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Telithromycin-Associated Hepatotoxicity
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  1. Telithromycin-Associated Hepatotoxicity Allen Brinker, MD, MS Epidemiology Team Leader Division of Drug Risk Evaluation (DDRE) Office of Surveillance and Epidemiology (OSE)

  2. Telithromycin-Associated Acute Liver Failure (ALF) and Clinically Significant Liver Injury • Outline of Speakers • Allen Brinker, MD (FDA) • Case material / DDRE signal assessment • Leonard Seeff, MD • Expert Consultant for FDA • Principles of ALF causality assessment • William Lee, MD • Expert Consultant for FDA • Telithromycin ALF causality assessment

  3. Telithromycin-Associated ALFOverview • Summarize DDRE review • Methods • spontaneous adverse event (MedWatch) reports • Analysis of cases • Pharmacoepidemiology • Reporting rates • Two supporting ALF reporting rate analyses • Telithromycin ALF reporting rate analysis • Conclusions and status as of September 2006

  4. Summary of DDRE AnalysisTelithromycin-Associated ALF • Spectrum of injury • Per FDA review, 12 cases of telithromycin-associated ALF “clinically remarkable” • Short time-to-onset (median 4 days) • One case following first dose • Profound hepatic injury • 4 deaths • 1 transplant • Patients appeared healthy and with few confounding factors

  5. Summary of DDRE AnalysisTelithromycin-Associated ALF • Reporting rate for telithromycin-associated ALF similar ALF reporting rates for selected comparators (moxi-, gatifloxacin) given variation inherent in spontaneous adverse event reporting

  6. Summary of DDRE AnalysisTelithromycin-Associated ALF • Recommended regulatory actions consistent with actions advanced for the fluoroquinolones • Review of this analysis included • DDRE recommendations realized with addition of WARNING for ALF within approved labeling for telithromycin - June 2006

  7. Summary of DDRE AnalysisTelithromycin-Associated ALF • Set a reporting rate level (bar) for further regulatory action for telithromycin • based on experience with trovafloxacin-associated ALF • Review of this analysis included

  8. MethodsSpontaneous Adverse Event Reports

  9. Spontaneous Adverse Event Reports “MedWatch reports” Designed to detect Rare Serious Unexpected Substantial variation in quality and information report to report

  10. Spontaneous Adverse Event Reports • Fraction of incident adverse events attributable to a selected drug AND reported is unknown • Estimates of 1% to 10% commonly cited • These are likely to be overestimates • Assume variation between products

  11. Spontaneous Adverse Event Reports • Three DDRE reviews of antibiotic-associated ALF • Separated in time and by authors • Utilized generally similar case definitions • Totality of information could not exclude telithromycin as a factor in liver injury • Typical for FDA case series • Inclusion “case” criteria • Exclusion “confounding” criteria

  12. DDRE review of telithromycin-Associated ALF • Conducted January - May 2006 • Ron Wassel and Allen Brinker • Telithromycin market appearance - July 2004

  13. DDRE Review of Telithromycin-Associated ALF • Ongoing review • Initial review (June 2005) • Continued monitoring • Annals of Internal Medicine • January 2006 • Three patients who experienced serious liver toxicity following administration of telithromycin • Concern for hepatotoxicity observed in controlled clinical trials

  14. DDRE Review of Telithromycin-Associated ALF • Identified cases of: • Acute Liver Failure (ALF) • Acute Serious Liver Injury (ASLI)

  15. DDRE review of telithromycin-associated ALF • Acute Liver Failure (ALF) defined as a report describing: • diagnosis of acute “liver failure,” or • acute and severe liver injury with encephalopathy, or • liver transplant following acute illness, or • death in the setting of acute severe liver injury

  16. DDRE Review of Telithromycin-Associated ALF • Acute Serious Liver Injury (ASLI) defined as a report of: • hepatic transaminase elevations, or • hyperbilirubinemia, or • clinical jaundice • leading to hospitalization

