# Presentation: 378697

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

**Alan M. Shapiro, MD, PhD, FAAP****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information 

**Drug: **Malarone® and Malarone Pediatric® (atovaquone-proguanil)
**Therapeutic Category: **anti-malarial
**Sponsor:  **GlaxoSmithKline
**Indication: **Treatment of  *P. falciparum* malaria in patients ≥5 kg and prophylaxis in patients ≥11 kg
**Original Market Approval: **July 14, 2000
**Pediatric Exclusivity Granted: **August 6, 2003

## Drug Use Trends in Outpatient Settings: Atovaquone-Proguanil

- Malarone® and Malarone Pediatric® accounted for roughly 5% and 0.2%, respectively, of the 3.7 million prescriptions dispensed for the antimalarial class in the U.S. (Aug 2003 to Jul 2004).1
- Dispensed prescriptions for Malarone Pediatric® increased roughly 34.5% from approximately 5,500 (Aug 2002 to Jul 2003) to over 7,300 (Aug 2003 – Jul 2004).1
- Pediatricians were responsible for roughly 4.3% (~7,800 prescriptions) of Malarone® and 40.4% (~2,900 prescriptions) of Malarone Pediatric® dispensed in the U.S. between August 1, 2003 and July 31, 2004.1

- 1IMS Health, National Prescription Audit *Plus*TM, Moving Annual Totals, Aug 2001 – Jul 2004, Extracted Oct 2004

## Pediatric Exclusivity Studies: Atovaquone-Proguanil

**Malaria Treatment**
**Trial 1 (n=200):** Compared the safety and efficacy of atovaquone-proguanil to amodiaquine in the treatment of acute uncomplicated *P. falciparum* malaria in pediatric patients weighing 5-11 kg
- Result: Adequate clinical response was obtained in 95% of patients treated with atovaquone-proguanil versus 53% of patients treated with amodiaquine.

## Pediatric Exclusivity Studies: Atovaquone-Proguanil

**Malaria Prophylaxis Trials**
**Trial 2 (n=330):** A double-blind placebo-controlled study evaluating the safety and efficacy of atovaquone-proguanil in the prevention of *P. falciparum* malaria in an endemic area in pediatric patients weighing 11-40 kg
- Method: Patients with acute *P. falciparum* malaria were treated with artesunate and subsequently randomized to either atovaquone-proguanil or placebo for malaria prophylaxis.
- Result: <1% of patients treated with atovaquone-proguanil  for prophylaxis had treatment failure versus 22% of untreated patients.

## Pediatric Exclusivity Studies: Atovaquone-Proguanil

**Malaria Prophylaxis Trials (continued)**
**Trial 3 (n=221):** An international, open label, randomized trial to compare atovaquone-proguanil to chloroquine-proguanil in the prevention of malaria in non-immune pediatric patients weighing 11-50 kg traveling to an endemic area
- Result:  Study was not large enough to allow for statements of comparative efficacy

## Labeling Changes Resulting from Exclusivity Studies

- Added pharmacokinetic clearance data as a function of body weight for pediatric patients ≥11 kg
- Extended labeling of atovaquone-proguanil down to 5 kg for the treatment of acute, uncomplicated *P. falciparum* malaria
- Added safety data for pediatric patients 5 to <11 kg who received atovaquone-proguanil for the treatment of acute uncomplicated *P. falciparum* malaria

- Pediatric Use-  Most commonly reported adverse events attributable to atovaquone-proguanil:
- Treatment of malaria (5- <11 kg): diarrhea
- Treatment of malaria (11-40 kg): vomiting and pruritis
- Pediatric Use-  Most commonly reported adverse events possibly attributable to atovaquone-proguanil or placebo:
- Prophylaxis of malaria (≥11 kg): headache, fever and abdominal pain
- Other treatment emergent adverse events observed in pediatric studies of prophylaxis:
- Abdominal pain & vomiting
- Headache
- Cough

**Relevant Safety Labeling**

## Labeled Post-Marketing Adverse Events

***Skin: ***Cutaneous reactions ranging from rash, photosensitivity, and urticaria to rare cases of  erythema multiforme and Stevens-Johnson syndrome
***Central Nervous System: ***Rare cases of seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established

