# Presentation: 665441

## Clinical Assessment of Liver Toxicity Due to Telithromycin (Ketek®)

**William M. Lee, MD**
**Professor of Internal Medicine**
**UT Southwestern Medical Center**
**Dallas, TX**
**www.acuteliverfailure.org**
**December 14, 2006**

## William M. Lee, MDUT Southwestern Medical Center at Dallas  

- I have no financial relationship(s) to disclose within the past 12 months relevant to my presentation.
- AND
- My presentation does not include discussion of off-label or investigational use.

## Assessment of Liver Safety/ToxicityGoals of this discussion/context

**Review post-marketing data regarding drug hepatotoxicity related to Ketek®**
**After the Annals of Internal Medicine article, we began to review cases with FDA group: Seeff, Avigan, Serrano, Brinker, Lee, beginning June 2006**
**We have now adjudicated 112 cases, held detailed discussion of 53 cases reported here**

## Ketek review groupFormat of meetings

**6 meetings over the past 5 months, 2 hours each**
**Individual review of AERS/Medwatch/DILIN docs**
**Discussion of each of the 53 cases on the telecon**
**Developed an opinion, not a consensus**
**All opinions were within one grade of probability**
**Used DILIN system for severity and likelihood**

## Very likely

- Probable

- Possible

- Unlikely

- Insufficient data

## Ketek review group II

**113 cases reviewed: 60 discarded as having another obvious cause, insufficient data or minor abnormality**
**53 cases subject of this further analysis**
**Pattern of cases has emerged, helped by seeing all cases side by side**

## Ketek®: Pattern of toxicityUnique features

**Very rapid onset**
**Prominent fever, joint aches, RUQ pain**
**Variable resolution: quick, sub-acute, chronic**
**Unusual features in some cases:**
**Ascites**
**Rhabdomyolysis**
**Eosinophilia**

## 28 very likely/probable, an additional 17 possible, 

- 28 very likely/probable, an additional 17 possible,
- 8 insufficient data

## Ketek®: Pattern of toxicity7/53 cases died or transplanted

**5 deaths, 2 transplants**
**1 very likely, 1 probable, 4 possible, 1 inad info**
**Mean age 59 (range 26-85) 5F/2M**
**3/7 with ascites not counting perit dialysis pt**
**2 with fever, 3 with abdominal pain**
**Mean AST 2288 IU/L**
**Mean latency 5 days, exc for one 4+ wks**

## Ketek®: Pattern of toxicity cont’d.  7/53 death/transplant cases

**Acetaminophen: yes in 2/7, ? amounts**
**Biopsy/explant/autopsy: 2 massive necrosis, 1 cirrhosis but after 6+ wks**
**Most had viral serologies and imaging **

## Ketek®: Overall data  53 cases

**Many hospitalized cases were quite severe**
**Mean latency 23.5 days (range 1-39 days)**
**Mean AST 1051**
**8 with increased Cr levels**
**9 with INR ≥ 1.5**
**Biopsy/explant/autopsy: N=9 **
**Most showed changes compatible with drug-induced hepatitis, massive necrosis**

## Ketek®: Pattern of toxicityTypical severe case

**80 yr old male, given Ketek for bronchitis**
**3 days later admitted with persistent bronchitis**
**Over the next 5 days, develops progressive liver failure and dies on 6th hospital day, few labs available**
**No significant past med hx, no drugs, no viruses **

- Prob 2/Severity 4

## Ketek®: Pattern of toxicityAnother severe case #5

**85 yr old woman, given Ketek for 7 days for CAP**
**Admitted on day 8, weak, to ICU**
**Following day AST/ALT 5525/3870; inc troponin**
**Blood cultures negative**
**Succumbs to liver failure, ? which day**
**No confounding issues**

- Prob 3/Severity 4

## Ketek®: Pattern of toxicityMilder case #16

**31 yr old health care executive**
**URI led to two courses of Ketek, back to back**
**On day 15, developed high fever, shaking chills, no RUQ pain. All imaging and serologies negative**
**AST 583/ALT 1091, no signif bilirubin elevation**
**“****It is highly probable that this is..drug induced liver injury due to this antibiotic.”**

- Prob 4/Severity 3

## Ketek®: Pattern of toxicityMilder case #15

**27 yr old male took Ketek for 5 days, no other meds**
**1 day after completion, developed dark urine**
**T Bili 8.7; AST 227/ALT272; Alk phos 413; INR 0.9**
**All viruses negative**
**Physician said “there is no alternative explanation of this event.”**

- Prob 4/Severity 3

## Ketek®: Pattern of toxicityAscites case #24

**22 yr old female took Ketek for one course, at day 12 began another course. At day 14, N/V, abdominal pain and fever; pale and weak.  No other PHI.**
**T Bili 9.5; AST 500/ALT1061; **
**CT large ascites, bilateral pleural effusions**
**Hospitalized briefly, began to improve, labs essentially WNL one month later**

- Prob 3/Severity 3

## Ketek®: Pattern of toxicityAnother ascites case #2 

**37 yr old male began Ketek one wk pta **
**Admitted with fever, RUQ abd pain, nausea.**
**T Bili 3.9; AST 812/ALT1385; INR 1.5**
**CT Prominent ascites, USG same. 800 ml clear fluid removed, all tests negative; serologies all negative**
**Hospitalized briefly, began to improve, labs essentially WNL one month later**

- Prob 4/Severity 3

## Charlotte casesClay et al., Ann Intern Med 2006:144:1415 

**1) 46 yr old with dark urine on 2nd day of taking Ketek**
**AST200/ALT948; T Bili 3.9, resolved after 8 weeks**
**2) 51 yr old physician’s wife, subacute course beginning within a week of starting Ketek; transplanted. Liver weighed 480 gm**
**3) 26 yr old with very acute multi-system failure 2 wks after beginning Ketek, died 3rd hospital day.**
**	****Both explant and autopsy showed massive hepatic necrosis**

## 21 hospitalized, very likely or probable

## Summary: Clinical Cases

**Careful adjudication of 53 cases: 5 experts **
**Most cases well- or moderately well-documented**
**Most confounded or insufficient data cases excluded**
**5 deaths/2 transplants**
**44/53 hospitalized**
**28 very likely or probable**

## Conclusion: Clinical Cases

**Clear-cut signal of hepatic necrosis of varying severity**
**Certain cases have unusual signature but this varies**
**Severity is of concern as is short latency **
**Lack of confounding issues in many cases**
**Adequate data in most of those reported here**
**Causality assessment by a panel of experts, despite its shortcomings, suggests that more than half the cases shown here are due to Ketek®**

## Return

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