# Presentation: 172651

## One Year Post-Pediatric Exclusivity Postmarketing Adverse Event ReviewSERTRALINE ( Zoloft)

**Dr. Solomon Iyasu****Medical Team Leader**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

**June 12, 2003**

**Notes:**
Good afternoon.  Dr. Chen Min Chu has provided you with a overview of FDA's postmarketing adverse event surveillance system. I will be talking with you about one specific surviellance activity, namely, 'adverse event tracking  as mandated by the Best Pharmaceuticals for Children Act.

## Best Pharmaceuticals for Children Act (1/4/03)

**Section 17: Adverse Event (AE) Reporting**
**review AE reports during the one-year after pediatric exclusivity is granted**
**refer AE reports to the Pediatric Advisory Sub-Committee for review****	****    **

**Notes:**
Under section 17 of the BPCA, FDA is required to perform the following activities.

- One, promulgate a rule to require the inclusion in labeling  a of toll free number for the puirpose of reporting adverse events 
-review AEs reports for a period of one year after a drug is granted pediatric exclusivity.
-report AEs to the Pediatric Advisory Sub-Committee for their review.

## Background Drug Information 

**Moiety: Sertraline (Zoloft)**
**Therap. Category: selective serotonin reuptake inhibitor (SSRI)**
**Sponsor: Pfizer**
**Indication: **
**Adults****: major depressive disorder, obsessive compulsive disorder, panic disorder, posttraumatic disorder, premenstrual disorder, social anxiety disorder**
**Children****: Obsessive compulsive disorder (**_**>**_** 6 years)**
**One-year post exclusivity dates: 2/01/02 - 3/01/03**

## Sources of Frequency of Drug Use Data

- IMS Health, National Prescription Audit *Plus* (NPA *Plus*)
- frequency of dispensed prescriptions by retail pharmacies
- IMS Health, National Disease and Therapeutic Index (NDTI)
- frequency of total drug mentions or appearances during patient visits in Office-Based Practices

## Drug use trends: Zoloft

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions for Zoloft increasing, all ages
- 21 mill in 1998 vs. 31 mill in 2002
- Leading prescribers:  Family Practice, Internal Medicine, and Psychiatry
- Pediatric specialty: about 392, 000 dispensed prescriptions in YR2002

## Drug use trends: Zoloft

- NDTI (2000-2002)
- Slight increase in frequency of drug mentions during patient visits in office-based practice for children age 0-16 years
- adolescent subgroup, ages 12-16, represented 2/3rd of use
- males predominate in pediatric groups vs. females in adult groups
- 692, 000 (8%) total mentions in YR2002 in ages 0-16 years.
- Leading Indications in YR2002:
- age 0-16 years: Depression (35.6%), Anxiety-related disorders (16.5%),  OCD (10.2%)
- age 2-11 years: Anxiety-related disorders, OCD, Depression
- age 12-16: Depression, anxiety-related disorders, OCD

## Limitations of Drug Use Data

- NPA *Plus* does not provide demographic information on prescription use
- NDTI is based on a sample size of 2000 - 3000 office-based physicians.  The small sample size can make these data projections unstable, particularly when use is not prevalent as in the case of the pediatric population.

## Pediatric labeling on AEs 

**Adverse events generally similar to those seen in adults**
**Other adverse events in pediatric patients **
**hyperkinesia, twitching, fever, malaise, purpura, weight decrease, concentration impaired, manic reaction, emotional lability, thinking abnormal, and epistaxis**
**Precaution: **
**mania/hypomania, weight loss, seizure, suicide**
**Pediatric use section**
**decreased appetite and weight loss**
**regular monitoring of weight and growth recommended**

## Limitations of AERS

- Spontaneous and voluntary system
- Underreporting
- reporting bias
- quality of report
- cannot estimate true incidence rate of events or exposure risk

## Frequency of Adverse Event Reports by Age (02/01/02 to 03/01/03)

**   **_**Age**_**	****	**_**All reports (US)**_**	**_**Serious (US)**_**	****     **_**Death (US)**_
**All Ages****	****    1249  (847)****	****	****  1039 (692)****	****       182 (123)**
**Adults (**_**>**_**17)****	****    889    (591)****	****	****  774   (508)****	****       134  (90)**
**Peds (0-16)****	****    54      (41)****	****	****  40      (28)****	****        5      (5)**

