# Presentation: 089776

## One Year Post Exclusivity Adverse Event Review:Esmolol Pediatric Advisory Committee Meeting February 14, 2005

**Lawrence Grylack, MD****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information

**Drug:** Brevibloc® (esmolol HCL)
**Therapeutic Category:** beta-1-selective (cardioselective) adrenergic receptor blocking agent
**Sponsor:** Baxter Laboratories
**Adult Indication:** Treatment of supraventricular tachycardia (SVT); intra-operative and post-operative tachycardia and/or hypertension
**No Pediatric Indication**
**Original Market Approval: **December 31, 1986
**Pediatric Exclusivity Granted:** August 22, 2003

## Drug Use Trends: Esmolol

- No change in total annual sales of 1.3 million units of esmolol between one year pre-exclusivity (9/02 -8/03) and one year post-exclusivity (9/03-8/04)1
- 99% of total sales to inpatient facilities1
- Almost all of the inpatient use is in adults.2
- Pediatric use  < 1% of all in-patient use2
- 161 of 17,172 (0.9%) discharges associated with esmolol during pre-exclusivity period of Mar 2003 - Aug 20032
- 151 of 16,557 (0.9%) discharges in 6 month post-exclusivity period of Sep 2003 - Feb 20042

- 1IMS Health, IMS National Sales PerspectivesTM, Moving Annual Totals, Sep 2000 - Aug 2004,  Data Extracted Nov 2004
- 2Premier Informatics, Mar 2003 – Feb 2004, Data Extracted Nov 2004

## Pediatric Exclusivity Studies: PK/PD

- 27 patients with SVT, 2-16 years of age
- Dosing of esmolol: 1000 ug/kg loading, followed by 15 minute infusion of 300 ug/kg/minute
- SVT terminated within 10 minutes in 65% of treated patients; mean termination time
-    2 minutes

## Pediatric Exclusivity Studies:Efficacy

- Randomized, double blind comparison of efficacy of three different doses (125, 250, 500 ug/kg) of drug in controlling intra- and post-operative hypertension with repair of coarctation of aorta
- 118 patients, neonates through 6 years of age
- Efficacy endpoints:
- systolic blood pressure (SBP) reduction at 5 minutes
- need for rescue medications at 5 minutes

##      Pediatric Exclusivity Studies:Efficacy Results

- SBP decreased in all dose groups with no significant difference among groups in change from baseline
- No significant difference across groups in percentage of patients meeting rescue criteria or receiving rescue therapy

## Pediatric Exclusivity Studies: Safety

- 145 patients in two studies evaluated
- 7 withdrawals due to adverse events (AEs): Hypotension (5), injection site reaction (1), wheezing (1)
- No deaths or other serious AEs
- 134 (92%) patients with one or more AEs
- AEs consistent with adult labeling

## Relevant Safety Labeling

- Safety results were reviewed individually and combined from both pediatric studies. Most of the safety findings appear consistent with current labeling or are known post-operative/post-procedure events.
- No new safety labeling resulted from the pediatric studies.

## Adverse Event Reports since Market Approval: Esmolol 12/31/86 - 9/22/04

- Total number of reports, all ages†*:
- 276 reports (230 US)
- 158 serious (136 US)
- 63 deaths (59 US)
- Pediatric reports*:
- 13 reports (13 US)
- 9 serious (9 US)
- 3 deaths (3 US)
- †Includes reports with unknown age	*Counts may include duplicate reports

## Pediatric Deaths since Market Approval (n=3)

- 2 1⁄2 month female with major heart defect; surgical repair of coarctation of aorta followed by dilation of aorta 2 weeks later
- Unspecified surgery 4 days later, during which SVT occurred and esmolol given.  BP “bottomed out” 12 hours post-operatively, patient had “inflammatory response” and expired.  Concomitant medications were dopamine and fentanyl.
- Autopsy: Necrotic tissue in patient's heart and lungs

## Pediatric Deaths since Market Approval (n=3)

- 16 y.o. female; overdose of theophylline in suicide attempt (serum level 180 mcg/ml)
- Tachycardia (HR>100) ensued and IV esmolol 600 mcg/kg infused during one minute followed by infusion of 60 mcg/kg/minute
- Grand mal convulsion occurred after three minutes and esmolol was stopped.
- Apnea, cardiac arrest, resuscitation medications given
- Irreversible coma, death

## Pediatric Deaths since Market Approval (n=3)

- 5 y.o. male; surgery for hypoplastic aortic arch; received nitroprusside for post-operative hypertension
- Esmolol added
- Increased levels of cyanide and thiocyanate; nitroprusside stopped and levels decreased
- Reactions described as “drug interaction” and “drug level above therapeutic”
- Death 5 days after surgery due to “surgical failure”

## Most Common Adverse Events since Market Approval

- Most common AEs (2-3 occurrences) for **pediatric **patients: cardiac arrest, hypotension, blood pressure decreased, convulsion, and _urticaria _
- Most common AEs (5 or more occurrences) for **adult **patients: cardiac arrest, hypotension, bradycardia, _accidental overdose_, _medication error_, injection site reaction, _tachycardia_, _apnea_, _overdose_, AV block,_ _convulsion, pulmonary edema, agitation, coma, _condition aggravated_, _hypertension_, injection site necrosis, skin necrosis, _myocardial infarction_
-       Underlined events = Unlabeled events

## Adverse Event Reports during the One-Year Post-Exclusivity Period: Esmolol 08/22/03 - 09/22/04

- Total number of reports, all ages†*:
- 7 reports (6 US)
- 7 serious (6 US)
- 3 deaths (3 US)
- Pediatric reports*:
- 1 report (1 US)
- 1  serious (1 US)
- No deaths
- †Includes reports with unknown age
- *Counts may include duplicate reports

## Pediatric Adverse Events during the One-Year Post-Exclusivity Period  (n=1)

- A teenage female patient undergoing osteotomy for correction of retrognathia received multiple medications during surgery.
- Normal pre-operative vital signs except for low temperature (35.4 oC)
- After 10 minutes of surgery, acute hypertensive crisis (200/100 mm Hg) and sinus tachycardia (150/minute) occurred for which IV **esmolol** was given.
- Chest x-ray: pulmonary edema
- ECG: global ST segment elevation
- Elevated Troponin level of 3.5 ng/ml (normal < 0.3) obtained one hour post-operatively, indicative of myocardial ischemia
- Surgery halted, patient stabilized and recovered

## Summary: Esmolol

- No pattern discernible in pediatric AEs
- This completes the one-year post-exclusivity AE monitoring as mandated by BPCA.
- FDA recommends routine monitoring of AEs for this drug in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

_**ODS**_
- Mark Avigan
- Gerald Dal Pan
- Laura Governale
- David Moeny
- Daniela Sanders

_**DCRDP**_
-   Melissa Robb
-   Shari Targum
_**ORP**_
-   Roy Castle, Jr.