# Presentation: 140153

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

**Felicia L. Collins, MD, MPH, 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: Ondansetron

**Drug:**  Zofran® (ondansetron hydrochloride)
**Therapeutic Category:  **Serotonin** **HT3 receptor antagonist
**Sponsor:  **GlaxoSmithKline
**Original Market Approval:  **January 4, 1991** **
**Pediatric Exclusivity Granted:  **December 1, 2004

## Background Drug Information: Ondansetron

**Indications:**
- Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high dose cisplatin **[chemotherapy induced nausea and vomiting (CINV)]**
- Prevention of **postoperative nausea and/or vomiting [PONV]**

## Drug Use Trends in Outpatient Settings: Ondansetron 

- 1.6 million dispensed prescriptions for all age groups during the 12-month post-exclusivity period
- 107,000 (6.6%) were dispensed for the pediatric population 0 - 16 years old
- 11% increase in prescriptions for all age groups between the 12-month pre and post-exclusivity periods
- 39% increase for the pediatric population

- Verispan, LLC, 2003 – 2006, Data Extracted January 2006

## Drug Use Trends in Outpatient Settings: Ondansetron 

- OB/GYN was the most frequent prescriber specialty during the 12-month post-exclusivity period
- OB/GYN: 23% (369,000)
- Pediatrics: 4% (68,000)
- Malignant neoplasm of the brain was the diagnosis most frequently associated with ondansetron use in the pediatric population: 18% (20,000)

- Verispan, LLC, 2003 – 2006, Data Extracted January 2006

## Drug Use Trends in Inpatient Settings: Ondansetron 

- ~390,000 discharges associated with ondansetron use for all age groups during the 6-month post-exclusivity period
- ~12,400 (3.2%) for the pediatric population 0 - 16 years old
- 2.7% decrease in the discharges associated with ondansetron use for all age groups between the 6-month pre and post-exclusivity periods
- 7.3% decrease for the pediatric population

- Premier Informatics Extracted 2-2-06

## Pediatric Exclusivity Studies: Ondansetron

**PONV** **PK study** in 1 month to 2 year olds:                           51 pediatric surgical patients utilized ondansetron prophylactically (24 hour observation period)
**PONV efficacy and safety study** in 1 month to 2 year olds: 670 pediatric surgical patients utilized ondansetron or placebo prophylactically (24 hour observation period)
**CINV efficacy and safety** **study** in 6 month to 4 year olds: 76 pediatric cancer patients receiving moderately to highly emetogenic chemotherapy utilized ondansetron prophylactically (24 hour observation period)

## Pediatric Exclusivity Studies: PK Study (n=51)

**Design:** Multi-center, two-arm, single dose (0.1 mg/kg or 0.2 mg/kg IV)
**Results:** Drug clearance was lower and half-life was prolonged in patients 1 to 4 months old compared to those > 4 months to 2 years old

## Pediatric Exclusivity Studies: Population PK Analysis (n=127)

**Design:** Combined data from PK and CINV studies
**Results:** 0.15 mg/kg/dose IV every 4 hours x 3 doses in cancer patients, aged 6 months to 4 years, results in systemic exposure levels similar to those achieved in older pediatric cancer patients at similar doses

## Pediatric Exclusivity Studies: PONV (n=670)

**Design:** Multi-center, double-blind, placebo-controlled, randomized study of a single dose of 0.1 mg/kg ondansetron IV administered within 5 minutes following anesthesia induction

## Pediatric Exclusivity Studies: PONV Efficacy

**Endpoints:**
- Primary:  Proportion of patients experiencing at least one episode of emesis during the 24 hour assessment phase
- Secondary:
- Time to first emetic episode
- Time to first rescue medication
- Incidence of emetic episodes
- Proportion of patients receiving rescue medications
- Proportion of patients with emetic episodes after the receipt of rescue medications

## PONV Exclusivity Study: Efficacy Results

- Fewer patients experienced at least one emetic episode in the drug group (11%) compared to the placebo group (28%)
- The drug performed better than placebo in 4 of the 5 secondary endpoints
- Time to first emetic episode
- Incidence of emetic episodes
- Proportion of patients receiving rescue medications
- Proportion of patients with emetic episodes after the receipt of rescue medications

