# Presentation: 930168

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

**Hari Cheryl Sachs, MD, FAAP****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information 

**Drug: **Xenical® (orlistat)
**Therapeutic Category: **lipase inhibitor
**Sponsor:  **Roche
**Original Market Approval:  **April 23, 1999
**Pediatric Exclusivity Granted: **September 12, 2003
**Mechanism of action: **inhibits absorption of dietary fats

## Background Drug Information

**Indication (12 years and older): **
- Obesity management in conjunction with weight loss
- Body Mass Index (BMI) > 30 mg/m2 or 27 mg/m2 with risk factors (hypertension, diabetes, dyslipidemia)
**Adult and Adolescent Dosage:  **120 mg TID

## Drug Use Trends in Outpatient Settings: Orlistat

- Dispensed prescriptions for all age groups have decreased from 1.6 million (Oct 2001- Sept 2002) to 1 million (Oct 2003- Sept 2004).1
- Orlistat is prescribed mainly in adults (male: female ratio of 1:3).2
- Pediatric patients (ages 1-16) account for <1 % (approximately 4,000) prescriptions annually.1,2*
**	****1**IMS Health, National Prescription Audit *Plus*, Oct 2001 – Sept 2004,  Data Extracted Nov 2004
**	****2**Caremark Dimension RxTM, Nov 2001 – Oct 2004, Data Extracted Dec 2004
- 	*Calculation based on application of proportions of pediatric orlistat prescriptions in Caremark Dimension RxTM to IMS Health, National Prescription Audit *Plus* to estimate number of orlistat  prescriptions dispensed nationwide to pediatric population

## Drug Use Trends in Outpatient Settings: Orlistat

- Prescribers (Oct 2003 to Sept 2004)1
- Internists, family practitioners and osteopathic medicine practitioners accounted for nearly 70% of the prescriptions written.
-  Pediatricians wrote <1%.
- Diagnosis2
- Adults:  obesity
- Pediatric use was not recorded during sampling period.
**	****1**IMS Health, National Prescription Audit *Plus*, Oct 2003 – Sep 2004,  Data Extracted Nov 2004
- 	2IMS Health, National Disease and Therapeutic Index,  Jan 2004 – Sep 2004, Data Extracted Nov 2004
***	***

## http://www.fda.gov/cder/pediatric/Summaryreview.htm

## Pediatric Exclusivity Studies: Orlistat

- Studies performed:
- 3 week effect of orlistat on mineral balance
- 54 week efficacy and safety study
- Population PK study as subset of both studies

## Pediatric Exclusivity Studies: Orlistat

- 3 week in-patient double blind, randomized, placebo-controlled study in obese adolescents (n=32)
- Reduced calorie diet plus 120 mg orlistat TID and multivitamin
- Mineral balance:
- Calcium, copper, iron, magnesium and zinc
- Plasma and urine sodium and potassium
- Urine creatinine
- Fecal fat (daily)

## Pediatric Exclusivity Studies: Mineral Balance Results

- No effect on balance of Ca, Mg, PO4, Zinc, copper, or creatinine
- Iron balance decreased by 49.7 μmoles/24 hours in orlistat group and decreased by 32.9 μmoles/24 hours in placebo group
- Fecal fat:  orlistat treatment increased fecal fat 15.9 grams/day vs. 4.1 grams/day in placebo group
- 94%  completed trial

## Pediatric Exclusivity Studies: Safety and Efficacy

- Double blind, placebo controlled, 54 week efficacy and safety trial of obese adolescent patients (age 12-16 years, n=539)
- All patients received reduced calorie diet, nutritional and behavioral counseling, and vitamin supplementation.
- Efficacy Endpoints
- Primary:  BMI (percent of patients achieving 5 or 10% reduction BMI)
- Secondary:  change in body weight, lipids, blood pressure, glucose tolerance and insulin levels

## Pediatric Exclusivity Studies: Safety and Efficacy

- Safety Endpoints
- Linear growth, Tanner Stage and sex hormone levels
- Gastrointestinal tolerability
- Body composition assessment by DEXA scan
- Fat soluble vitamins, Beta-carotene, serum calcium levels
- Gallbladder and renal ultrasound
- EKG

## Pediatric Exclusivity Studies: Efficacy Results

- ~65% completed in each treatment group
- Orlistat vs. placebo significantly:
- Decreased BMI (-0.55 kg/m2 vs. +0.31 kg/m2, p=.001)
- Decreased waist and hip circumference
- Increased percent with 5 or 10% reduction in BMI
- 5% - 26.5% vs. 15.7% (p=.005)
- 10% - 13.3% vs. 4.5% (p=.002)
- Decreased weight gain
- Increased percent with 5 or 10% reduction weight
- 5% - 19% vs. 11.7% (p<.05)
- 10% - 9.5% vs. 3.3% (p<.05)

