Global Medical Cures™ | Crestor- Post Marketing Adverse Event Review

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Global Medical Cures™ | Crestor- Post Marketing 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 December 3, 2010 To: Lisa L. Mathis MD, Acting Director Pediatric and Maternal Health Staff (PMHS) Office of New Drugs (OND), CDER M. Dianne Murphy, MD, Director Office of Pediatric Therapeutics (OPT), OC Thru: Ann McMahon, MD, Deputy Director Lanh Green Pharm.D. Safety Evaluator, Team Leader Division of Pharmacovigilance (DPVI) Office of Surveillance and Epidemiology (OSE), CDER From: Quocbao Pham Pharm.D., Safety Evaluator Division of Pharmacovigilance (DPV) I Office of Surveillance and Epidemiology (OSE), CDER Subject: BPCA & PREA: Pediatric Postmarketing Adverse Event Review Drug Name(s): Crestor (Rosuvastatin Calcium) Pediatric Exclusivity Approval Date: July 7, 2009 Application Type/Number: NDA 21-366 Applicant/sponsor: IPR Pharmaceuticals, Inc. OSE RCM #: 2010-2017 Reference ID: 2871042
  • 2. 1 INTRODUCTION In accordance with the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA), this review summarizes post-marketing cases of adverse events associated with the use of Crestor (rosuvastatin) in pediatric patients 0-16 years of age identified in the Adverse Events Reporting System (AERS) database. The Office of Pediatric Therapeutics requested this review in preparation for the Pediatric Advisory Committee (PAC) meeting scheduled for March 2011. The focus of this review is on all serious (fatal and non-fatal) adverse events in children 0-16 years of age and from August 12, 2003 (approval) to August 18, 2010. OSE was requested to compare the adverse events between children and adults, highlighting growth, liver, kidney, and muscle disorders. Rosuvastatin calcium is an HMG Co-A reductase inhibitor (statin) approved for use in pediatric patients 10-17 years of age with heterozygous familial hypercholesterolemia (HeFH) to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy. Pediatric studies for safety and efficacy were performed in response to a Written Request on March 7, 2006 and fulfilled the Pediatric Research Equity Act (PREA) post-marketing requirement (PMR) for the supplemental application in patients 10-17 years. Exclusivity was granted on July 7, 2009. The pediatric study requirement for ages 0 to 9 years were waived (reason not specified). Pertinent Pediatric Safety Labeling: Contraindications, Women who are pregnant or may become pregnant and nursing mothers. Dosing and Administration, HeFH in Pediatric Patients 10 to 17 years of age (2.2): The usual dose range of Crestor is 5-20 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Adverse Reactions, Pediatric Patients 10 to 17 years of age (6.2): Elevations in serum creatine phosphokinase (CK) > 10x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Use in Specific Population, Pregnancy (8.1): Crestor may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking Crestor, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy. Use in Specific Population, Pediatric Use (8.4): Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. Use in Specific Population, Pediatric Use (8.4): Crestor has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. 2 AERS SEARCH CRITERIA AERS database was searched for all adverse events reported for NDA #021-366 (to include tradename Crestor and synonyms) from an FDA received date of August 12, 2003 to August, 18, 2010. Reference ID: 2871042
  • 3. 3 AERS RESULTS FOR ROSUVASTATIN (TABLE 1) Table 1: Crude counts1 of AERS Reports from All Sources From Approval Date (August 12, 2003) to (August, 18, 2010) All reports (US)2 Serious3 (US) Death (US) Adults (≥ 17 yrs.) 11690(9205) 8191(5912) 270(111) Pediatrics (0-16 yrs.) 17(8) 14(5) 3(2) Age unknown (Null values) 4006(3653) 2272(1955) 59(43) Total 15713(12866) 10447(7872) 332(156) 1 May include duplicates 2 US counts in parentheses 3 Serious adverse drug experiences per regulatory definition (CFR 314.80) include outcomes of death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events. AERS retrieved a total of 17 cases of adverse events in children aged 0-16 years from August 