharmacometrics review, the pharmacokinetic and pharmacodynamic data appear to support the proposed weight-based doses for infants aged 1 to 11 months. The safety assessment was obtained from two previous clinical trials (Studies 251 and 250) as well as from post-marketing data. Overall, no major safety concerns were identified. The reviewer concluded that the reported adverse events during the clinical studies were mostly related to the natural history and/or disease-related events in this patient population. The Sponsor submitted post-marketing experience adverse event data up until October 15, 2013. The clinical reviewer concluded that with the exception of “off label use”, most of the adverse events were likely related to the natural history and/or disease-related events. From February 1989 to October 2013, there were five cases with a fatal outcome in infants less than 1 year of age. A review of the case narratives failed to provide evidence that these outcomes could be treatment related. 7 'I Total pediatric reports with a serious outcome reviewed (11=281) • Pediatric reports with the outcome of death (n=l7) I ! l Excluded Cases* (n=276) (Including 17 deaths) • Duplicates (n=l33) • Strong alternative cause (n=49) • Labeled event/known adverse event (n=40) • Transplacental exposure (n=24) • Limited inf01mation (n=23) • No adverse event (11=6) • Report coded with the wrong age (n= l): adult patient Pediatric Case Series (n=5) (Including 0 deaths) See Table 3.2.3 .. .. * DPV reviewed these cases, but they were excluded from the case series for the reasons listed above Of the 281 serious pediatric reports, 276 were not included in the pediatric case series. Seventeen of the 276 excluded repo1ts had an outcome of death. Of the 17 repo1ts with an outcome ofdeath, seven reports were duplicates, three repo1ts described transplacental exposure, two reports had insufficient info1mation to assess the c.ause of death, and one repo1i described a labeled adverse event (Steven-Johnson syndrome (SJS) and toxic epide1mal necrolysis (TEN) after receiving antibiotics and omeprazole). The remaining four repo1ts described patients who died because of a strong alternative cause: cardiac failure in patients with multiple co-morbidities (n=2), cardiorespiratory anest and aspiration after choking on an omeprazole tableta (n=l), and multi-organ failure in a patient receiving multiple immunosuppressant medications (n= l). Fo1ty-five repo1ts with a non-fatal serious outcome had a strong alternative cause for the adverse events: 11 repo1ied labeled events or known events associated with concomitant medications (psoriasis with adalimumab, anticholinergic syndrome with se1iraline, drng reaction with eosinophilia and systemic symptoms (DRESS) with sulfamethoxazole/trimethoprim, elevated amylase and lipase with ceritinib), 15 reported symptoms likely attributable to an underlying disease (such as an aggravated gastrointestinal disorder, respiratory distress in a patient with pneumonia, psychiatric adverse events in a patient with a history ofbipolar disorder), seven • The parents gave their 8-month-old child a whole omeprazole dispersible tablet, which was administered inappropriately according to the Losee Mups (omeprazole) tablet product label. The administration instmctions in the product label state that for patients unable to swallow whole tablets break the Mups tablet and disperse in a spoonful ofwater, any acidic fmit juice, or apple sauce. 10 reported intentional overdoses with multiple medications, seven reported adverse events related to a medication error, and five reported infections while receiving at least one concomitant immunosuppressant medication. Thirty-nine cases with a non-fatal serious outcome reported a labeled or known adverse event associated with omeprazole. The labeled or known adverse eventsb included: abdominal pain (n=4), diarrhea (n=4), rash (n=4), hypersensitivity reaction (n=3), pancreatitis (n=3), drug interactions (n=3), vomiting (n=2), flatulence (n=2), melena (n=2), hepatitis (n=2), SJS (n=2), pyrexia (n=2), anxiety (n=2), constipation (n=2), neutropenia (n=1), fatigue (n=1), headache (n=1), visual impairment (n=1), malaise (n=1), C. difficile (n=1), confusion (n=1), dizziness (n=1), psychotic disorder (n=1), cholestasis (n=1), liver injury (n=1), hyponatremia (n=1), increased alkaline phosphatase (n=1), erythematous (n=1), sleep disturbance (n=1), anaphylaxis (n=1), interstitial nephritis (n=1), dermatitis (n=1), fracture (n=1), esophageal candidiasis (n=1), nausea (n=1), carcinoid tumor (n=1), depression (n=1), and abnormal thinking (n=1). 