# Presentation: 704943

## Antiviral Drug Products Advisory Committee Meeting

- NDA 21-266	voriconazole tablets
- NDA 21-267	voriconazole for injection
- 				Rosemary Tiernan, MD, MPH

**Notes:**
Good morning
My name is Rosemary Tiernan and I work in the Division of Special Pathogen and Immunologic Drug Products
Today,  I’d like to begin the FDA presentation of our review of NDA 21-266 and 21-267
voriconazole tablets and  
voriconazole for injection.

## Division of Special Pathogen and Immunologic Drug ProductsVoriconazole Review Team

- Jouhayna Saliba, RPh		     Marc 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

**Notes:**
Before we begin the presentation, I would just like to acknowledge the efforts of all of the members of the voriconazole review team who are listed on this slide.

I would like to especially thank Drs. Regina Alivisatos, Dr. Rosemary Johann-Liang and Dr. Edward Cox for their help in this review. 

## 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

**Notes:**
The purpose of this advisory committee is to specifically discuss the indications of  treatment of invasive aspergillosis and the empiric antifungal therapy of febrile neutropenic patients.
However,  it is important to note the other indications submitted in this voriconazole NDA and listed on this slide. 
We are in general agreement with Pfizer,  that voriconazole is efficacious in the treatment of  Candida albicans esophagitis and  in the treatment of serious fungal infections due to Fusarium and Scedosporium apiospermum. 
Efficacy in these areas should be taken into account when considering the indication of empiric antifungal therapy of febrile neutropenic patients.
The serious candida infection study is still ongoing and the study of  serious fungal infections in patients refractory or intolerant to other therapy is still under review.

## FDA Presentation

- Treatment of Invasive Aspergillosis
- Empiric Antifungal Therapy of Febrile Neutropenic Patients
- Clinical Safety
- Questions to the Advisory Committee

**Notes:**
Our presentation will cover the following areas:
I’ll summarize our review of study 307/602 and study 304 with the historical control which were submitted to support the indication of treatment of invasive aspergillosis.
Dr. John Powers will then discuss study 603 which was submitted for the indication of empiric antifungal therapy of febrile neutropenic patients.
 Then, I will return  to summarize specific areas of  clinical safety.
Finally, Dr. Goldberger will  present the questions to the advisory committee.

## Treatment of Invasive Aspergillosis

- Study 307/602
- Study 304 and
- Historical Control Study 1003

## 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

**Notes:**
The basis of evidence to support the treatment of invasive aspergillosis was supported by  two trials---study 307/602 and study 304. Study 307/602 was a randomized, controlled, open-label, initial therapy study of voriconazole vs Amphotericin B-- both of which could be followed by other licensed antifungal therapy (OLAT). 
Study 304 was an uncontrolled study of voriconazole use in primary and salvage patients conducted in Europe. A retrospectively designed historical control study(study 1003) was used as the comparator for study 304.  Cases were obtained from both the United States and Europe.
The Division is in general agreement with the Applicant’s presentation of the aspergillosis data.  The goal of this presentation is to  highlight the main aspects of the aspergillosis trials.

## 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%

**Notes:**
The Modified intent to treat or MITT population (the primary analysis population) consisted of 144 voriconazole subjects and 133 amphotericin B subjects. These subjects were primarily white males, with hematologic malignancies as their underlying disease and pulmonary sites for their aspergillus infection. 
The studies were designed to allow a switch from randomized therapy to OLAT.  More Amphotericin B patients switched to OLAT when compared to patients randomized to voriconazole.
Details of the OLAT regimen for the amphotericin B arm were reviewed and felt to represent adequate antifungal therapy.
Backup slide D/C IRT
 Studies 307/602 were identical protocols (entry criteria, treatment regimens and study procedures and outcome assessments)  Umbrella analysis plan powered to meet specified objectives and preserve study integrity.Blinded DRC for certainty of DX, global response to RX  and cause of death  Characterize OLAT---use of Cancidas. Details regarding  reasons for the amphotericin B switch to OLAT and the type of OLAT treatment utilized thereafter were reviewed.  Major reason for ampho B patients to switch from IRT was elevated creatinine.  OLAT regimens were  felt to constitute adequate antifungal regimen.

