One Year PostExclusivity Adverse Event Review: Linezolid Pediatric Advisory Committee Meeting Novemb - PowerPoint PPT Presentation

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One Year PostExclusivity Adverse Event Review: Linezolid Pediatric Advisory Committee Meeting Novemb

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Title: One Year PostExclusivity Adverse Event Review: Linezolid Pediatric Advisory Committee Meeting Novemb


1
One 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
2
Background 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

3
Drug 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
4
Pediatric 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

5
Pediatric 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

6
Pediatric 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

7
Pediatric 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

8
Pediatric 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

9
Pediatric 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

10
Labeling 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

11
Labeling 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

12
Adverse Event Reports since Market Approval
(April 2000) Linezolid
may include duplicates and unknown ages
13
Adverse Event Reports 13 Month Post Exclusivity
Period Linezolid
may include duplicates and unknown ages
14
Safety Concerns in Linezolid LabelWarnings
Section
  • Hematologic myelosuppression
  • Pseudomembranous colitis standard warning for
    all antibacterials

15
Safety 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

16
Postmarketing Reports in Linezolid Label Adverse
Events Section
  • Myelosuppression
  • Peripheral and optic neuropathy
  • Lactic acidosis
  • Serotonin syndrome

17
Pediatric 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
18
Serious 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
19
Pediatric 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

20
Pediatric 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

21
Pediatric 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

22
Summary 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?

23
Acknowledgements
  • OND
  • Alfred Sorbello
  • Sumathi Nambiar
  • OSE
  • Ronald Wassel
  • Rosemary Johann-Liang
  • Mark Avigan
  • Laura A. Governale
  • Toni Piazza-Hepp
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