2.2.3 Characteristics of Pediatric Case Series Appendix B lists all the FAERS case numbers, FAERS version numbers and Manufacturer Control Numbers for the pediatric case series. Table 2.2.3 Characteristics of Pediatric Case Series with Omeprazole (N=5) Age Sex 0 - < 1 month 1 month - <2 years 2 - < 6 years 6 - <12 years 12 - < 17 years Female 0 3 1 1 0 4 Male 1 Country Reported Reason for Use United States Foreign GERD 3 2 5 Serious Outcome* Hospitalized Other serious 3 3 * For the purposes of this review, the following outcomes qualify as serious: death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly, required intervention, and other serious important medical events. Reports may have more than one outcome. 2.3 SUMMARY OF NON-FATAL PEDIATRIC SERIOUS ADVERSE EVENT CASES (N=5) b Events are not mutually exclusive 11 Unlabeled Events 2.3.1 Nervous System Disorders (n=3) There were two cases of the unlabeled event of seizures identified and one case of the unlabeled event of dystonia. Case 10667404, Hospitalization (HO), Great Britain, 2014: A report from a parent describes a 17-month-old male (weight 12 kg) that was receiving omeprazole 15 mg orally daily for the treatment of GERD. The patient started receiving omeprazole at 8 weeks of age. On an unknown date, the dose of omeprazole was increased to 20 mg orally daily, divided in two doses, for worsening GERD. The mother reported that the patient was suffering from convulsions or what appeared to be shivering episodes for 6 weeks and was waking up 2-5 times per night. The patient was admitted to the hospital for assessment of seizures. The patient was discharged home after a negative work-up (tests and laboratory results were not provided). The patient’s mother discontinued omeprazole after reading the omeprazole (Losec Mups) product label and discovered that the “shivering fits” may be due to a magnesium deficiency. The patient was given a banana daily in an attempt to increase his magnesium levels. The mother reported that the “shivering fits” appear to have gone away and the patient is having undisturbed sleep at night. Concomitant medications included ranitidine and multivitamins. Reviewer comment: The recommended dose for pediatric patients 1 to 16 years of age and 10 to less than 20 kg is 10 mg once daily. This patient was receiving higher than the recommended dose (15- 20 mg daily), which may have contributed to the adverse events. The patient had a negative workup for seizures; however, the “shivering fits” and sleep disturbances resolved after discontinuation of omeprazole. Seizures associated with hypomagnesemia is labeled in the Warnings and Precautions section of all PPI labels. The patient’s magnesium level was not reported; however, the report states that a banana was given in an attempt to increase the patient’s magnesium level. Of note, there were 10 additional unique pediatric cases of seizures and one unique pediatric case of myoclonus that were excluded from the case series. Reasons for exclusion included past medical history of seizures (n=6), labeled event associated with concomitant medication (n=2), medical history of an underlying disease that can result in seizures (n=1), intentional overdose on multiple medications (n=1), and limited clinical information to make an assessment (n=1). Case 12679934, HO, Other serious (OT), U.S., 2016: A report from a parent describes an 11­ year-old female that was started on omeprazole 20.6 mg (route and frequency not reported) for the treatment of heartburn. Three days after of starting omeprazole, the patient had an extremely violent seizure type episode. The patient also had difficulty breathing, her “head turned extreme to side,” right arm and leg numbness, diarrhea, and muscle spasms. Reported tests included a CT scan, vital signs, blood work (including electrolytes); however, results were not provided. Reviewer comment: This case reports a temporal relationship between initiation of omeprazole treatment and onset of seizures. As already mentioned, seizures associated with 12 toxicity and concomitant administration with domperidone). These cases do not represent a new safety signal. 