  17. DDRE Review of Telithromycin-Associated ALF • Exclusion criteria included: • “Hearsay” reports • Infectious hepatitis • Sepsis • Pancreatitis • Rhabdomyolysis • Cancer • Selected concomitant therapies

  18. DDRE Review of Telithromycin-Associated ALF • 110 unduplicated, domestic reports of liver injury in association with telithromycin • Excluded 31 as confounded or hearsay reports • Excluded 44 as minor liver injury • 23 cases of Acute Serious Liver Injury • 12 cases of Acute Liver Failure

  19. DDRE Review of Telithromycin-Associated ALF • Causality assessment project • 2 FDA + 3 expert consultants • Review of 109 unduplicated, domestic reports of liver injury with telithromycin by Seeff • 38 cases as very likely, possible or probable • 12 cases “ALF” or “ASLI” per DDRE review • 3 cases from DILIN network • Reviewed 53 cases in total

  20. DDRE Review of Telithromycin-Associated ALF AERS # 4892304-3 51 year old female (North Carolina) PMHx-Non significant; Current meds-ASA, MVit, Vit E no prior hx of liver disease social drinker (up to 2-3 glasses wine/day) Received telithromycin after presentation to her PCP with 2 wk h/o symptoms c/w URI. Developed icterus and elevated liver enzymes, bilirubin, and PT 7 days after initiation of therapy with telithromycin; alk phos only mildly elevated. Negative for hepatitis A, B, and C. Abdominal US that showed a small, echogenic liver with ascites. One month later bili increased; listed for liver transplant. Subsequently pt readmitted with systemic symptoms and underwent liver transplant. Explanted liver was small and remarkable for massive necrosis on histologic examination. **As published within: Clay KD, Hanson JS, Pope SD, et al. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006;144(6):415-20.

  21. DDRE Review of Telithromycin-Associated ALF

  22. DDRE Review of Telithromycin-Associated ALF • Case material sufficient for addition of serious liver injury including ALF to telithromycin label • What is risk compared to similar agents? • Reporting rates • Two supporting analyses

  23. Pharmacoepidemiology • Reporting rates • Drug-against-drug comparisons • Observed versus expected comparisons

  24. Pharmacoepidemiology • Reporting rates calculated as: Spontaneous cases of selected event ----------------------------------------------------------- exposure or utilization • Expressed as: • Cases per million Rx, per 10 million Rx • Incidence density (cases per unit person-time) • Typically restricted to cases that arise during oral (ambulatory) therapy.

  25. Pharmacoepidemiology • Spontaneous reports data offer limited insight into population risk • Reporting rates are not incidence rates • Have been used in addition to other data to support previous regulatory actions by the agency • Large differences in reporting rate ratios may support differential in risk

  26. Pharmacoepidemiology • Drug-against-drug reporting rate comparisons require very similar drug products • time on market • Assumption that reporting practices are similar for similar drug products over the observed reporting period.

  27. Relevant Case Studies Including Reporting Rate Comparisons and Regulatory Recommendations • ALF in association with trovafloxacin • ALF in association with moxifloxacin, gatifloxacin, and levofloxacin

  28. Acute Liver Failure in Association with Trovafloxacin • July 1999 • David Graham and Sarah Singer • Analysis included drug-against-drug reporting rate comparisons • trovafloxacin • levofloxacin

  29. ALF in Association with Trovafloxacin: Reporting Rate Analysis *IMS Health, National Prescription Audit Plus™, Years 1997 and 1998, Hardcopy book.

  30. Acute Liver Failure in Association with Trovafloxacin • Absolute ratio in case counts • 12:1 • Adjusted ratio in case counts (reporting rate ratio) • 39:1

  31. Acute Liver Failure in Association with Trovafloxacin • Regulatory action: June 1999 • Trovafloxacin restricted to initial therapy for in-hospital use for treatment of life and limb-threatening infections

  32. Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin • August 2004 • Sarah Singer and Allen Brinker • Analysis included drug-against-drug reporting rate comparisons • levofloxacin • moxifloxacin • gatifloxacin

  33. ALF with Moxi-, Gati-, and Levofloxacin:Reporting Rate Comparison IMS Health, National Prescription Audit Plus™, Years 1997 through September 2003, extracted July 2004.