*******Total for all ages includes reports with unknown age**
**Numbers may include duplicates**

## Most Frequently Reported Adult & Pediatric Adverse Events from (2/02/02-3/1/03)

**Adults**
**Dizziness**
**Nausea**
**drug withdrawal syndrome**
**agitation**
**drug interaction**
**confusion**
**headache**
**feeling abnormal**
**suicidal ideation**
**tremor **
**vomiting**
***AE not in label**

**Pediatric**
**maternal drug affecting fetus***_** **_
**dyspnea**
**aggression**
**insomnia**
**abnormal behavior **
**c- section**
**complication of maternal exp***
**convulsions**
**crying**
**memory impairment***
**                               **
**               **

## Pediatric Adverse Events by Age and Gender (2/02/02-3/1/03) (N=49 unduplicated)

**Age**
**0-<1 mo****	****	****9**
**1 mo- <2 yrs****	****	****5**
**2-5 yrs****	****	****	****4**
**6-11 yrs****	****	****9**
**12-16 yrs****	****	****22**
**Gender**
**Female (21), Male (27), unknown (1)**

## Adverse Event Categories (2/02/02-3/1/03) 

- Psychiatric events: 13  patients
- aggression/hostility (7), hallucination (2), aphasia (1), self-injurious behavior (1), impulsive/risk-taking (1), withdrawal syndrome (1)
- Neurologic events: 10 patients
- Extrapyramidal/movement disorders (5), tremors (1), seizures (2), possible serotonin syndrome (2)
- Congenital anomalies/prenatal or breast milk exposure: 13 patients
- Cong Malformation (4), possible neonatal withdrawal syndrome (4),  developmental delay/abnormalities (2), Premature births (2)

## Advent Event Categories (2/02/02-3/1/03) 

- Overdose: 9 cases
- 5 non-fatal overdoses:  2 accidental ingestion in preschoolers and 3 intentional overdoses in adolescent children
- 1 fatal toxicity
- 2 completed suicides in adolescent children
- 1 medication error
- Others: 4 cases
- priapism (1), hematological (1), restrictive lung disease (1), prothrombin time increased (1)

## Serious Outcomes in Pediatric Patients (2/02/02-3/1/03) 

**  ****4   Deaths**
**19   Hospitalization**
**26  Others (life threatening or required interventions or medically important events)**

## Diagnosis (Indication) for Sertraline use from the Pediatric Adverse Event Report (2/02/02-3/1/03) 

**Depression = 16**
**ADHD = 4**
**Obsessive compulsive disorders= 3**
**Vocal cord disorder = 1**
**Stress emotional problems = 1**
**Anxiety = 1**
**Adjustment disorder = 1**
**Accidental overdose = 3**
- Maternal exposure (prenatal or breastfeeding)=13
- Others: medication error (1), abuse (1), intermittent explosive disorder (1), Unknown indication (4)

## Review of Pediatric Deaths (2/02/02-3/1/03) 

**Case 1: **
**Young school age child prescribed sertraline for depression**
**also using  amitriptyline, clonidine**
**dose and duration unknown**
**“****drug levels 2-3 times higher in the liver than the prescribed amount”**
**possible conclusion: death due to chronic multiple drug toxicity**

## Review of Pediatric Deaths (2/02/02-3/1/03) 

**Case 2: **
**premature child born to an HIV positive mother **
**mother using sertraline for depression (100 mg/day) also using multiple other medications during last three months of pregnancy**** **
**baby died 15 days after birth from pneumothorax and septic shock**
**possible conclusion: death unrelated to sertraline**

## Review of Pediatric Deaths (2/02/02-3/1/03) 

**Case 3: **
**Adolescent child committed suicide following one-week trial of  50 mg /day of  Sertraline therapy for Depression**
**patient remained significantly depressed during therapy**
**parents did not notice any agitation or mood changes**
**exact event date unknown but initial report in 1997**
**suicide ideation is labeled but rare**
**possible conclusion: unclear relationship to sertraline**

## Review of Pediatric Deaths (2/02/02-3/1/03) 

**Case 4: **
**Adolescent child committed suicide (gun shot) after taking Zoloft without prescription several times over a 10 day period. **
**No prior history of depression.**
**Possible conclusion: drug abuse, unclear if suicide is causally related to Zoloft use.**

## Information about ‘Suicide’ on Zoloft label 

- Precaution
- The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high risk patients should accompany initial drug therapy. Prescriptions for ZOLOFT should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose

## Summary 

- Most Pediatric adverse event reports
- involved multiple drug exposures
- had confounding medical disorders
- generally similar to adult events
- labeled or previously described events except
- maternal drugs affecting fetus, complications of maternal exposure, memory impaired
- Two adolescent suicide deaths:
- patient with depression
- one in a patient with no history of depression: unclear if suicide is causally related to Sertraline abuse

## Acknowledgement 

- ODS
- Carol A. Pamer, R. Ph,  Safety Evaluator
- Laura Governale, Pharm D, Drug Use Specialist

## One Year Post-Pediatric Exclusivity Postmarketing Adverse Event ReviewOXYBUTYNIN (Ditropan)

## Background Drug Information 

**Moiety: Oxybutynin (Ditropan)**
**Therap. Category: Antispasmodic and anti-cholinergic**
**Sponsor: Johnson and Johnson**
**Indications: **
**Adults****: symptoms of bladder irritability associated with voiding in patients with uninhibited neurogenic bladder (urgency, frequency, urinary leakage, urge incontinence, dysuria)**
**Children: Ditropan tabs and syrup in **_**>**_**5 years and XL in **_**>**_**6 years for**** detrusor muscle over-activity in association with a neurological condition (e.g.. Spina bifida).**

## Drug use trends: Ditropan

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions increasing
- 3,532,000 in 1998 and 6,494,000 in 2002,
- predominant dosage form: Oral
- Leading prescriber:  Urology and Internal Medicine
- Pediatric specialty: about 82, 000 prescriptions dispensed in YR2002.

## Pediatric Drug Use Trends: Ditropan

- NDTI (2000-2002)
- frequency of drug mentions in office visits decreased  to 82,000 in 2002, down from 138,000 in 2001 in ages 0-16 years
- children 2-11 represented 70-80% of use
- almost two-thirds of use in Females (pediatric and adults)
- Leading Indications in YR2002:
- Gender and age differences in leading indications
- Males, ages 2-11 years: frequency of urination and polyuria and in ages 12-16 years: incontinence of urine
- 2-16 year, females: other bladder function disorders predominate (hyperactive bladder, paralysis of bladder, neurogenic bladder excluding cauda equina syndrome with neurogenic bladder)

## Drug use trends: Ditropan

- NDTI (2000-2002)
- Leading prescribing specialties for pediatric patients
- Urology
- Pediatrics
- Nephrology

## Counts of Adverse Event Reports by Age during the one year after granting exclusivity (02/08/02 to 03/19/03) 

**   **_**Age**_**	****	**_**All reports (US)**_**	**_**Serious (US)**_**	****     **_**Death (US)**_
**All Ages****	****    40   (22)****	****	****  36  (18)****	****       4   (2)**
**Adults (**_**>**_**17)****	****    29   (17)****	****	****  15   (13)****	****       3   (1)**
**Peds (0-16)****	****    5      (3)****	****	****  5      (3)****	****        0   (0)**

*******Total for all ages includes reports with unknown age**
**Numbers may include duplicates**

## Top 10 Most Frequently Reported Adult & Pediatric Adverse Events During the One Year after Granting Exclusivity (02/08/02 to 03/19/03)

**Adults (n=29)**
**Drug ineffective * (4)**
**Dry eye NOS (3)**
**Dyspnoea NOS* (3)**
**Vision blurred (3)**
**Atrial fibrillation* (2)**
**Condition aggravated * (2)**
**Dizziness (2) (ex. Vertigo) (2)**
**Dry mouth (2)**
**Dysphagia* (2)**
**Eye Hemorrhage NOS* (2)**
***AE not in label**

**Pediatric (n=5)**
**Depression NOS* (2)**
**Hallucination, visual (2)**
**Panic reaction* (2)**
**Abnormal behavior NOS* (1)**
**Acidosis NOS* (1)**
**Aggression* (1)**
**Anger* (1)**
**Anxiety Nec* (1)**
**Bladder Disorder NOS* (1)**
**Bld Osmolality Decreased* **** ****(1)**
**               **

## Unlabeled Adverse Events from drug approval  date (7/16/75 to 03/19/03)

**Adults (n=745)**
**Drug Ineffective  (33)**
**Pruritus NOS  (29)**
**Condition aggravated (26)**

**Pediatric (n=74)**
**Dermatitis NOS (5)**
**Personality  disorder (4)**
**Thinking abnormal (4)**
**Agitation (3)**
**Diplopia (3)**
**Skin disorder NOS (3)**
**Vertigo (3)**
**Abnormal dreams (2)**
**               **

