Review of post-marketing safety of Factive (gemifloxacin)

1
Review of post-marketing safety of Factive
(gemifloxacin)
Andrew Mosholder, M.D., M.P.H. Medical Officer
Division of Drug Risk Evaluation Office of
Surveillance and Epidemiology, FDA
2
Outline

• Extent of use of gemifloxacin
• Overview of AERS data for gemifloxacin
• Non-skin adverse event reporting data
• Skin adverse events
• Special review of serious skin reports
• Conclusions

3
Extent of Use of Gemifloxacin

• Approved in 2003, launched in 2004
• Large number of drug samples given to patients
  makes estimations difficult
• Oscients estimate of exposure
• U.S. 760,000 patients
• Outside U.S. 205,000 patients
• Verispan LLC Vector One
• Total Patient Tracker estimates approximately
• 332,114 pts filled prescriptions
• Physician Drug and Diagnosis Audit estimates
• approximately 1.2 million uses
• Drug samples given to patients may account for
  some of discrepancy

Verispan Total Patient Tracker, Year 2002 -
June 2006 Aggregate Time, Extracted 8-23-06
Verispan, Physician Drug and Diagnosis Audit
(PDDA), Years 2004 - June 2006, Extracted 8-23-06
4
Postmarketing Data from AERS

• Voluntary, spontaneous reports collected through
  MedWatch system
• Useful for detecting rare but significant adverse
  drug reactions in the population post-marketing
• Subject to usual limitations of spontaneous
  reporting systems
• Under-reporting (see next slide)
• Biases in reporting
• Variable quality of information in reports
• Spontaneous reports entered in FDAs Adverse
  Event Reporting System (AERS) database
• On the MedWatch form, serious cases are those
  designated by the reporter as fatal,
  life-threatening, involving hospitalization,
  causing disability, involving a congenital
  anomaly, requiring intervention to prevent
  permanent impairment, or other (fill in blank)

5
Under-reporting of severe cutaneous reactions

• In Canada over a five year period, 250 cases of
  toxic epidermal necrolysis were admitted to
  hospital burn units, but only 25 of these were
  reported to the Canadian postmarketing
  surveillance system
• Mittman et al. Drug Saf 200427477-87

6
Overview of AERS reports for gemifloxacin (Aug
2006)

• Total of reports 960
• of serious reports 84 (8.5)
• Origin 957 US, 3 non-US
• Gender distribution 589 F, 257 M
• Age distribution 207 40, 319gt40
• Leading System Organ Class
• Skin and Subcutaneous Tissue Disorders
  (n783, 82 of total)

7
(No Transcript)
8
Gemifloxacin AERS data

• Non-cutaneous reports
• Selected events
• (As of August 2006)

9
Summary of non- skin reportsAugust 2006

• Approximately 20 (184) of all AERS reports were
  not a cutaneous reaction
• 43 with serious outcome
• Majority of the serious reports were in adult
  patients

10
Summary of non- skin reports with Serious Outcome
(n43)

• Indication for (n28)
• bronchitis 9, sinusitis 9, pneumonia 7
• Most frequently reported serious AEs
• Allergic phenomena (anaphylaxis, allergic
  reactions)
• Total 16 serious allergic event reports
  including both cutaneous and non-cutaneous
• Clostridium difficile infection, 7
• Bleeding/increased INR with warfarin, 6

11
Reports with fatal outcomesAugust 2006

• 74 yo m died with C. difficile colitis, toxic
  megacolon and sepsis, one week after completing
  gemifloxacin treatment for bronchitis
• 47 yo m died after one dose pt had renal failure
  and was candidate for dialysis no autopsy
• 33 yo m died from hemophagocytic syndrome of
  unknown etiology (also had mild rash)
• 44 yo m with dilated cardiomyopathy hx seizures
• 66 yo f with hives, photosensitivity died months
  later during a surgical procedure
• Of the above, the death from C. difficile colitis
  can be reasonably attributed to gemifloxacin
  treatment

12
Events of Interest

• Cardiac events 6
• Hepatic events 12
• Clostridium colitis 10
• Drug ineffective 31
• Drug Interactions 10
• Thrombocytopenia 3

13
Cardiac Events (n6)

• QT prolongation N1
• 46 yo F, hosp. with respiratory failure,
  hypokalemic
• Tachycardia N5
• One supraventricular tachycardia
• no ventricular tachycardia

