Title: One Year PostExclusivity Adverse Event Review: Linezolid Pediatric Advisory Committee Meeting Novemb
1One Year Post-Exclusivity Adverse Event
ReviewLinezolidPediatric Advisory Committee
Meeting November 16, 2006
Alan M. Shapiro, MD, PhD, FAAP Medical
Officer Pediatric and Maternal Health
StaffOffice of New Drugs Center for Drug
Evaluation and Research Food and Drug
Administration
2Background Drug Information
- Drug Zyvox (linezolid)
- Therapeutic Category Anti-infective
- Sponsor Pfizer- Pharmacia Upjohn Division
- Indications Treatment of vancomycin resistant
Enterococcus faecium (VRE), nosocomial pneumonia
caused by Staph. aureus (including MRSA),
complicated skin and skin structure infections,
uncomplicated skin and skin structure infections,
community-acquired pneumonia - Original Market Approval April 18, 2000
- Pediatric Exclusivity Granted February 11, 2005
3Drug Use Trends in Inpatient Settings Linezolid
- Pediatric patients accounted for roughly 1.2, of
the 27,900 discharges associated with linezolid
use in the U.S. (Aug 2004 to Jul 2005) 1 - Pediatric discharges associated with linezolid
use increased 30 from 141 discharges in the six
months prior to exclusivity (Aug 2004 to Jan
2005) to 184 discharges in the six months
following exclusivity (Feb 2005 Jul 2005) 1
1 Premier Informatics Data Extracted 5-1-2006
4Pediatric Exclusivity Studies Linezolid
- Study 1 Assessment of linezolid pharmacokinetics
in full term and pre-term infants less than 3
months of age - Study 2 A randomized, blinded comparison of the
safety and efficacy of oral linezolid versus a
cephalosporin for the treatment of skin and skin
structure infections in pediatric patients aged 5
to 17 years
5Pediatric Exclusivity Studies Linezolid (cont.)
- Study 3 A randomized, open-label comparison of
IV linezolid/oral linezolid and IV vancomycin in
suspected resistant Gram-positive infections in
pediatric patients aged birth to 11 years - Study 4 A prospective study of
vancomycin-resistant enterococcal (VRE)
infections in pediatric patients aged 5 years to
17 years - Study 5 Pharmacokinetic study in pediatric
patients aged birth to 11 years with
cerebrospinal fluid shunts
6Pediatric Exclusivity Studies Efficacy Results
- Overall results of Studies 2-4 support the
efficacy of linezolid in treating the following
infections in children - Nosocomial pneumonia
- Community-acquired pneumonia
- Vancomycin-resistant Enterococcus faecium
infections - Complicated skin and skin structure infections
- Uncomplicated skin and skin structure infections
- Highly variable CSF penetration
7Pediatric Exclusivity Studies Safety Results in
Linezolid Treated Patients
- Studies 2 and 3 (Randomized Comparative Studies)
- Most common AEs diarrhea, fever, vomiting,
headache and skin rash - Most common lab abnormalities reduction in
hemoglobin, platelet counts, white blood cell
counts elevation of alanine aminotransferase
(ALT) - Study 4 (Prospective Treatment Study of VRE)
- Most frequent AEs gastrointestinal events
- Most frequent significant lab abnormalities
decreased platelet count elevations in ALT and
bilirubin - Overall, the safety profile in children is
similar to that in adults and is consistent with
the known safety database and current labeling
8Pediatric Exclusivity Studies Pharmacokinetic
Results
- Systemic exposure to linezolid varies as a
function of age - Rapid clearance in patients gt1 week old to 11
years, hence, need every eight hour dosing - Mean clearance in adolescents approaches adults,
hence, need every 12 hour dosing - Reduced clearance in neonates less than 34 weeks
gestation and less than 7 days post natal age
hence, need every 12 hour dosing
9Pediatric Exclusivity Studies Pharmacokinetic
Results (cont.)
- Due to the wide variability in clearance of
linezolid in pediatric patients - Possibility of subtherapeutic levels with the
recommended dosing regimens - One concern is in treatment of infections with
high MIC of infecting organisms ( 4µg/mL) - especially in the context of severe life
threatening infections - Thus the recommended dose of linezolid depends on
weight (mg/kg), age of the pediatric patient
(dosing interval) and the clinical indication
10Labeling Changes Resulting from Exclusivity
Studies
- Pediatric labeling for the following indications
- Nosocomial pneumonia
- Community-acquired pneumonia
- Vancomycin-resistant Enterococcus faecium
infections - Complicated skin and skin structure infections
- Uncomplicated skin and skin structure infections
11Labeling Changes Resulting from Exclusivity
Studies (cont.)