## Pediatric Adverse Events by Age and Gender (02/08/02 to 03/19/03) (N=5 unduplicated)

**Age**
**0-<1 mo****	****	****0**
**1 mo- <2 yrs****	****	****0**
**2-5 yrs****	****	****	****2**
**6-11 yrs****	****	****3**
**12-16 yrs****	****	****0**
**Gender: ****Female (2), Male (3)**
**Doses: Range 5-37.5 mg per day**

## Diagnosis (Indication) for Ditropan use from pediatric adverse event report

**Enuresis (1)**
**Nocturnal enuresis (1)**
**Neurogenic bladder (1)**
**Detrusor muscle spasms (1)**
- Not stated (1)

## Serious Outcomes in Pediatric Patients

**  ****Hospitalization (1 patient)**
**School age child on Ditropan Syrup for 4 months (37.5 mg/day) and Desmopressin developed hyponatremia, low osmolality, weight gain, EEG changes. Prior h/o of vertigo.**
**  ****Medically significant (3 patients)**
**School age child had seizure after taking Benadryl while on Ditropan XL; Treated in ER and Ditropan XL resumed and patient is seizure-free.**
**Preschool child with history of tracheostomy and vertriculo-peritoneal shunt and quadriplegia had loss of consciousness after one week of Ditropan syrup given via G tube. Ditropan Syrup discontinued**

## Serious Outcomes in Pediatric Patients

**Medically significant (cont’d)**
**Pre-school child born with brain damage developed behavioral events, irritability, anxiety, sensitivity to light/noise, overheating, lack of sweat, dry mouth and hands after 6-12 months of therapy with Ditropan for bed wetting.  After Paxil was added, patient became violent, a danger to herself and others, developed personality changes.  Paxil discontinued and reintroduced at half dose after patient became depressed and suicidal. Patients symptoms improved but wetting accidents continued. Ditropan discontinued and patient put on Detrol and Paxil. Bed wetting improved as the patient matured. **

## Serious Outcomes in Pediatric Patients

**Disability (1 patient)**
**Anxious school age child put on Ditropan for nocturnal enuresis**
**developed psychiatric symptoms: night terror, panic attacks, self-harming behavior, imaginations of being followed or seeing monsters, and difficulty falling asleep**
**Started on Atarax to help the patient sleep and Ditropan discontinued after a month.**

## Summary of Post-exclusivity Pediatric Adverse Events (n=5)

- All 5 reports had serious outcomes
- Several adverse event terms were unlabeled
- Psychiatric events primarily reported from two patients with possible underlying psychiatric conditions
- events cannot be solely attributed to Ditropan use
- concomitant drugs in three patients (desmopressin, Benadryl, Paxil)
- overdosing (2 patients)
- underlying condition (2 patients)

## Question for the Committee

- Because of the small number of reports, should we consider an additional one-year of AERS follow-up?

## Acknowledgement 

- ODS
- Laura Governale, Pharm D., Drug Use Specialist
- Evelyn R. Farinas, R. Ph, Safety Evaluator
- DPDD
- Shirley Murphy, MD, Director

## One Year Preliminary Post-Pediatric Exclusivity Postmarketing Adverse Event Review: Simvastatin (ZOCOR)

**Notes:**
Good afternoon.  Dr. Chen Min Chu has provided you with a overview of FDA's postmarketing adverse event surveillance system. I will be talking with you about one specific surviellance activity, namely, 'adverse event tracking  as mandated by the Best Pharmaceuticals for Children Act.

## Background Drug Information

- Moiety: Simvastatin (ZOCOR)
- Therap. Category: Lipid lowering agent
- Sponsor:Merck &Co.,Inc.
- Indications:
- Adults: Coronary Heart Disease with hypercholesterolemia

## Pediatric Indication

- Heterozygous Familial Hypercholesterolemia in children 10 years or older
- Prevalence of 1:500; increased risk of premature coronary heart disease in adulthood
- As an adjunct to diet to reduce total-C and LDL-C and Apo B levels in boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
- a. LDL-C remains>=190mg/dl or
- b. LDL-C remains>=160 mg/dl and:
-        There is a family history of premature cardiovascular disease or
-         Two or more other CVD risk factors are present in the pediatric patient

## Drug use trends: Zocor

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions increasing
- 18.5 million in 1998; increased to 28.8 million in 2002