14
Hepatic events (n12)

• Liver failure/hemophagocytic syndrome N1
• Cholestasis/Liver necrosis N1
• Hepatic steatosis N1
• Acute cholecystitis N1
• Elevation of liver enzymes N8
• Confounded by other drugs, prior history or
  disease

15
Clostridium colitis (n10)

• Clostridium colitis infection was reported in 10
  patients
• 6/10 were females
• 40 had a positive culture or toxin, or had the
  diagnosis confirmed by biopsy
• One patient died of megacolon and sepsis

16
Drug Interactions (n10)

• 7 out of 10 gemifloxacin warfarin
• Increased PT or INR
• Some with bleeding

17
Gemifloxacin AERS data

• Cutaneous manifestations reports

18
Background

• Strong signal for rash in clinical trials data
• Rash in 32 of patients treated in special study
  344 (enriched for susceptibility to rash)
• Rashes designated serious by investigator in 1
  in 1200 patients treated in clinical trials
• Purpose of postmarketing data review to expand
  upon the clinical picture of gemifloxacin
  cutaneous toxicity observed in clinical trials

19
Initial AERS Skin Events Review AERS Data
cutoff May 31, 2006

• N799 total reports
• Crude count, may include duplicates
• 83 of all AERS reports listed a skin adverse
  event
• 73 of skin events were in females
• 6 of skin events listed a serious outcome

20
Age and Gender

• Females where age/gender stated (n247), 42 of
  skin event reports from 40 years age group.
  Approximate drug use (prescriptions) for this age
  group accounted for 21.
• Males (n93), 45 of skin events were reported
  from 40 years age group. Approximate drug use
  (prescriptions) for this age group accounted for
  23.

Verispan Vector One National, 2002-2006, data
extracted July-2006
21
Time to onset of Rash

• Subset review of n291 cases coded with the
  MedDRA term Rash
• Median time to onset (when data provided) 4 d

22
Serious Outcome Cases

• Death cases already discussed
• Hospitalized cases required treatments including
  steroids, antihistamines, oxygen, and intravenous
  fluids
• Medically important cases with hypersensitivity
  component urticaria, swelling of face,
  allergic vasculitis etc. needed intervention
  with epinephrine, steroids and antihistamines
• Some with previous FQ use, history of drug allergy

23
Crude US AERS Reporting rates for serious skin
event cases (5/2006)
Product (Approval) Moxifloxacin (1999) Gatifloxacin (1999) Gemifloxacin (2003) Cefditoren (2001) Telithromycin (2004)
Estimated Rx (in 1000s) 5386 8237 363 360 5340
of AERS serious cutaneous reports 226 141 38 5 109
Reporting rates Per million RX 42 17 105 14 20
Verispan Vector One National, 1996-2006,
data extracted July-2006 First two and a half
years for telithromycin and gemifloxacin first
three years for moxifloxacin and gatifloxacin
and first 4 years for cefditoren (only 1,000
prescriptions were dispensed in 2001)
24
Addendum Review

• Data cutoff August 2, 2006

25
Addendum Review

• Individual review and analysis of U.S. AERS skin
  disorder reports with serious outcomes (8-2-06)
• Special attention to cases that might represent
  known severe drug reactions
• Stevens-Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• Allergic/hypersensitivity reactions
• Exclusions
• Cases designated serious by reporter but which
  did not seem to warrant that classification on
  review (e.g., severe rash)
• Cases in which the only skin events were not
  relevant to assessment of cutaneous drug
  reactions (e.g., petechiae)
• Drugs
• Gemifloxacin
• Cefditoren

26
Individual review of serious skin events Results
Drug 2002-6/2006 TPT total patients PDDA uses 2002-6/2006 Numbers of U.S. AERS reports per manual review Numbers of U.S. AERS reports per manual review Numbers of U.S. AERS reports per manual review Numbers of U.S. AERS reports per manual review Numbers of U.S. AERS reports per manual review
Drug 2002-6/2006 TPT total patients PDDA uses 2002-6/2006 Definite SJS Possible SJS Serious allergic skin Other serious skin All serious skin
Gemifloxacin 332,114 1,183,000 0 3 9 12 24
Cefditoren 512,156 1,412,000 0 0 3 0 3
Verispan Total Patient Tracker, Year 2002 -
June 2006 Aggregate Time, Extracted 8-23-06
Verispan, Physician Drug and Diagnosis Audit
(PDDA), Years 2004 - June 2006, Extracted 8-23-06
27
Selected case descriptions

