Clinical Assessment of Liver Toxicity Due to Telithromycin (Ketek®) William M. Lee, MD Professor of Internal Medicine UT Southwestern Medical Center Dallas,

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

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

Professor of Internal Medicine

UT Southwestern Medical Center

Dallas, TX

www.acuteliverfailure.org

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

William M. Lee, MDUT Southwestern Medical Center at Dallas

William M. Lee, MDUT 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.

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

Assessment of Liver Safety/ToxicityGoals of this discussion/context

Assessment of Liver Safety/ToxicityGoals 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

• 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 groupFormat of meetings

Ketek review groupFormat 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

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

variance in causality scores pre and post conference

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

causality scores

vari

ance

PrePost

0 1 2 3 4

Very likelyProbablePossibleUnlikelyInsufficient data

Ketek review group IIKetek 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

• 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 toxicityUnique features

Ketek®: Pattern of toxicityUnique features

• Very rapid onset

• Prominent fever, joint aches, RUQ pain

• Variable resolution: quick, sub-acute, chronic

• Unusual features in some cases:– Ascites

– Rhabdomyolysis

– Eosinophilia

• Very rapid onset

• Prominent fever, joint aches, RUQ pain

• Variable resolution: quick, sub-acute, chronic

• Unusual features in some cases:– Ascites

– Rhabdomyolysis

– Eosinophilia


Probability Severity Number Very likely Probable Possible Unlikely Insuffic

data 4 7 1 1 4 0 1 3 37 6 13 11 0 7 2 1 1 0 0 0 0 1 8 1 5 2 0 53 9 19 17 0 8

Ketek®: Pattern of toxicityOverall 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 toxicity7/53 cases died or transplanted

Ketek®: Pattern of toxicity7/53 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

• 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

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

• 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

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

• 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 toxicityTypical severe case

Ketek®: Pattern of toxicityTypical 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

• 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 4Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006December 14 & 15, 2006

Ketek®: Pattern of toxicityAnother severe case #5

Ketek®: Pattern of toxicityAnother 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

• 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


Ketek®: Pattern of toxicityMilder 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.”

• 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.”




• 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.”

• 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.”


Ketek®: Pattern of toxicityAscites case #24

Ketek®: Pattern of toxicityAscites 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

• 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




Ketek®: Pattern of toxicityAnother ascites case #2

Ketek®: Pattern of toxicityAnother 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



• 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




Charlotte casesClay et al., Ann Intern Med 2006:144:1415

Charlotte casesClay 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

• 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

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

Probability Severity Number Very likely Probable Possible Unlikely Insuffic

data 4 7 1 1 4 0 1 3 37 6 13 11 0 7 2 1 1 0 0 0 0 1 8 1 5 2 0 53 9 19 17 0 8

Ketek®: Pattern of toxicityOverall results: 53 cases

7 died or transplanted, 37 hospitalized (44 total)

21 hospitalized, very likely or probable

Summary: Clinical CasesSummary: 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

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

Conclusion: Clinical CasesConclusion: 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®

• 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®


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Clinical Assessment of Liver Toxicity Due to Telithromycin (Ketek®) William M. Lee, MD Professor of Internal Medicine UT Southwestern Medical Center Dallas,