## Adverse Event Reports since Market Approval: Atovaquone-Proguanil 07/14/00 – 09/06/04

- Total number of reports, all ages†*:
- 293 reports (76 US)
- 240 serious (37 US)
- 6 deaths (0 US)
- Pediatric reports*:
- 17 reports (3 US)
- 15 serious (2 US)
- 3 deaths (0 US) (2 unduplicated reports)
**	**
- †Includes reports with unknown age
- *Counts may include duplicate reports

## Pediatric Deaths Prior to Post-Exclusivity Period (n=2)(Foreign Reports)

**Both deaths occurred while on treatment for *****P. falciparum***** malaria**
- 14 month old with severe anemia, three days presumed fever, and hepatosplenomegaly
- Treated with chloroquine and paracetamol for two days
- Parasite count of 733/200 WBC and hematocrit of 12%
- Received two days of atovaquone-proguanil and became dyspneic with increasing anemia and severe hypoglycemia.  Placed on oxygen and died before receiving blood transfusion
- Death presumed to be due to severe malarial anemia and hypoglycemia but causal link to atovaquone-proguanil could not be excluded

## Pediatric Deaths Prior to Post-Exclusivity Period (n=2)(Foreign Reports cont.)

- 22 month old with severe anemia, five days of presumed fever, anorexia, occasional vomiting and tachycardia
- Treated with chloroquine and paracetamol for three days
- Parasite count of 730/230 WBC and hematocrit of 14%
- Received one dose of atovaquone-proguanil and subsequently patient deteriorated and died 45 minutes after the dose
- Death presumed to be due to severe malarial anemia but causal link to atovaquone-proguanil could not be excluded

## Adverse Event Reports during the One-Year Post-Exclusivity Period: Atovaquone-Proguanil 08/06/03 – 09/06/04

- Total number of reports, all ages†*:
- 122  reports (40 US)
- 89 serious (8 US)
- No deaths
- Pediatric reports*:
- 7 reports (3 US)
- 6 serious (2 US)
- No deaths
- †Includes reports with unknown age	*Counts may include duplicate reports

## Top 10 Reported Adult Adverse Events during the One-Year Post-Exclusivity Period

- Nausea
- Vomiting
- Abdominal Pain
- Headache
- Dizziness
- Insomnia
- _Nightmares_
- Pyrexia
- _Fatigue  _
- _Abortion spontaneous_  **	****	**

- Underlined events = Unlabeled events

## Pediatric Adverse Events during the One-Year Post-Exclusivity Period

- 4 cases of allergic type reactions
- _Facial edema_ +fever
- Blepharitis +drug ineffective +malaria
- Drug hypersensitivity +pruritus +urticaria
- Acute psoriaform reaction (AST and ALT increased)

- Underlined events = Unlabeled events

- Unduplicated pediatric reports in patients on atovaquone- proguanil for malaria prophylaxis:

## Pediatric Adverse Events during the One-Year Post-Exclusivity Period (cont.)

- 16 yr. old on atovaquone-proguanil for 19 days for malaria prophylaxis
- 1-2 days after completing malaria prophylaxis patient woke up with blurry vision and was “unable to see 3 inches”.  Saw MD, ophthalmologist, and retinal specialist and was given prescription glasses.   Reported by non-health professional who described this patient as being “legally blind”.
- Ophthalmologist diagnosis was “Acute myopia possible drug effect”.  Retinal specialist noted retinal striae in both eyes.
- Resolved  after one week

## Summary: Pediatric Adverse Events

- Eye Disorders
- Current labeling for atovaquone-proguanil derived from the results of an adult malaria prophylaxis trial lists “visual difficulties” in 2% of patients on atovaquone-proguanil versus 3% in patients on mefloquine.
- Since marketing approval, there have been post-marketing AERS reports in adults of visual blurring (3), eye pain (2), eye swelling (2), and eye disorders (2).
- Hypersensitivity, including cutaneous reactions, has been addressed in current labeling.
- Elevation of transaminases associated with treatment of malaria have also been described in current labeling.

## Summary: Atovaquone-Proguanil

- This completes the one-year post-exclusivity AE monitoring as mandated by BPCA.
- FDA recommends routine monitoring of AEs for this drug in all populations.
- Does the Advisory Committee concur?

## Acknowledgements

_**ODS**_
- Mark Avigan
- Gerald Dal Pan
- Michael Evans
- Andrea Feight
- Melissa Truffa

_**DSPIDP**_
-   Renata Albrecht
-   Maureen Tierney
-   Yon Yu
_**ORP**_
-   Roy Castle, Jr.