# Presentation: 778325

## One Year Post-Exclusivity Adverse Event Review:Insulin Aspart Recombinant  Pediatric Advisory Committee Meeting November 16, 2006

**Hari Cheryl Sachs, MD, FAAP**
**Medical Officer**
**Pediatric and Maternal Health Staff****Office of New Drugs**
**Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information 

**Drug: **NovoLog® (insulin aspart recombinant)
**Therapeutic Category:  **human insulin analog
**Sponsor:  **Novo Nordisk Inc
**Original Market Approval: **June 7, 2000
**Pediatric Exclusivity Granted:  **May 24, 2005
**Mechanism of action:**  regulation of glucose metabolism
- Binds to insulin receptors on muscle and fat
- Facilitates cellular uptake of glucose
- Inhibits output of glucose from liver

## Background Drug Information

**Indication:**  treatment of patients with diabetes mellitus, for the control of hyperglycemia
- Normally with regimen of intermediate or long-acting insulin
- May be infused via external insulin pumps
- May be used intravenously under medical supervision
**Dosage:**
- Individualized, immediately prior to a meal

**Notes:**
Note:  more rapid onset and shorter duration of regular insulin, usually used win regimens with intermed or long acting

Dosage individualized, immediately before meal (within 5 to 10 min)
Total daily requirement:  typically 0.5 to 1.0 units/kg/day
Meal related:  50 to 70 % total insulin may be provided by NovoLog

## Drug Use Trends (Outpatient Settings): Insulin Aspart Recombinant

- Dispensed prescriptions for NovoLog have been increasing (June 2004 to May 2006)1
- Total NovoLog® and NovoLog® Mix 70/30 prescriptions increased by estimated 29% (~ 2.4 to 3.4 million)1
- Relative increase in pediatric patient count: 22% (~47,000 to 57,000)2
- Pediatric patients accounted for ~13% of  prescriptions2
- Majority of pediatric NovoLog® prescriptions to patients ages 12-16 years1
**	**** **1Verispan LLC, Vector One National, Jun 2003 to May 2006,  Data extracted Jul 2006
- 	2Verispan LLC, Vector One National: Total Patient Tracker, Data Extracted 7/2006  Excludes NovoLog® Mix 70/30

## Pediatric Exclusivity Labeling changes: Insulin Aspart Recombinant

- Indicated for use in pediatric patients
- Pk and clinical studies described, including those in children ages 2 to 6 years
- Glycemic control and adverse events, particularly hypoglycemia comparable to regular insulin

## Adverse Event Reports since Market Approval (June 2000): Insulin Aspart 

|  | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All Ages* | 1338 (1056) | 616 (341) | 36 (8) |
| Adults (> 17) | 1051 (828) | 491 (275) | 30 (8) |
| Pediatrics (0-16) | 154 (117) | 72 (35) | 5 (0) |

- *may include duplicates and unknown ages
- Serious outcomes per regulatory definition include death, hospitalization, life-threatening, disability, congenital anomaly, requiring intervention, and other

## Fatal Serious AE since approval: Insulin Aspart (n= 4, unduplicated) 

- Infants born to participants in post-marketing clinical trial in pregnant women with diabetes:
- 4 month old female with truncus arteriosus communis
- 4 day old male with hypoxic ischemic encephalopathy and seizures
- Direct exposures
- 14 year old male with type I DM and remote history of asthma found dead in bed, treated for 4-5 months with insulin detemir and aspart; post mortem:  “consistent with acute asthma attack, although patient had not had attack in 8 years.”
- 9 year old male with type 2 DM on insulin glargine for 6 months and aspart for unknown period, died, “possible alcohol overdose”
- _Underlined_ events are not specifically labeled

**Notes:**
Meds- NPH insulin, paracetamol, MVI, clotrimazole and aluminaum glycinate magnesium oxide  

## Adverse Event Reports One Year Post Exclusivity Period: Insulin Aspart 

| Raw counts* | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All ages | 284 (169) | 249 (135) | 15 (1) |
| Adults (> 17) | 230 (135) | 202 (108) | 12 (1) |
| Pediatrics (0-16) | 28 (18) | 24 (14) | 3 (0) |

- * may include duplicates and unknown ages

## Adverse Event Reports during One-Year Post Exclusivity Period:  Unlabeled Serious Non-fatal cases: Insulin Aspart

- .

*In utero* exposure (n =4)
- Newborn with  _neonatal hypoglycemia_ and _ankyloglossia,_ first trimester exposure insulin lispro, regular insulin, NovoLog®
- 37 week with _urinary retention_, _neonatal asphyxia_, and _hypoxic-ischemic lesion_ of the central nervous system, first trimester exposure multiple drugs
- Neonate with _dysmorphy of the right frontal lobe, increased frontal subarachnoid space, and assymetry of lateral ventricle_
- 32 week preterm with _neonatal hypoglycemia_ (blood glucose 24 mg/dl)
- _Underlined_ events are unlabeled

**Notes:**
Medications:

## Summary:  Insulin Aspart

- Labeling updated after exclusivity studies
- Treatment of type I DM > 2 years
- Most frequent AE is hypoglycemia
- During post exclusivity period
- Although AEs related to *in utero* exposure observed, no pattern
- No new pediatric AEs identified
- This completes the one-year post-exclusivity AE reporting as mandated by BPCA.
- The FDA recommends routine monitoring of insulin aspart recombinant for AEs in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

- _OSE_
- Andrea Feight
- Lanh Green
- Solomon Iyasu
- Rosemary Johann-Liang
- David Moeny
- Joslyn Swann

- _DMEP_
- David Orloff
- Joanna Zawadzki
- _PMHS_
- Lisa Mathis
- Kristin Phucas
- Jean Temeck