2.3.3 Renal and Urinary Disorders (n=1) There was one case of the unlabeled events of chromaturia and abnormal urine odor. Case 10227290, OT, U.S., 2014: One-month-old twins were started on omeprazole (2 mg/ml) compounded suspension 3.4 mg orally twice daily for acid reflux. Approximately 3 hours after the third dose, both babies developed “light pink” urine. The report stated that, “the prescribed dose by the pediatrician is 3.4 mg (1.7 ml) orally twice daily. If one is to calculate the recommended dose range (0.5 to 1.5 mg/kg/dose orally once daily) based upon current clinical literature, the dose prescribed by the pediatrician is greater than the current clinical literature recommended dose range using the patient’s weight of 7.9 lbs.” In subsequent follow-ups with the patient’s grandmother, it was reported that the color of the urine was more “orangey pink” than “light pink.” On the evening of the first episode, the patient had, “black urine with a strong odor.” After the patient’s family stopped the omeprazole treatment, the twin’s urine had cleared. Omeprazole suspension was reintroduced a few days later and the twin’s urine became “orangey­ pink” after one dose of omeprazole. The omeprazole was stopped again and the urine cleared. At the twins two-month check-up, the pediatrician discontinued omeprazole and started them back on ranitidine (the patients received ranitidine prior to omeprazole). The patient’s grandmother reported that the pediatrician did not comment on what could have possibly caused the “black urine with strong odor.” The patient’s frequency of urine output has not changed during and since the reported events. Reviewer comment: This case reports a temporal relationship between omeprazole and the adverse event of chromaturia. In addition, a positive dechallenge and rechallenge was reported in both patients. Omeprazole was used off-label for the treatment of GERD (recommended age is 1 to 16 years). According to the reporter, the twins were receiving higher than the current literature recommended dose of 0.5 to 1.5 mg/kg/dose orally once daily, which may have contributed to the adverse events. An alternative explanation for the “pink urine” may be the development of “pink diaper syndrome,” which results from the deposition of urate crystals found in the setting of concentrated urine in infants.4 For completeness, we searched the FAERS database for additional pediatric reports (all reports prior to October 16, 2013) of chromaturia with omeprazole. We retrieved three additional pediatric cases of chromaturia. Of the three cases, one lacked sufficient detail to assess causality and two had strong alternative causes (hepatitis/increased bilirubin and porphyria). These cases do not represent a new safety signal. DISCUSSION We evaluated all pediatric postmarketing adverse event reports with a serious outcome for Prilosec (omeprazole) in the FAERS database from October 16, 2013 through November 2, 15 3 2017. The start date of October 16, 2013 was chosen to capture all reports from the data lock date of a previous DGIEP review for NDA 22056/S-018, which reviewed all pediatric postmarketing adverse events with Prilosec (omeprazole) from February 1989 (U.S. approval date) through October 15, 2013. Of the 281 pediatric reports, including 17 death cases, 133 were duplicates, 49 contained strong alternative causes for the reported adverse events, 40 reported a labeled event for a concomitant medication, 24 described transplacental exposures, 23 contained limited information for assessment, 6 reported no adverse event, and 1 was an adult case coded with the wrong age. The remaining five non-fatal pediatric cases described unlabeled adverse eventsd (seizures n=2, dystonia n=1, chromaturia n=1, autism spectrum disorder n=1, antisocial disorder n=1, speech disorder n=1, and communication disorder n=1). In three of the five cases, patients were receiving higher than recommended doses of omeprazole which may have contributed to the adverse events. In addition, all five cases either had other plausible explanations to account for the adverse event or lacked sufficient information to assess causality. No new safety signals were identified after review of the pediatric postmarketing cases with omeprazole. 4 CONCLUSION We did not identify any new safety signals with omeprazole in pediatric patients. There is no evidence from these data that there are pediatric safety concerns with omeprazole delayed- release oral suspension at this time. 5 RECOMMENDATIONS OSE recommends returning to routine pharmacovigilance monitoring for all adverse events with omeprazole. 6 APPENDICES 6.1 APPENDIX A FDA ADVERSE EVENT REPORTING SYSTEM (FAERS) FDA Adverse Event Reporting System (FAERS) The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. The informatic structure of the database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation. Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities d Events are not mutually exclusive 16 (MedDRA) terminology. The suspect products are coded to valid tradenames or active ingredients in the FAERS Product Dictionary (FPD). FAERS data 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 reports for every adverse event or medication error that occurs 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, FAERS data cannot be used to calculate the incidence of an adverse event or medication error in the U.S. population. 17