12, 2003 to August, 18, 2010 for Crestor (rosuvastatin) NDA #021-366. A similar search for adult patients yielded 11,690 reports for the same period. After a hands-on review, one duplicate case and four cases1 involving adult patients were excluded. Twelve unduplicated adverse events reports in children remained. Characteristics of the 12 pediatric cases in this series are presented in Table 2. The 59 fatal cases involving patients with “unknown” ages were also retrieved. A hands-on review of these cases found three duplicates2 to a case already included in this review (ISR #6299864). Of the remaining 56 cases, 34 cases involved adult patients, and 22 cases did not identify the patient as an adult or child. 1 ISR# 6120652, 6138390, 5903147, 5236734 2 ISR# 6267856, 6252460, 6253638 Reference ID: 2871042
  • 4. Table 2. Characteristics of Serious and Severe Pediatric Adverse Event Cases with Rosuvastatin (n=12) ISR # Source Reporter Age Gender Adverse Events Comments 5371700 Foreign Physician 23 Months Female Accidental Exposure Child was asymptomatic. It was not known if she swallowed any pills. Activated charcoal was administered and blood was collected. Results and outcome not reported. 5239254 Domestic Consumer 24 Months Female Accidental Exposure Child took one Crestor 10mg tablet and was then “dancing around”. No other information reported. Case was reported as Non-serious. 6147080 Foreign Foreign Regulator NR Male In Utero Exposure, Congenital Hemangioma 37-year-old mother was on ezetimibe and rosuvastatin. When pregnancy was diagnosed, ezetimibe was stopped. Mom delivered a “healthy female baby”. The baby then experienced congenital hemangioma which persisted. Reporter did not feel that hemangioma was related to rosuvastatin. 6299864 Domestic Physician 5 Hours Male In Utero Exposure; Death 28-year-old mother was on rosuvastatin, glyburide/metformin, modafinil, oxybutynin, gabapentin, and interferon-beta while pregnant. Diagnosis of pregnancy made at 4 weeks gestation, all medications were stopped. Ultrasound at 12 weeks and 18 weeks showed significant anomalies. Mother refused advice to abort pregnancy. She had an emergency c-section at 36-week gestation. Baby boy passed away 5 hours after birth. 6405264 Foreign Consumer 30 Months Female Accidental Exposure Child took 2.5mg of Crestor 2-3 times. No other information reported. 6405319 Foreign Consumer 14 Months Female Accidental Exposure Child took 1.5 tablets of 5mg Crestor. Unspecified symptoms developed. No other information reported. 6405328 Foreign Foreign Regulator 22 Months Male Accidental Exposure Child took 5mg tablet of Crestor with four other drugs (names not reported). No outcome or other information was reported 6405356 Foreign Consumer 18 Months Male Accidental Exposure Child took 2.5mg tablet of Crestor. No other information was reported. 6511079 Domestic Physician 16 Years Female Diarrhea, ↑LFT Complicated 16-year-old patient with medical history of liver transplant and double lung transplant was started on Crestor 2.5-10mg (exact dose not reported) for high triglycerides on 1/7/2009. She experienced diarrhea and elevated liver enzymes and Crestor was discontinued on 2/19/2009. Outcome was not reported. 6547230 Foreign Physician NR Female In Utero Exposure; Death Mother was on Crestor 20mg daily while pregnant. On ultrasound the fetus was diagnosed with extreme bradycardia (date not reported). Crestor was stopped and the fetus subsequently died. No other information reported. 6714852 Foreign Physician 13 Years Male Suicide Attempt 13-year-old girl attempted suicide by taking 3 tablets of Crestor and candesartan that were prescribed to her father. The girl experienced paleness and tremor. She was taken to the ER. Cardiac function did not show any alteration. Hepatic, renal, and electrolyte tests were done but results not reported. However, her symptoms were improving. No other information or outcome was reported. 6719206 Foreign Consumer 18 Months Male Possible Accidental Exposure Child took 6 Crestor 10 mg tablets and he was taken to the hospital. He experienced pyrexia and peripheral coldness. The reporting father stated that the symptoms might have been due to “teething” and that the child might not have taken Crestor. Reference ID: 2871042
