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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 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. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

Insufficient data Unlikely Possible Probable Very likely

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

Ketek®: Pattern of toxicity Overall results: 53 cases 7 died or transplanted, 37 hospitalized (44 total) 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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.” Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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.” Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

Ketek®: Pattern of toxicity Overall results: 53 cases 7 died or transplanted, 37 hospitalized (44 total) 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 Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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® Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006

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