## Pediatric Drug Use Trends: Zocor

- NDTI (2000-2002)
- frequency of drug mentions in office-based practice among 0-16 year old patients
- no mentions in 2000-2001
- 4000 mentions in 2002 and represented  <1% of the total Zocor mentions of approximately 9 million in all ages.
- Leading Pediatric Indication in 2002
- Hyperlipidemia

## Counts of Adverse Event Reports by Age during the one year after granting exclusivity (02/22/02 to 03/22/03) 

**   **_**Age**_**	****	**_**All reports (US)**_**	**_**Serious (US)**_**	****     **_**Death (US)**_
**All Ages****	****    1309   (765)****	****	****  1240  (713)****	****       102   (45)**
**Adults (**_**>**_**17)****	****    1299   (761)****	****	****  1230   (709)****	****       101   (45)**
**Peds (0-16)****	****          8      (3)****	****	****        8       (3)****	****        1       (0)**

*******Total for all ages includes reports with unknown age**
**Numbers may include duplicates**

## Preliminary analysis02/22/02 to 03/22/03 

- Four unlabeled, unduplicated events with serious outcomes
- Too few reports for meaningful interpretation in the pediatric population
- All were foreign reports
- Events cannot be solely attributed to Zocor use
- In utero exposures (2 patients):
- 1st trimester exposure; no other concomitant medications; fetal distress; healthy infant
- multiple concomitant medications; pre-maturity; post-natal death
- Concomitant medications (2 patients):
- confounding underlying conditions

## Question for the Committee 

- Because of the small number of reports and relatively low pediatric use, should we consider an additional one-year of AERS follow-up?

## Acknowledgement

**Laura Governale, Pharm D., Office of Drug Safety**
**Jennie Chang, Pharm D., Office of Drug Safety**
**Beverly Lindsay MD, FAAP, Div of Pediatric Drug Development**

**Notes:**
Good afternoon.  Dr. Chen Min Chu has provided you with a overview of FDA's postmarketing adverse event surveillance system. I will be talking with you about one specific surviellance activity, namely, 'adverse event tracking  as mandated by the Best Pharmaceuticals for Children Act.

## One Year Preliminary Post-Pediatric Exclusivity Postmarketing Adverse Event ReviewAtorvastatin (Lipitor)

**Notes:**
Good afternoon.  Dr. Chen Min Chu has provided you with a overview of FDA's postmarketing adverse event surveillance system. I will be talking with you about one specific surviellance activity, namely, 'adverse event tracking  as mandated by the Best Pharmaceuticals for Children Act.

## Background Drug Information

- Moiety:Atrovastatin (Lipitor)
- Therap Category: Lipid lowering agent
- Sponsor:Pfizer Parke Davis
- Indications:
- Adults as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and non familial  and mixed dyslipidemia(fredrickson types Ia and IIb)
- adjunct to diet for treatment of patients with elevated serum TG levels(fredrickson typeIV)
- treatment of primary dysbetalipoproteinemia fredrickson typeIII who do not respond to diet
- reduce total-c and LDL-C in patients with homozygous familial hypercholesterolemia as adjunct to other lipid lowering agents

## Pediatric Indication

- Heterozygous Familial Hypercholesterolemia in children 10 years or older
- Prevalence of 1:500; increased risk of premature coronary heart disease in adulthood
- As an adjunct to diet to reduce total-C and LDL-C and Apo B levels in boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
- a. LDL-C remains>=190mg/dl or
- b. LDL-C remains>=160 mg/dl and:
-        There is a family history of premature cardiovascular disease or
-         Two or more other CVD risk factors are present in the pediatric patient

## Drug use trends: Lipitor

- NPA *Plus* (1998-2002)
- Total dispensed prescriptions increasing
- 24.8 million in 1998; increased to 65.7 million in 2002

## Pediatric Drug Use Trends: Lipitor

- NDTI (2000-2002)
- Frequency of drug mentions in office-based practice among 0-16 year old patients
- 9,000 in 2000; increased to 14,000 mentions in 2002
- represented  <1% of total Lipitor mentions of 17 million in all ages
- Leading Pediatric Indication in 2002:
- Hypercholestrolemia

## Counts of adverse events during the one year after granting exclusivity (02/22/02-03/22/03)

- There were no pediatric adverse events reported

## Question for the Committee 

- Because of the small number of reports and relatively low pediatric use, should we consider an additional one-year of AERS follow-up?

## Acknowledgement 

**Laura Governale, Pharm D., Office of Drug Safety**
**Jennie Chang, Pharm D., Office of Drug Safety**
**Beverly Lindsay MD, FAAP, Div of Pediatric Drug Development**