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One Year Post-Exclusivity Adverse Event Review:

Ondansetron

Pediatric Advisory Committee Meeting November 16, 2006

Felicia L. Collins, MD, MPH, FAAPMedical OfficerPediatric and Maternal Health StaffOffice of New DrugsCenter for Drug Evaluation and Research Food and Drug Administration

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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

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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]

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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Adverse Event Reports Since Market Approval and Prior to Pediatric Exclusivity

1/4/91 – 12/1/04Raw

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

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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)

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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)

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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)

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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

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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)

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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)

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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)

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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?

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AcknowledgementsAcknowledgements

OSEOSE DGPDGPAnn Corken Mackey Ann Corken Mackey Lolita Lopez Lolita Lopez Lanh GreenLanh Green Ruyi HeRuyi HeRosemary Johann-Liang Rosemary Johann-Liang Joyce KorvickJoyce KorvickMark Avigan Mark Avigan

Michael EvansMichael Evans OCPOCPLaura GovernaleLaura Governale Suliman Al-Fayoumi Suliman Al-Fayoumi Sigal KaplanSigal Kaplan Suresh DoddapaneniSuresh DoddapaneniToni Piazza-HeppToni Piazza-Hepp