## Pediatric Exclusivity Studies: CINV Efficacy (n=76)

**Design:** Multi-center, open-label, 3 doses of 0.15 mg/kg IV
**Primary Endpoints:**
- Incidence of emesis
- Proportion of patients who received supplemental antiemetic medication during the 24-hour assessment period
- Time to first rescue antiemetic medication
- Parent/guardian overall satisfaction

## CINV Exclusivity Study: Efficacy Results

- More than half of the patients had no emetic episodes
- More than half of the patients did not require rescue medications
- 80% of parents/guardian were satisfied with drug use

## Pediatric Exclusivity Studies: Safety Results (n=797) (drug group = 463, placebo group = 334)

- No deaths
- 1% of patients had non-fatal serious adverse reactions in both the drug (5) and placebo (3) groups
- Drug group: convulsions (1), dehydration (1), respiratory depression (1), staphylococcal infection (1), nodal arrhythmia, hypocapnia, & hypoxia (1)
- Placebo group: tachycardia (1), bronchospasm (1), exacerbated pain (1)

## Pediatric Exclusivity Study: Labeling Changes

**Clinical Pharmacology – **Pharmacodynamics:
- Population PK analysis of PK and CINV studies
**Clinical Studies: **
- CINV & PONV studies
**Precautions **– Pediatric Use:
- Little information available about the use in pediatric surgical patients <1 month old and pediatric cancer patients younger than 6 months old
- Slower drug clearance and half-life ~2.5 fold longer in pediatric patients 1 to 4 months old compared to older children > 4 months to 2 years old

## Pediatric Exclusivity Study: Labeling Changes

**Dosage and Administration:**
**CINV** in 6 month to 4 year old patients:
- 3 doses of 0.15 mg/kg IV
**PONV** in 1 month to 2 year old patients:
- Single 0.1 mg/kg IV dose for patients weighing 40 kg or less
- Single 4 mg dose for patients weighing more than 40 kg

## Adverse Event Reports Since Market Approval and Prior to Pediatric Exclusivity 1/4/91 – 12/1/04

| Raw Counts* | All Reports (US) | Serious (US) | Death 
(US) |
| --- | --- | --- | --- |
| All Ages | 3180 (2373) | 1435 (656) | 204 (79) |
| Adults 
(> 17) | 2075 (1398) | 1145 (487) | 166 (55) |
| Pediatrics 
(0-16) | 204 (148) | 126 (74) | 18 † (11) |

- *May include duplicates and unknown ages
- † Crude count is 18 with 14 unduplicated cases

## Pediatric Deaths Since Market Approval and Prior to Pediatric Exclusivity 

- 18 crude count reports
- 14 unduplicated cases
- 7 cases excluded due to confounding or insufficient information
- 1 - Erroneous classification of death
- 1 - Unspecified cause of death in infant with in utero exposure
- 2 - Significant time delay between symptoms and/or death and  last ondansetron dose (17 hrs, 12 days)
- 3 - Complicated underlying medical conditions, some with concomitant medications (stage IV neuroblastoma with    multi-organ failure and chemotherapy, medulloblastoma with radiation and chemotherapy, idiopathic pneumonitis with progressive germ cell disease)

## Deaths Since Market Approval and Prior to Pediatric Exclusivity (continued)

- 7 remaining cases also confounded by complicated underlying medical conditions, concomitant medications, and/or insufficient details
- 14 y.o. female with asthma, 1 day s/p scoliosis surgery, with decreased RR, BP, SaO2 after morphine and 1 hour after 4 mg   ondansetron IV for nausea (concomitant meds: cyclizine, albuterol, beclomethasone, terfenadine)
- 10 y.o. male on chemotherapy for rhabdomyosarcoma with dizziness and collapse after 0.15 mg/kg ondansetron IV for vomiting (concomitant meds: methylprednisolone mesna, ifosfamide, etoposide)
- 9 m.o. male with bone marrow allografts developed acidosis, bundle branch block, and cardiac arrest with QT prolongation after cisapride and 6 mg ondansetron for nausea (concomitant meds: cyclosporin, ganciclovir, omeprazole, amikacine, hydrocortisone, cyclophsphamide, foscarnet, alizapride, tienam, and ornidazole)