## Pediatric Exclusivity Studies: Safety Results

- Orlistat compared with placebo
- No statistically significant differences
- BP
- Glucose and insulin levels
- Lipid parameters
- Statistically significant differences
- Lower serum Vitamin E  (p=.089) and Beta-carotene levels (p=.001) in orlistat vs. placebo
- Increased fatty/oily stools

- Precautions
- Take multivitamin supplement containing fat-soluble vitamins
- Pediatric patients
- Clinical trial described
- Adverse Reactions
- Profile similar to adults

**Labeling Changes Resulting from**
**Exclusivity Studies**

- Contraindication
- Chronic malabsorption syndrome
- Known cholestasis
- Precautions
- Adhere to dietary guidelines
- GI symptoms with high fat diet
- Multivitamin including fat-soluble
- Increased urinary oxalate
- Misuse in anorexia

**Additional Relevant Safety Labeling**

- Pregnancy Category B
- Adverse events
- Oily stools
- Infectious diarrhea
- Nausea
- Rectal pain/discomfort
- Vomiting

**Relevant Safety Labeling**

## Adverse Event Reports since Market Approval: Orlistat 04/23/99 - 10/12/04

- Total number of reports, all ages†*:
- 6,261 reports (4,989 US)
- 6,128 serious (4,910 US)
- 58 deaths (19 US)
- Pediatric reports*:
- 22 reports (13 US)
- 21 serious (13 US)
-  No deaths
**	****	**
- †Includes reports with unknown age
- *Counts may include duplicate reports

## Top 20 Reported Adverse Events since Approval (Adults: n=3,828)

_**Labeled **_
- Steatorrhea
- Abdominal pain
- Flatulence
- Frequent bowel movements
- Nausea
- Headache
- Dizziness
- Vomiting
- Fatigue
- Defecation urgency

_**Unlabeled**_
- Constipation
- Diarrhea
- Weight increased
- Loose stools
- Abdominal distension
- Feces discolored
- Condition aggravated
- Anorectal disorder
- Rectal hemorrhage
- Dyspnea

## Top 20 Reported Adverse Events since Approval (Pediatrics: n=22)

_**Labeled**_
- Steatorrhea
- Flatulence
- Abdominal pain

-                           _**Unlabeled**_
- Maternal exposure to therapeutic drug
- Pregnancy
- Caesarian section
- Feces discolored
- Maternal drugs affecting fetus
- Neonatal jaundice
- Neonatal disorder
- Abnormal feces

- Accidental exposure
- Accidental overdose
- Acne
- Asthenia
- Bowel sounds abnormal
- Fetal bradycardia
- Cardiac murmur
- Cataract
- Cholelithiasis

## Adverse Event Reports during the One-Year Post-Exclusivity Period: Orlistat 09/12/03 – 10/12/04 

- Total number of reports, all ages†*:
- 211 reports (71 US)
- 211 serious (71 US)
- 6 deaths (2 US)
- Pediatric reports:
- 1 report (0 US)
- 1 serious (0 US)
-  No deaths
- †Includes reports with unknown age	 *Counts may include duplicate reports

## Top 20 Serious Adverse Events during the One-Year Post-Exclusivity Period (Adults: n=159)

_**Labeled**_
- Abdominal pain
- Dizziness
- Steatorrhea
- Depression

**                       **_**Unlabeled**_
- Cholelithiasis
- Diarrhea
- Drug interaction
- Circulatory collapse
- Pulmonary embolism
- Hematochezia
- International normalized ratio increased

- Hypoglycemia
- Pancreatitis
- Rectal  hemorrhage
- Asthenia
- Convulsion
- Diverticulum
- Drug ineffective
- Dysarthria
- Dyspnea

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

- Term neonate with suspected developmental hip dysplasia, normal x-rays with orthopedic follow-up
- Maternal tobacco exposure
- Contraceptive implant removed 5 months prior to pregnancy
**	****	****	****	****	**

## Summary:  Orlistat

- Minimal use in pediatric patients
- Insufficient events to draw any conclusions
- Reports of cholelithiasis during trial and post-marketing surveillance (relationship to therapy vs. underlying obesity and rapid weight loss unclear)
- FDA recommends continued monitoring of AEs, particularly for the risk of cholelithiasis, for this drug in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

_**ODS**_
- Mark Avigan
- Gerald Dal Pan
- Laura Governale
- Sigal Kaplan
- Joslyn Swann

_**DMEDP**_
- Eric Colman
- Oluchi Elekwachi
- Theresa Kehoe
- Bruce Stadel
_**ORP**_
- Roy Castle, Jr.