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

2. 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. 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. 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. 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. 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. 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. 8 Pediatric Exclusivity Studies Pharmacokinetic Results 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. 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. 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. 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. 12 Adverse Event Reports since Market Approval (April 2000): Linezolid Raw counts*All reports (US)Serious (US)Death (US) All Ages1846 (1264)1418 (864)168 (39) Adults (> 17)1350 (861)1132 (663)140 (30) Pediatrics (0-16)50 (38)40 (30)2 (1) *may include duplicates and unknown ages

13. 13 Adverse Event Reports 13 Month Post Exclusivity Period: Linezolid Raw counts*All reports (US)Serious (US)Death (US) All ages395 (236)377 (220)61 (13) Adults (> 17)300 (169)286 (157)48 (10) Pediatrics (0-16)18 (10)16 (8)1 (0) * may include duplicates and unknown ages

14. 14 Safety Concerns in Linezolid Label Warnings Section Hematologic: myelosuppression Pseudomembranous colitis: standard warning for all antibacterials

15. 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. 16 Postmarketing Reports in Linezolid Label Adverse Events Section Myelosuppression Peripheral and optic neuropathy Lactic acidosis Serotonin syndrome

17. 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 of 3/11/2006

18. 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 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. 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. 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) on day 6 of therapy (foreign) –Hypokalemia and abnormal ECG improved following discontinuation of linezolid –On multiple other medications

21. 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 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. 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. 23 Acknowledgements OSE Ronald Wassel Rosemary Johann-Liang Mark Avigan Laura A. Governale Toni Piazza-Hepp OND Alfred Sorbello Sumathi Nambiar