## Deaths Since Market Approval and Prior to Pediatric Exclusivity (continued)

- 16 y.o. female with disseminated lupus developed septic shock or cardiomyopathy 3 days after ondansetron IV [unknown dose] to prevent nausea (concomitant meds: prednisone, cyclophosphamide, mesna, dextropropoxyphene/paracetamol combination, furosemide, alizapride, ergocalciferol)
- 2 y.o. male with h/o renal failure and renal hypoplasia with unknown cause of death after 17 days of 3 mg ondansetron po for nausea and vomiting  (concomitant meds: sodium polystyrene sulfonate, alfacalcidol, erythropoietin, calcium, growth hormone)
- 11 y.o. female with congenital heart disease on antibiotics developed decreased SaO2, headache, dizziness, and respiratory failure 1 hour after 4 mg ondansetron IV for nausea of unknown etiology (concomitant meds: clarithromycin, cefuroxime. PMH: allergy to amoxicillin and codeine)
- 16 y.o. male with end stage cystic fibrosis developed decreased SaO2 and arrested minutes after 2 mg ondansetron IV for nausea (numerous allergies to foods and medications, especially antibiotics)

## Adverse Event Reports During the Post-Exclusivity Period 12/1/04 – 1/1/06 

| Raw Counts* | All Reports (US) | Serious 
(US) | Death (US) |
| --- | --- | --- | --- |
| All ages | 338 (145) | 256 (68) | 27 (10) |
| Adults 
(> 17) | 238 (75) | 201 (42) | 22 (6) |
| Pediatrics 
(0-16) | 20 (8) | 16 (5) | 1 (0) |

- *May include duplicates and unknown ages

## Pediatric Death During the 

**Post-Exclusivity Period** (n=1, 0 US)

- 1 death case with insufficient information to assess causality
- 3 year old male with unreported cause of death receiving 4 mg ondansetron po (unknown indication and duration)

## Serious Adverse Events During the 

**Post-Exclusivity Period **(n=16, 5 US)

- Unlabeled events are unlined

**1 respiratory case** (_respiratory depression _with bradycardia)
**2 hepatic cases** (1- increased aspartate aminotransferase;              1- increased alanine aminotransferase with _ascites_)
**3 allergic reactions/anaphylaxis cases** (1 - cyanosis, hypotension, and urticaria; 1- dyspnea, hypotension, and pruritus; 1- anaphylactic shock)
**5 neurologic cases** (1- dystonia and agitation; 1 - auditory hallucinations, headache, and blurred vision; 1 - seizure, hypotonia, musculoskeletal stiffness, and urinary incontinence; 1- extrapyramidal reaction, speech impairment, clenched jaw;  1- seizure and oculogryic crisis)
**5 other cases** (2 - _birth defects_, 1- drug precipitation in IV,        2 - drug ineffectiveness)

## Unlabeled Serious Adverse Events

- 1 year old child (gender unspecified) with _respiratory depression_ and bradycardia after receiving 2 mg ondansetron IV x 1 dose to treat an unknown condition (foreign case with very little information)
- 9 year old boy with neuroblastoma experienced increased alanine aminotransferase, _ascites_, and pleural effusion after receiving several cancer chemotherapy agents and 4 mg ondansetron qd (duration and route of administration unknown)
- Infant (age and gender unspecified) whose mother had used ondansetron during pregnancy experienced a _foot/limb malformation_ (ondansetron dose, duration and route of administration unknown)
- Infant (age and gender unspecified) whose mother had used ondansetron during pregnancy experienced _tracheomalacia _(ondansetron dose, duration, and route of administration unknown)

## Summary: Ondansetron 

- This completes the one-year post-exclusivity adverse event reporting as mandated by BPCA.
- FDA recommends routine monitoring of ondansetron for adverse events in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

- _OSE_                           		_DGP_
- Ann Corken Mackey           		Lolita Lopez
- Lanh Green	                       		Ruyi He
- Rosemary Johann-Liang         	Joyce Korvick
- Mark Avigan
- Michael Evans				_OCP_
- Laura Governale			Suliman Al-Fayoumi
- Sigal Kaplan				Suresh Doddapaneni
- Toni Piazza-Hepp