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Antiviral Drug Products Advisory Committee Meeting. NDA 21-266 voriconazole tablets NDA 21-267 voriconazole for injection Rosemary Tiernan, MD, MPH. Division of Special Pathogen and Immunologic Drug Products Voriconazole Review Team. Jouhayna Saliba, RPh Marc Cavaillé-Coll, MD, PhD

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antiviral drug products advisory committee meeting
Antiviral Drug Products Advisory Committee Meeting

NDA 21-266 voriconazole tablets

NDA 21-267 voriconazole for injection

Rosemary Tiernan, MD, MPH

division of special pathogen and immunologic drug products voriconazole review team
Division of Special Pathogen and Immunologic Drug ProductsVoriconazole Review Team

Jouhayna Saliba, RPhMarc Cavaillé-Coll, MD, PhD

Gene W. Holbert, PhD Norman R. Schmuff, PhD

Owen G. McMaster, PhD Kenneth L. Hastings, PhD

Linda L. Gosey, MS Shukal Bala, PhD

Philip M.Colangelo, PharmD, PhD Funmi O. Ajayi, PhD

Joette M. Meyer,PharmD Wiley A. Chambers, MD

Cheryl A. Dixon, PhD Karen M. Higgins, ScD

M. Regina Alivisatos, MD Edward M. Cox, MD, MPH

Rosemary Johann-Liang, MD Rigoberto A. Roca, MD

John H. Powers III, MD Rosemary Tiernan, MD, MPH

indications requested in the nda
Indications Requested in the NDA

Treatment of invasive aspergillosis

Empiric antifungal therapy of febrile neutropenic patients

Treatment of:

-candida esophagitis

-serious candida infections

-serious fungal infections due to Fusarium and Scedosporium spp.

-serious fungal infections in patients refractory or intolerant to other therapy

fda presentation
FDA Presentation

Treatment of Invasive Aspergillosis

Empiric Antifungal Therapy of Febrile Neutropenic Patients

Clinical Safety

Questions to the Advisory Committee

treatment of invasive aspergillosis

Treatment of Invasive Aspergillosis

Study 307/602

Study 304 and

Historical Control Study 1003

treatment of invasive aspergillosis6
Treatment of Invasive Aspergillosis
  • Study 307/602
    • Randomized, controlled, open-label, initial therapy
    • Blinded Data Review Committee
    • voriconazole vs. amphotericin B followed by “other licensed antifungal therapy” (OLAT)
  • Study 304
    • Uncontrolled study of primary and salvage cases
    • Expert Panel
    • Retrospectively designed historical control
study 307 602
Study 307/602
  • MITT
    • voriconazole (N = 144)
    • amphotericin B (N = 133)
  • Patient Characteristics
    • White male, hematologic malignancies, pulmonary site
  • Switch to OLAT
    • voriconazole 36.1%
    • amphotericin B 80.5%
study 307 602 primary efficacy endpoint
Study 307/602Primary Efficacy Endpoint
  • Satisfactory Response at Week 12 (MITT)
    • voriconazole 76/144 52.8%
    • ampho B 42/133 31.6%
      • 95% CI stratified by protocol (9.6, 33.6)
study 307 602 additional efficacy analyses
Study 307/602Additional Efficacy Analyses
  • Not allowing DRC to upgrade investigator assessment
    • vori 46.5% vs. ampho B 29.3%
  • “Modified Week 12”
    • vori 45.1% vs. ampho B 31.6%
  • Week 16 follow-up
    • vori 45.8% vs ampho B 33.1%
study 307 602 survival
Study 307/602Survival
  • Probability of Survival at Day 84
    • vori 0.708
    • ampho B 0.579
study 304
Study 304
  • Expert Evaluable Population
    • Overall N = 112
      • Primary therapy N = 58
      • Salvage therapy N = 54
  • Patient Characteristics
    • White male, hematologic malignancies, pulmonary site, European population
study 30412
Study 304
  • Expert Global Response at EOT (expert evaluable population)
    • Overall 55/112 49.1%
      • Primary 35/58 60.3%
      • Salvage 20/54 37.0%
historical control hc study 1003
Historical Control (HC)Study 1003
  • Substantial effort to provide the most comparable population to primary therapy patients in Study 304
    • primary therapy was <5 days prior antifungal therapy
  • Matched on certainty of diagnosis, underlying disease, and site of infection
study 304 historical control study 1003
Study 304/ Historical Control Study 1003
  • Global Response
    • Study 304 vori 26/50 52.0%
    • Historical Control 23/92 25.0%
  • Probability of Survival at Day 90
    • Study 304 vori 0.554
    • Historical Control 0.417
historical control issues
Historical Control Issues
  • Patient populations
    • Study 304 only in Europe
    • Historical Control both in Europe and US
    • Global Response
        • US HC 11/51 21.6%
        • EU HC 12/41 29.3%
        • Study 304 vori 26/50 52.0%
    • Probability of Survival at Day 90
        • US HC 0.290
        • EU HC 0.573
        • Study 304 vori 0.554
historical control issues cont
Historical Control Issues (cont.)
  • Duration of treatment
    • longer for voriconazole treated patients
  • Difference in inclusion/exclusion criteria
    • which could possibly allow for sicker patients in the HC
aspergillosis summary
Aspergillosis Summary
  • HC good effort but still concerns about comparability of the study populations
  • Study 304 results are used to support the randomized controlled study
  • Study 307/602showed
    • Non-inferior Global Response
      • Statistically superior
    • Survival Benefit
clinical safety