- Pharmacokinetic data in pediatric patients with
ventriculoperitoneal shunts - variable cerebrospinal fluid (CSF) concentrations
- therapeutic concentrations were not consistently
achieved or maintained in the CSF - Therefore, use of linezolid for the empiric
treatment of pediatric patients with central
nervous system infections is not recommended
12Adverse Event Reports since Market Approval
(April 2000) Linezolid
may include duplicates and unknown ages
13Adverse Event Reports 13 Month Post Exclusivity
Period Linezolid
may include duplicates and unknown ages
14Safety Concerns in Linezolid LabelWarnings
Section
- Hematologic myelosuppression
- Pseudomembranous colitis standard warning for
all antibacterials
15Safety Concerns in Linezolid Label Precautions
Section
- Lactic Acidosis
- Serotonin syndrome
- Drug interaction with adrenergic agents
(including phenylpropanolamine and
pseudophedrine) and serotonin agents (including
antidepressants such as SSRIs) - Food-Drug interaction with foods containing
tyramine - Peripheral and optic neuropathy usually with use
greater than 28 days
16Postmarketing Reports in Linezolid Label Adverse
Events Section
- Myelosuppression
- Peripheral and optic neuropathy
- Lactic acidosis
- Serotonin syndrome
17Pediatric Deaths Since Marketing Approval (n3)
- 2 year old with severe thermal burns with
vancomycin resistant enterococcus - Poor prognosis when starting anti-bacterial
therapy - 3 year old with graft versus host disease, acute
respiratory distress syndrome, renal failure, GI
candidiasis, staphylococcal infection (foreign
report) - On multiple medications including cyclosporin,
other antibacterials, micafungin, acyclovir - 12-month-old patient treated for MRSA sepsis and
endocarditis (foreign report) - No additional details available
Occurred after the safety review cut-off date
of 3/11/2006
18Serious Pediatric Adverse Events inPost
Exclusivity Period15 UNDUPLICATED pediatric
reports in patients on linezolid
- Neurologic 5
- Convulsions 1
- SSRI syndrome 1
- Optic Neuropathy 1
- Peripheral neuropathy 2
- Cardiac 6
- Tachycardia 3
- Irregular heart beat/ chest pain 1
- Arrhythmia 1
- Abnormal EKG 1
- Gastrointestinal /Hematologic 1
- Diarrhea/emesis/
- pancytopenia 1
- Metabolic 3
- Lactic acidosis 2
- Other metabolic acidosis 1
Underlined events Unlabeled events
19Pediatric Adverse Event Cardiac (n6)
- Tachycardia
- 2 year old male treated for an enterococcal
urinary tract infection with tachycardia - additional history is unavailable
- 16 year old male with osteomyelitis experienced
persistent tachycardia (120 bpm) which normalized
2 to 3 days after stopping therapy - patient had consumed a large amount of beef jerky
- interaction between the tyramine and the weak
monoamine oxidase inhibition of linezolid - 6 year old female with MRSA catheter infection
with sepsis developed a tachycardia of 220 bpm,
hypertension and rapid breathing within the first
minutes of the initial infusion (foreign) - patient recovered after the treatment was stopped
20Pediatric Adverse Event Cardiac (n6) (cont.)
- Case of chest pressure and irregular heart beat
- 9 year old female with cystic fibrosis on
multiple other antibiotics for an upper
respiratory infection - After the first dose of linezolid, crushing
chest pressure and irregular heart beat - Irregular heart beat and chest discomfort
persisted after linezolid stopped - Case of abnormal electrocardiogram
- 10 year old female with MRSA pneumonia developed
hypokalemia and an abnormal electrocardiogram
(ECG) on day 6 of therapy (foreign) - Hypokalemia and abnormal ECG improved following
discontinuation of linezolid - On multiple other medications
21Pediatric Adverse Event Cardiac (n6) (cont.)
- Case of cardiac arrhythmia
- 15 year old male experienced chest discomfort and
AV disassociation and a junctional rhythm (USA) - arrhythmia persisted despite a reduction of
linezolid dose and resolved over two days after
linezolid was stopped - History of premature atrial contractions with
junctional escape beats and wandering atrial
pacemaker
22Summary Linezolid
- OSE will conduct a full review of cases of
cardiac arrhythmias reported with linezolid in
patients of all ages - We will provide the Committee with the results of
this OSE review - This completes the one-year post-exclusivity AE
reporting as mandated by BPCA - FDA recommends routine monitoring of AEs for
linezolid in all populations. - Does the Advisory Committee concur?
23Acknowledgements
- OND
- Alfred Sorbello
- Sumathi Nambiar
- OSE
- Ronald Wassel
- Rosemary Johann-Liang
- Mark Avigan
- Laura A. Governale
- Toni Piazza-Hepp