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Telithromycin-Associated Hepatotoxicity Allen Brinker, MD, MS Epidemiology Team Leader Division of Drug Risk Evaluation (DDRE) Office of Surveillance and Epidemiology (OSE)
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
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
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
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
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
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
Spontaneous Adverse Event Reports “MedWatch reports” Designed to detect Rare Serious Unexpected Substantial variation in quality and information report to report
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
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
DDRE review of telithromycin-Associated ALF • Conducted January - May 2006 • Ron Wassel and Allen Brinker • Telithromycin market appearance - July 2004
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
DDRE Review of Telithromycin-Associated ALF • Identified cases of: • Acute Liver Failure (ALF) • Acute Serious Liver Injury (ASLI)
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
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
DDRE Review of Telithromycin-Associated ALF • Exclusion criteria included: • “Hearsay” reports • Infectious hepatitis • Sepsis • Pancreatitis • Rhabdomyolysis • Cancer • Selected concomitant therapies
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
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
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.
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
Pharmacoepidemiology • Reporting rates • Drug-against-drug comparisons • Observed versus expected comparisons
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.
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
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.
Relevant Case Studies Including Reporting Rate Comparisons and Regulatory Recommendations • ALF in association with trovafloxacin • ALF in association with moxifloxacin, gatifloxacin, and levofloxacin
Acute Liver Failure in Association with Trovafloxacin • July 1999 • David Graham and Sarah Singer • Analysis included drug-against-drug reporting rate comparisons • trovafloxacin • levofloxacin
ALF in Association with Trovafloxacin: Reporting Rate Analysis *IMS Health, National Prescription Audit Plus™, Years 1997 and 1998, Hardcopy book.
Acute Liver Failure in Association with Trovafloxacin • Absolute ratio in case counts • 12:1 • Adjusted ratio in case counts (reporting rate ratio) • 39:1
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
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
ALF with Moxi-, Gati-, and Levofloxacin:Reporting Rate Comparison IMS Health, National Prescription Audit Plus™, Years 1997 through September 2003, extracted July 2004.
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
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
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.
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)
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
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
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
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.
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
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
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.
DDRE Review of Telithromycin-Associated ALF End of Presentation Acknowledgements Jenna Lyndly, RN Ron Wassel, PharmD Melissa Truffa, PharmD Mark Avigan, MD, CM
Back-up Slides Return to agenda
Crude Assessment of Agreement on ALF “Case” Status between 3 Disparate DDRE Reviews of Antibiotic-Associated ALF
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