The AERS search identified 2 fatal pediatric cases and 10 non-fatal serious pediatric cases associated with rosuvastatin use from 2003-2010. Both fatal cases involved in utero exposure to rosuvastatin. Of the 10 non-fatal cases, 7 involved accidental exposure in children under 3 years old. The other cases included a suicide attempt, in utero exposure, and diarrhea with increased liver enzymes in a 16-year-old transplant patient taking rosuvastatin. The cases did not identify adverse events unique to pediatrics. More information would be needed to determine if rosuvastatin caused the reported events.

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