  • 5. 4 SUMMARY OF RESULTS The AERS search identified two fatal pediatric cases and 10 non-fatal serious pediatric cases from August 12, 2003 to August, 18, 2010, in association with rosuvastatin use. Both fatal cases involved in utero exposure to rosuvastatin. The 10 non-fatal cases had the following adverse events: accidental exposure (n=7), suicide attempt (n=1), in utero exposure / hemangioma (n=1), and diarrhea / increased liver function tests (n=1). 4.1 FATAL CASES (N=2, 1 FOREIGN, 1 DOMESTIC) Case 1 (ISR# 6299864) involved in utero exposure with rosuvastatin. A 28-year-old mother was taking rosuvastatin 10mg daily for high cholesterol. Her other maintenance medications included glyburide/metformin, modafinil, oxybutynin, gabapentin and interferon beta. She had a history of two previous pregnancies (one vaginal, one cesarean), high cholesterol, diabetes, and multiple sclerosis. Her last menstrual period was April 21, 2007. She found out she was pregnant on May 26, 2007 (approximately 4 weeks gestation). All medications were stopped. At 12-weeks, an ultrasound showed that her baby had a large fluid pocket on his neck. At 18-weeks, an ultrasound showed that baby had a club foot, shortened thigh bone, curvature of his spine. The mother was advised to abort the pregnancy, but she refused. She did not feel her baby move until 28-weeks. On December 25, 2007, at 36-weeks gestation, she had contractions and went into labor. Attempts to stop labor were unsuccessful and a cesarean section was performed. The baby was born blue with underdeveloped bones and lungs. He was sedated, intubated, and brought to the NICU. On December 26, 2007, at five-hour-old, the baby died. The mother refused to have an autopsy performed. Case 2, (ISR# 6547230) involved in utero exposure with rosuvastatin. The mother was taking rosuvastatin 20mg daily and escitalopram (dose not reported) while pregnant. By ultrasound, the baby was diagnosed with extreme bradycardia (date not reported). Rosuvastatin was stopped and the fetus subsequently died. No other information was reported. 4.2 NON-FATAL (N=10, 7 FOREIGN, 3 DOMESTIC) Seven of the 10 non-fatal cases involved accidental exposure of rosuvastatin to a baby. However, none of the seven cases provided enough detail to evaluate for adverse reactions. Three cases assessed for symptoms: 1) pyrexia with peripheral coldness; 2) “dancing around”; 3) “asymptomatic”. In the case (ISR#6719206) involving pyrexia and peripheral coldness, the reporter (consumer) stated that the symptoms might have been due to “teething” and that his son might not have been exposed to rosuvastatin. The remaining four accidental exposure cases did not provide information beyond the fact that rosuvastatin was ingested. Two other cases included a suicide attempt and an in utero exposure to rosuvastatin. 1) A 13- year-old girl attempted to commit suicide by taking 3 tablets each of rosuvastatin and candesartan (strengths of tablets were not reported) that were prescribed to her father. The girl experienced “paleness and tremor” and was taken to the ER. Cardiac function “did not show any alteration”. Hepatic, renal, and electrolyte tests were performed but results were not reported. The girl’s symptoms improved but a final outcome was not reported. 2) A 37-year-old mother was taking ezetimibe and rosuvastatin (dose and duration not reported). When she became pregnant, ezetimibe was stopped (status of rosuvastatin was not reported). It was reported that she delivered a “healthy female baby”. Subsequently, the baby experienced congenital hemangioma which persisted (dates not provided). No other information was provided. The remaining case involved a 16-year-old girl with a past medical history of liver transplant and double lung transplant. On January 7, 2009, she started rosuvastatin 2.5-10mg (exact dose not Reference ID: 2871042
