# Presentation: 319883

## 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**

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## Adverse Event Reports since Market Approval (April 2000): Linezolid 

| Raw counts* | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All Ages | 1846 (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

## Adverse Event Reports 13 Month Post Exclusivity Period: Linezolid 

| Raw counts* | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All ages | 395 (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

## Safety Concerns in Linezolid LabelWarnings Section

- Hematologic: myelosuppression
- Pseudomembranous colitis: standard warning for all antibacterials

## 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

## Postmarketing Reports in Linezolid Label Adverse Events Section

- Myelosuppression
- Peripheral and optic neuropathy
- Lactic acidosis
- Serotonin syndrome

## 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

## 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

## 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

## 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

## 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

## 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?

## Acknowledgements

_**OSE**_
**Ronald Wassel**
**Rosemary Johann-Liang**
**Mark Avigan**
**Laura A. Governale**
**Toni Piazza-Hepp**

_**OND**_
**Alfred Sorbello**
**Sumathi Nambiar**