• 37 yo M completed 5 d treatment for
  sinusitis/bronchitis. On day 6 morbilliform
  rash, sore throat, periorbital swelling, fever
  hospitalized and received antihistamine therapy.
  Dx dermatitis medicamentosus
• 40 yo M after one dose for sinusitis anaphylaxis
  with difficulty breathing, rash, facial and oral
  swelling, cough, dyspnea, hives, light headed
  treated in ER with epinephrine, antihistamines,
  prednisone
• 44 yo M completed 5 d treatment for sinusitis
  day 6 dyspnea, trouble swallowing, confusion,
  progressive macular rash hospitalized and
  treated with IV steroid and antihistamine
• 20s F, one day after completing 5 day treatment
  for unspecified respiratory tract infection, was
  hospitalized for rash. Treatment and outcome ?.

28

U.S. AERS reports of seriouscutaneous events per million PDDA occurrences, by drug (as of 8/2/06) U.S. AERS reports of seriouscutaneous events per million PDDA occurrences, by drug (as of 8/2/06) U.S. AERS reports of seriouscutaneous events per million PDDA occurrences, by drug (as of 8/2/06) U.S. AERS reports of seriouscutaneous events per million PDDA occurrences, by drug (as of 8/2/06) U.S. AERS reports of seriouscutaneous events per million PDDA occurrences, by drug (as of 8/2/06)
Drug Possible SJS Serious allergic rash Other serious skin All serious skin
Gemifloxacin 2.5 3.4 5.1 11.0
Cefditoren 0 2.1 0 2.1
29
Addendum review of AERS serious skin reports
Comments

• In the postmarketing environment, as in the
  clinical trials, gemifloxacin is associated with
  serious skin adverse events
• Serious allergic responses with cutaneous
  manifestations
• Rashes requiring hospital treatment (even without
  meeting criteria for SJS or TEN)
• Possible SJS cases?
• Many reports lacked critical clinical information
  that might have permitted more definitive
  classification

30
Addendum review of AERS serious skin reports
Comments, cont.

• Serious skin events in the U.S. were reported at
  a higher rate for gemifloxacin than for the
  comparator drug cefditoren, in both the initial
  crude reporting rate analysis and the analysis
  following individual case review
• Such comparisons must be made very cautiously
  because of uncertainties in both the numerator
  and denominator

31
Review of Postmarketing Data for Gemifloxacin
Conclusions

• Cefditoren has been marketed in Japan since 1994
  and has been associated with SJS and TEN in
  foreign postmarketing data
• Slightly more U.S. patients have used cefditoren
  compared to gemifloxacin
• Thus, absence of U.S. reports of definite SJS/TEN
  with gemifloxacin provides only limited
  reassurance, given similar absence of U.S.
  reports for cefditoren to date

32
Review of Postmarketing Data for Gemifloxacin
Conclusions

• 1 mil or fewer patients exposed to gemifloxacin
  to date
• Because of short duration of exposure with a
  typical course of treatment, even a single case
  of SJS would be more than expected

33
Conclusions

• Important adverse events associated with
  gemifloxacin in the postmarketing environment
  thus far include
• Serious allergic reactions
• Clostridium colitis
• Rashes which require hospitalization
• Others
• SJS?
• Increased INR with coumadin?
• Thrombocytopenia?

34
Conclusions continued

• Post-marketing data do not give us assurance that
  our concerns regarding cutaneous toxicity should
  be any less when larger patient populations are
  exposed.
• The magnitude of the benefit gained from the use
  of gemifloxacin for the indication under
  discussion (Acute Bacterial Sinusitis) needs to
  be clearly defined to weigh against the magnitude
  of this risk associated with gemifloxacin.

35
Acknowledgements

• Evelyn R. Farinas, R.Ph., M.G.A.
• Melissa Truffa, R.Ph.
• Syed Rizwanuddin Ahmad, M.D., M.P.H.
• Allen Brinker, M.D., M.S.
• Lois La Grenade, M.D., M.P.H.
• Brenda Marques, Pharm.D.
• Laura A. Governale, Pharm.D., MBA
• Vicky Borders-Hemphill, Pharm.D.
• Carol Pamer, R.Ph.
• Rosemary Johann-Liang, M.D.