Clinical Safety

Rosemary Tiernan, MD, MPH

clinical safety19
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
clinical safety20
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
ocular safety
Ocular Safety
  • Pre-clinical studies
  • Incidence in clinical studies is 1 out of every 3 subjects
  • Symptoms

Decreased vision, photophobia, altered color perception and ocular discomfort

  • Unknown Mechanism
  • No human histopathology
  • Ocular biomicroscopy has not detected ocular lesions
ocular safety22
Ocular safety

Results from study 150-1004

  • Effects noted in
    • ERG
    • Farnsworth-Munsell 100 hue test (color vision)
    • Humphrey Perimetry (visual field)
  • Drug effect on both rod and cone function
  • Decreased vision on day 1 and continued through 28 days of therapy
  • Testing 2 weeks after the end of treatment demonstrated return to normal function
ocular safety23
Ocular Safety

Additional issues regarding use of this drug

-re-challenge or re-treatments

-ocular development in pediatric patients

-patients with underlying eye disease

-treatment beyond 28 days

clinical safety24
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
cardiac safety
Cardiac Safety
  • In vitro data
  • In vivo data
  • Clinical data
    • One sudden death
cardiac safety26
Cardiac Safety
  • Clinical data
    • Adverse Events
      • Cardiac arrhthymias, CHF, cardiac arrests
    • Discontinuations
clinical safety27
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
hepatic safety summary
Hepatic Safety Summary
  • Phase I/II Studies
    • Positive dose (exposure) response with ALT and AST
  • Phase III Comparative Studies
    • Hepatic adverse events and ALT & AST abnormalities were more frequent with voriconazole than fluconazole
    • Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied
    • Serious hepatic adverse events reported more frequently in voriconazole treated patients.
clinical safety29
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
slide30
Rash
  • Difficulties in assessment of rash include:
    • Concomitant medications that can also cause rash
    • Concomitant medications can affect the type or severity of skin exanthem observed
    • Underlying conditions such as GVHD
slide31
Rash

Observed in 18.6% of patients on voriconazole in therapeutic studies program

  • Most rashes mild to moderate
  • No major differences in discontinuations for rash
  • 4 non-fatal cases of Stevens-Johnson
clinical safety32
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
drug interactions with voriconazole in vitro metabolism
Drug Interactions with VoriconazoleIn Vitro Metabolism
  • Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4
  • Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4
      • CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole
  • Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa)
      • HIV-PI, NNRTI, and Immunosuppressant Drugs
drug interactions with voriconazole in vivo metabolism
Drug Interactions with VoriconazoleIn Vivo Metabolism
  • Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction
    • Example: HIV-PI and NNRTI drugs not studied in vivo
      • CYP3A4 inhibitors and/or inducers
      • Exception: Indinavir  no significant interaction
  • The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber
clinical safety35

Clinical Safety

Rosemary Tiernan, MD, MPH

clinical safety36
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
clinical safety37
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
ocular safety38
Ocular Safety
  • Pre-clinical studies
  • Incidence in clinical studies is 1 out of every 3 subjects
  • Symptoms

Decreased vision, photophobia, altered color perception and ocular discomfort

  • Unknown Mechanism
  • No human histopathology
  • Ocular biomicroscopy has not detected ocular lesions
ocular safety39
Ocular safety

Results from study 150-1004

  • Effects noted in
    • ERG
    • Farnsworth-Munsell 100 hue test (color vision)
    • Humphrey Perimetry (visual field)
  • Drug effect on both rod and cone function
  • Decreased vision on day 1 and continued through 28 days of therapy
  • Testing 2 weeks after the end of treatment demonstrated return to normal function
ocular safety40
Ocular Safety

Additional issues regarding use of this drug

-re-challenge or re-treatments

-ocular development in pediatric patients

-patients with underlying eye disease

-treatment beyond 28 days

clinical safety41
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
cardiac safety42
Cardiac Safety
  • In vitro data
  • In vivo data
  • Clinical data
    • One sudden death
cardiac safety43
Cardiac Safety
  • Clinical data
    • Adverse Events
      • Cardiac arrhthymias, CHF, cardiac arrests
    • Discontinuations
clinical safety44
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
hepatic safety summary45
Hepatic Safety Summary
  • Phase I/II Studies
    • Positive dose (exposure) response with ALT and AST
  • Phase III Comparative Studies
    • Hepatic adverse events and ALT & AST abnormalities were more frequent with voriconazole than fluconazole
    • Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied
    • Serious hepatic adverse events reported more frequently in voriconazole treated patients.
clinical safety46
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
slide47
Rash
  • Difficulties in assessment of rash include:
    • Concomitant medications that can also cause rash
    • Concomitant medications can affect the type or severity of skin exanthem observed
    • Underlying conditions such as GVHD
slide48
Rash

Observed in 18.6% of patients on voriconazole in therapeutic studies program

  • Most rashes mild to moderate
  • No major differences in discontinuations for rash
  • 4 non-fatal cases of Stevens-Johnson
clinical safety49
Clinical Safety
  • Focus on 5 specific areas:
    • Ocular safety
    • Cardiac safety
    • Hepatic safety
    • Rash
    • Drug interactions
drug interactions with voriconazole in vitro metabolism50
Drug Interactions with VoriconazoleIn Vitro Metabolism
  • Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4
  • Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4
      • CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole
  • Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa)
      • HIV-PI, NNRTI, and Immunosuppressant Drugs
drug interactions with voriconazole in vivo metabolism51
Drug Interactions with VoriconazoleIn Vivo Metabolism
  • Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction
    • Example: HIV-PI and NNRTI drugs not studied in vivo
      • CYP3A4 inhibitors and/or inducers
      • Exception: Indinavir  no significant interaction
  • The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber