# Presentation: 938207

## Telithromycin Integrated Summary of Safety 

**Anti-Infective Drugs Advisory Committee **
**January 8, 2003**
**Charles Cooper, M.D.**
**Medical Officer **
**Division of Anti-Infective Drug Products**
**Center for Drug Evaluation and Research**
**U.S. Food and Drug Administration**

## Outline

**Description of safety database**
**Overview of safety-related events**
**Cardiac risk profile**
**Hepatic risk profile**
**Visual risk profile**
**Summary**

## Phase 3 safety database*

-  **Treatment groups balanced for age, sex, race, weight**
** ****15.8% telithromycin pts were ******** 65 yo, vs. 19.4% of comparator pts**
** ****59 telithromycin pts were <18 yo for NDA**

******* ****Does not include data from study 3014**

## Deaths in Phase 3 trials

## Nonfatal serious AEs in controlled Phase 3 trials

## AEs in controlled Phase 3 trials

## AEs resulting in discontinuation in controlled Phase 3 trials

## Cardiac Risk Profile

## Cardiac toxicity: Pre-clinical/Phase 1

**Blocks IK****r**** (major repolarization current)**
**Prolongs action potentials in isolated fibers**
**Prolongs QT and increases HR in dogs**
**Concentration-dependent ******** in ********QTc in Phase 1 studies (2 msec/mg/L)**
**Increased exposure w/ CrCl <30 mL/min and/or concomitant CYP 3A4 inhibitor/ substrate**

## Cardiac AEs in controlled Phase 3 trials

## Serious cardiac AEs in all Phase 3 trials

**Telithromycin patients:**
**3 / 2702 (0.1%) in controlled studies**
**5 / 1770 (0.3%) in uncontrolled studies**
**Comparator patients:****   **
**8 /2139 (0.4%)**
**No serious cardiac AEs related to study drug**

**Serious cardiac AEs in telithromycin patients:**
**Cardiac arrest**
**Cardiac failure NOS**
**LV failure (drug discont.)**
**Acute MI (drug discont.)**
**Angina pectoris**
**Cardiac failure aggrav.**
**Cardiomyopathy NOS**
**LV failure**

**Notes:**
Table SS-62 ISS Report page 2573

## ECG data in Phase 3 trials

**ECG data from 3013 added to previous NDA********* **
**Mean on-therapy ********QT****C**** (Bazett’s formula):**
**1.5 ******** 22.3 msec in telithromycin-treated patients for all Phase 3 trials combined**
**3.8 ******** 19.3 msec for telithromycin vs. 3.3 ******** 19.6 msec for clarithromycin in controlled studies (3006, 3008, 3013)**
**	****	**

*** ECG data not consistently collected for new studies 4003 and 3012**

## Hepatic Risk Profile

## Hepatic toxicity: pre-clinical

**Hepatotoxicity in rats, dogs, monkeys**
**Increased AST and ALT**
**Hepatic necrosis in 4-week rat study**
**Hepatocellular hypertrophy and multinucleated hepatocytes**
**Hepatic effects of telithromycin greater than those of clarithromycin in animals**

## Hepatic toxicity: Phase 1

_**Study 1030**_** **
**8 elderly subjects**
**Single doses of 1200, 1600, 2000 mg telithromycin or placebo**
**3 subjects with ******** ALT/AST to 100-300 U/L (ALT>AST)**
**72 yo  F - 7 days post 2000 mg **
**69 yo M - 17 days post 2000 mg **
**62 yo M - 7 days post placebo (14 days post 2000 mg)**
**Patients asymptomatic**
**Possible drug effect with 7-17 day latency period**

## Hepatic AEs in controlled Phase 3 trials

## Serious hepatic AEs in all Phase 3 clinical trials

**Four patients with serious hepatic AEs (3 telithromycin, 1 comparator)**
**Drug effect unlikely in comparator patient and 1 telithromycin patient**
**Drug effect plausible in 2 telithromycin-treated patients**
**76 yo F on allopurinol/pravastatin; asympto-matic ******** in ALT/AST on telithromycin**
**53 yo M with eosinophilic hepatitis**

## Patient 502/1069 

**PMH: 53 yo M w/ asthma, DM **
**Meds: Inhaled salbutamol, fluticasone, Atrovent, Nasonex, po Ca****++****, ? DM medication**
**Course: D1-10 Telithromycin 800 mg po qd for CAP**
**              ****D13 -? Acetaminophen **** (500 mg x 6 over 1 wk)**
**	****    ****D14 fever/vomiting/diarrhea - fever persists**

## Patient 502/1069 (cont.)

**D23****	****Hospitalized for hepatitis**
**	****	****Hepatitis A, B, C serologies negative**
**D29****	****Liver bx: centrilobular necrosis and ****	****	****	****eosinophilic infiltration**
**D94****	****LFTs virtually normal**
**At follow up, 9 mos after event, on routine testing: ALT 1331, tot. bili. 25 uM (nl < 20). Hep A, B, C neg.  Anti-smooth muscle Ab + (1:1000). No eosinophilia. Patient asymptomatic.**
**Second liver bx: Zone 3 and portal fibrosis, piecemeal necrosis, plasma cell infiltrate; ****	****consistent with autoimmune hepatitis**

## Incidence of ALT increases in controlled CAP trials*

*** Patients with normal ALT at baseline**

## Visual Risk Profile

## Blurred vision in Phase 3 trials

*** Patients not randomized by 3A4 inhibitor intake**

** ****15/20 telithromycin-treated patients with mild blurring; 4 with moderate blurring; 1 with severe blurring**
** ****Median duration 2d (range1-10d); median onset 2****nd**** d (range1-6 )**
**4 discontinuations due to visual adverse events**

## Blurred vision in Phase 1 studies

**Two studies (1059 and 1064) of telithromycin-associated visual blurring**
**13-50% incidence of blurring in subjects receiving 2400 mg telithromycin**
**Higher incidence in younger subjects**
**Median onset 3 h (range 1-5 h)**
**Median duration 2.8 h (range 0.9-20.3 h)**
**Likely due to interference with accommodation**

**Notes:**
Tears in younger patients

## Serious visual adverse events

**One telithromycin-treated subject with SAE of “unable to accommodate.”**
**AE determined to be “significantly disabling”**
**Began 2 hours after study drug administered**
**Patient seen by ophthalmologist who gave diagnosis of “unable to accommodate.”**
**AE was initially assessed as related to study drug**
**Telithromycin was discontinued and AE resolved**
**5 months later, causality of AE changed to “not related to study medication”**

## Summary of ISS

**Overall**
**Most common AEs are GI**
**Cardiac**
**Concentration-dependent QT **
**No drug-related serious cardiac adverse events**
**Hepatic**
**Hepatotoxicity in pre-clinical studies**
**Cluster of pts with ******** transaminases in Phase 3**
****** ****incidence of low-level ALT elevations in Phase 3**
**One patient with eosinophillic hepatitis in Phase 3**
**Visual**
**Incidence of blurred vision 0.6% in controlled studies**
**Possibly due to interference with accommodation**

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