1. One Year Post-Exclusivity Adverse Event Review: Linezolid Pediatric Advisory Committee MeetingNovember 16, 2006 Alan M. Shapiro, MD, PhD,FAAP Medical Officer Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and ResearchFood and Drug Administration

2. Background Drug Information

Drug:Zyvox (linezolid)

Therapeutic Category:Anti-infective

Sponsor:Pfizer- Pharmacia & Upjohn Division

Indications:Treatment of vancomycin resistantEnterococcus 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 linezoliduse intheU.S. (Aug 2004 to Jul 2005)1

Pediatric discharges associated with linezolid use increased30% 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

1Premier Informatics Data Extracted 5-1-2006 4. Pediatric Exclusivity Studies: Linezolid

Study 1: Assessment of linezolid pharmacokinetics in full term and pre-term infantsless 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 to17 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 StudiesEfficacy 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-resistantEnterococcus faeciuminfections

• 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 TreatmentStudy 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 PharmacokineticResults

Systemic exposure to linezolid varies as a function of age

• Rapid clearance in patients>1 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 PharmacokineticResults (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 ( 4g/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-resistantEnterococcus faeciuminfections

• 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 2 (1) 40 (30) 50 (38) Pediatrics (0-16) 140 (30) 1132 (663) 1350 (861) Adults ( >17) 168 (39) 1418 (864) 1846 (1264) All Ages Death (US) Serious (US) All reports (US) Raw counts* 13. Adverse Event Reports 13 Month Post Exclusivity Period: Linezolid* may include duplicates and unknown ages 1 (0) 16 (8) 18 (10) Pediatrics (0-16) 48 (10) 286 (157) 300 (169) Adults ( >17) 61 (13) 377 (220) 395 (236) All ages Death (US) Serious (US) All reports (US) Raw counts* 14. Safety Concerns in Linezolid Label Warnings 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(n=3)**

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 of3/11/2006 18. Serious Pediatric Adverse Events in Post Exclusivity Period 15 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 pain1

• Arrhythmia1

• 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 (n=6)

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 (n=6) (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) onday 6 of therapy (foreign)

• Hypokalemia and abnormal ECG improved following discontinuation of linezolid

• On multiple other medications

21. Pediatric Adverse Event: Cardiac (n=6) (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 linezoliddose 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

OSE

Ronald Wassel

Rosemary Johann-Liang

Mark Avigan

Laura A. Governale

Toni Piazza-Hepp

OND Alfred Sorbello Sumathi Nambiar