  34. Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin • Absolute ratio in case counts • About 2:1 • Adjusted ratio in case counts (reporting rate ratio) • About 3:1

  35. Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin • Observed ALF reporting rates for these three agents appeared similar • DDRE recommended addition of ALF as a WARNING within product labeling for all fluoroquinolones

  36. Telithromycin-Associated ALF:Reporting Rate Comparison *IMS Health, National Prescription Audit Plus™, Years 1997 through September 2003, extracted July 2004. **Verispan Vector One®:National, months May 2004-April 2006, extracted May 2006.

  37. DDRE Review of Telithromycin-Associated ALF • Absolute ratio in case counts • About 2:1 • Adjusted ratio in case counts (reporting rate ratio) • About 4:1 (April 2006)

  38. DDRE Review of Telithromycin-Associated ALF • Observed reporting rates generally similar • Not consistent with trovafloxacin analysis • Absolute ratio of case count not ~12:1 • Adjusted ratio of case count not ~39:1 • Recommended regulatory actions similar to that advanced for the recent ALF-FQ review

  39. DDRE Review of Telithromycin-Associated ALF • Also noted rising trend in the cumulative telithromycin-ALF reporting rate • 12 per 10 million Rx through Dec 2005 • 17 per 10 million Rx through February 2006 • 23 per 10 million Rx through April 2006 • Liver injury was a concern pre-approval • to be addressed within Study 3014

  40. DDRE Review of Telithromycin-Associated ALF • DDRE recommended a “bar” for further regulatory actions based on ALF-reporting rate for trovafloxacin (58 per 10 million Rx) • Would not wait until: • Absolute ratio of case counts ~12:1, or • Adjusted ratio of case counts ~39:1 • As seen with ALF with trovafloxacin

  41. DDRE Review of Telithromycin-Associated ALF - Update • 13th case added in 2 QTR 06 • Reporting rate for telithromycin-associated ALF through September 2006 with: • 13 cases / 5,650,000 Rx* • 23 per 10 million Rx • Unchanged from RR observed in April 2006 *Verispan Vector One®:National, months May 2004-September 2006, extracted Nov 2006.

  42. Sanofi-Aventis Population-Based Epidemiology Studies • Received completed studies last week (early December 2006) • Pharmetrics • i3 drug safety • Review ongoing • Comments at this time preliminary

  43. Sanofi-Aventis Population-Based Epidemiology Studies • Comments (preliminary) • Both studies appear underpowered for both drug-associated ALF and serious liver injury • Medical record validation required • Done in i3 study; not done in Pharmetrics study

  44. Sanofi-Aventis Population-Based Epidemiology Studies • Comments (preliminary) • The point estimate for severe liver injury observed in the i3 study is consistent with an elevated risk for serious liver injury with telithromycin in comparison to clarithromycin. • The finding in the i3 study of an elevated risk of serious liver injury with sequential use of telithromycin and clarithromycin • deserves attention (further study) but based on 3 cases.

  45. DDRE Review of Telithromycin-Associated ALF End of Presentation Acknowledgements Jenna Lyndly, RN Ron Wassel, PharmD Melissa Truffa, PharmD Mark Avigan, MD, CM

  46. Back-up Slides Return to agenda

  47. Crude Assessment of Agreement on ALF “Case” Status between 3 Disparate DDRE Reviews of Antibiotic-Associated ALF

  48. Rx Versus Person-Time Reporting Rate Comparison • Rx-based comparisons preferred by this reviewer as: • 1 Rx = 1 Pt (in most cases) • Time to onset falls within typical treatment course for most cases • Rx-based reporting rates • Absolute difference in case counts • About 2:1 • Adjusted difference (reporting rate ratio) • About 4:1