  • 6. reported) for high triglycerides. She subsequently experienced diarrhea and elevated levels of liver enzymes. Rosuvastatin was discontinued on February 19, 2009. 5 DISCUSSION A review of the AERS pediatric cases did not identify adverse events unique to the pediatric population. Two fatal cases involved in utero exposure to rosuvastatin. However, both cases were difficult to assess for causality because of the mothers’ complicated medical situation in one case and insufficient details reported in the other. The consult requested DPVI to focus on growth, liver, kidney, and muscle disorders. However, 11 of the 12 cases in this series did not specifically involve these disorders. Seven cases were accidental exposures to children less than 3-year-old; three cases were in utero exposures; and one case was a suicide attempt by a 13-year-old. Three adverse reactions from rosuvastatin in children were observed in these 11 cases. One case described paleness and tremors but the patient also ingested three tablets of candesartan during her suicide attempt. A second case described pyrexia and peripheral coldness but little detail was reported. A third case reported the child was “dancing around” after ingesting rosuvastatin, which did not provide enough detail to assess. No other symptoms were described in these 11 cases. The remaining 12th case in this series involved a 16-year-old girl with history of liver and bilateral lung transplants experiencing diarrhea and increased levels of liver enzymes (LFTs) after starting rosuvastatin. Increased LFTs are labeled events for Crestor, and diarrhea is a non-specific symptom. It is plausible that Crestor is associated with these adverse events. However considering the patient’s complex health status, other possible etiologies also exist. For instance, immunosuppressant therapies used after transplantation can cause diarrhea and increased LFTs. Additionally, signs and symptoms of liver graft rejection include diarrhea and increased LFTs. Thus, with one confounded case of increased LFTs and diarrhea, DPV1 will continue to monitor these events. From this case series, two concerns were indentified: accidental exposure of rosuvastatin in children and the use of rosuvastatin during pregnancy. The former concern will require further analysis by the Division of the Medication Error Prevention Analysis (DMEPA) to assess the risk of unintended exposure of rosuvastatin in children. The relevant cases in this review have been forwarded to DMEPA. The latter concern appears to be adequately addressed in rosuvastatin’s label. Crestor is contraindicated in women who are or may become pregnant. It has a pregnancy category of “X” and the Use in Specific Population, Pregnancy Section (8.1) of the label states that rosuvastatin “may cause fetal harm when administered to a pregnant woman” and that “the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.” Reference ID: 2871042
  • 7. 6 CONCLUSION Based on the review of AERS pediatric cases associated with rosuvastatin calcium, accidental exposure and use during pregnancy were identified as potential concerns. The risk of Crestor use during pregnancy appears to be adequately addressed in the label. Crestor’s label contains strong language to discourage its use during pregnancy, and Crestor has a pregnancy category of “X”. The risk of accidental exposure in children, however, has not been assessed. DPVI defers to DMEPA for this risk assessment. The relevant cases in this review have been forwarded to DMEPA for further analysis. Few adverse reactions were identified in AERS for the pediatric population because most cases described were either accidental or in utero exposures. The two adverse events (diarrhea and increased LFTs) observed in this case series occurred in a patient with a history of liver and bilateral lung transplants. Post-transplant therapies and liver transplant rejection are known to increase LFTs and cause diarrhea. Thus, alternative etiologies for these adverse reactions exist and confound Crestor’s role. Additionally, increase in LFTs is known to occur with Crestor use in adults and is described in the labeling. At this time, DPVI recommends no labeling changes and will continue to monitor the adverse events for Crestor. Reference ID: 2871042
  • 8. --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- QUOCBAO PHAM 12/03/2010 LANH GREEN 12/03/2010 ANN WARD W MCMAHON 12/03/2010 I concur. Reference ID: 2871042