# Presentation: 503452

## One Year Post Exclusivity Adverse Event Review:Fluconazole  Pediatric Advisory Committee Meeting November 18, 2005

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

## Background Drug Information 

**Drug: **Diflucan® (fluconazole)
**Therapeutic Category: **Antifungal
**Mechanism of action**:  Inhibits arm of  fungal C450 pathway
**Sponsor:  **Pfizer
**Original Market Approval: **January 28, 1990
**Pediatric Exclusivity Granted:  **January 21, 2004 for studies of tinea capitis

## Background Drug Information

**Indication:** Adults and children > 6 months
- Vaginal, oropharyngeal and esophageal candidiasis
- Cryptococcal meningitis
- Infection due to *Candida* (urinary tract infection, peritonitis, systemic)
- To decrease incidence of candidiasis s/p bone-marrow transplant** **
**Dosage:  **3-12 mg/kg/day depending on severity and location of infection (q 3 days preterm neonates)

## Pediatric Exclusivity Studies:  Safety

- Two efficacy and safety superiority studies
- Fluconazole (6 mg/kg/day) vs. griseofulvin (11 mg/kg/day) in treatment of tinea capitis for 3 & 6 weeks
- Children ages 3-12 years
- Patients enrolled = 880. Fluconazole 6 wks = 286; Fluconazole 3 wks = 302; Griseofulvin 6 wks= 292
- Efficacy not established:  no labeling change
- Animal study to evaluate QTc
- Beagles (14 days on fluconazole)
- QTc interval increased: reaffirmed class labeling

- Warning
- Bolded: serious hepatic toxicity, including fatality
- Hypersensitivity (rash)
- Precautions
- Class effect: prolongation of QT interval
- Weigh benefit and risk from single oral dose therapy for vaginal yeast infections
- Multiple significant drug interactions
- Pregnancy Category C: If animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks

**Existing Safety Labeling Relevant**
**to Reported Adverse Events**

## Fluconazole Outpatient Drug Use

- Over 11 million outpatient prescriptions for oral fluconazole products are dispensed annually
- Approximately 95 % of these are in adults.1
- Approximately 3 % of these are the oral suspension.2
- Oral suspension
- Infants 1 to 2 years of age accounted annually for almost 72 % of all outpatient oral suspension prescriptions (over 300,000).2,3*
- Pediatricians and family practitioners were top prescribers (> 70 %).2
**	**

- 1Verispan Vector OneTM: National,  MAT April 2002 - March 2005, data extracted 9-21-200**	**
**2**IMS Health, National Prescription Audit *Plus*, Feb 2002 - Jan 2005, Data Extracted Mar 2005
**3**Caremark Dimension RxTM, Jan 2002- Dec 2004, Data Extracted Mar 2005
- *Calculation based on application of proportions of pediatric fluconazole prescriptions in Caremark Dimension RxTM to IMS Health, National Prescription Audit *Plus* to estimate number of fluconazole prescriptions dispensed nationwide to pediatric population

## Adverse Events (AEs) during the One-Year Post-Exclusivity Period (n=19)

- Total reports during one-year post-exclusivity period (all formulations):
- 395 reports, all ages*
- pediatric reports = 29 (19 unduplicated, 8 US)
- 4 deaths
- Most reports were highly confounded (underlying illness, concomitant medications)
- Although serious adverse events occurred, most were expected or addressed in the labeling.
**	****	**
- *includes duplicate reports**	****	****	**

## Pediatric AEs during the One-Year Post-Exclusivity Period

- Fatality (4):
- IV and multiple dose therapy
- Coma and multi-organ failure in 7 year old (y.o.) with h/o medulloblastoma, radiation therapy and chemotherapeutic agents*
- 6 week-old with suspected fungal infection, hepatomegaly, elevated liver enzymes and bilirubin, while on fluconazole and cefozopran*; cause of death unspecified
- Oral:  single dose therapy
- Congenital anomaly (Trisomy 18), stillborn, exposure 6 months prior to pregnancy
- Sudden death (breast milk exposure) in 40 day old infant
- *concomitant medications associated with similar toxicity
- Labeling for fluconazole includes seizures, hepatic toxicity, and transmission through breast milk
**	****	****	****	****	**

## Pediatric AEs during the One-Year Post-Exclusivity Period

- Non-fatal AEs (n =15 patients)
- Congenital anomalies (n=3)
- Cardiac events (n=3)
- Metabolic (n =2)
- Hepatic (n= 2)
- Nonfatal fungemia (n=2)
- Dosing errors (n=2)
- Hypersensitivity  (n=1)

## Pediatric AEs during the One-Year Post-Exclusivity Period Maternal Exposure (n=3)

- Congenital Anomalies
- Single dose (or short term) treatment
- Hypospadias and bifid scrotum, exposure 8 weeks prior to pregnancy
- Syndactyly and finger hypoplasia, exposure 1 week prior to pregnancy
- Multiple dose treatment
- Microcephaly, cataract, blindness, small gestation (during first trimester: radiation*, INH*, pyridoxine)
- *concomitant medications associated with similar toxicity

## Summary:  Fluconazole

- Number of pediatric AE reports small compared with adult AE reports, paralleling use
- Most reports confounded
- Although serious AEs occurred, no new unlabeled safety concerns identified
- This completes the one-year post-exclusivity AE reporting as mandated by BPCA.
- FDA recommends routine monitoring of AEs for fluconazole in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

_**ODS**_
- Mark Avigan
- Gerald Dal Pan
- Evelyn Farinas
- David Moeny
- Judy Staffa

_**OND**_
-  Ozlem Belen
-  Marc Cavaille Coll
-  Markham Luke
-  Brenda Marques
-  Bindi Nikhar