## Study 307/602Primary 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)

**Notes:**
Recall that the  primary efficacy endpoint was outcome at week 12 as assessed by the Data review committee (DRC) and satisfactory response rates of 52.8% for voriconazole and 31.6% for the Amphotericin B regimen were seen.
The 95% CI for the difference in satisfactory response rates, stratified by protocol, was (9.6, 33.6).  Since the lower limit of the confidence interval was greater than –20%, voriconazole is considered to be non-inferior to the ampho B regimen and, in this case, the 95% confidence interval does not include zero and, thus, voriconazole is statistically superior.

## Study 307/602Additional 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%

**Notes:**
The Division performed 3 additional analyses to assess the robustness of the previous results.
 In the Process Plan and Operating Procedures for the Data Review Committee, it was possible to upgrade investigator assessment of response. Consequently, the Division performed a conservative analysis which did not allow the DRC to upgrade the investigator assessment.  
In the second analysis, “Modified Week 12” the Division  treated voriconazole patients who switched to OLAT as “failures”, with the exception of a few patients.  These few patients had completed at least 84 days of  voriconazole treatment with a satisfactory response and were then placed on prophylaxis. 
In addition, response at week 16 was assessed.
All of these analyses, demonstrate that the response of voriconazole  was consistently greater than the response of the amphotericin B regimen.

## Study 307/602Survival

- <footer>

- <date/time>

**Study 307/602****Survival**

**Probability of Survival at Day 84**
**vori  ****	****	****0.708**
**ampho B ****	****0.579**

**Notes:**
Survival through day 84 was a secondary endpoint.  Voriconazole was shown to have a survival advantage compared to the amphotericin B regimen. 

## 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

**Notes:**
In study 304:
The expert evaluable population (the primary analysis population) consisted of 112  voriconazole subjects.  The experts classified 58 patients into the primary therapy group and 54 patients as salvage therapy.  
As assessed by the experts, a patient was considered to be on  primary voriconazole therapy if they  received less than 10 days of adequate antifungal treatment.  All other patients were considered to be on salvage therapy.
As seen in study 307/602, these subjects were primarily white males, with hematologic malignancies as their underlying disease and pulmonary sites for their aspergillus infection. This study was conducted solely in Europe.
***As assessed by the experts,  patients were descibed as “salvage” if they had received > 10 mg/kg of amphotericin B or 40 mg/kg liposomal amphotericin B or 400 mg/day of itraconazole per day for 10 days and a diagnosis of definite aspergillosis (did not always have a definite diagnosis however).
Primary therapy received less than the aforementioned doses of amphotericin B, liposomal amphotericn B and itraconazole and a diagnosis of definite or probable.

## 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%

**Notes:**
The primary endpoint was the expert’s global response at end of treatment.
The Overall satisfactory response rate was 49.1%.
A satisfactory response of 60.3% was seen in the primary patients and a satisfactory response of  37% was seen in the salvage patients.

Define Global Response

## 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

**Notes:**
Since study 304 was a non-comparative study,  the Division requested that a retrospective historical control study be performed to act as the comparison group for the primary treated patients in study 304.
It should be noted that for this comparison,  the definition of primary therapy  was less than 5 days of prior antifungal therapy.	
In order to provide the most comparable population, patients were matched on a 2:1 basis by the prognostic factors of:
certainty of diagnosis, underlying disease and site of infection.

## 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

**Notes:**
The best matched, less than 5 day prior therapy population, consisted of 50 study 304 voriconazole subjects and 92 historical control patients. 
Satisfactory global response rates were 52% for study 304 voriconazole patients and 25% for the historical control patients. 
Probability of survival was  0.554 for Voriconazole and 0.417 for the historical control.

Percentage of ampho B and liposomal ampho B in the historical control?

## 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**

**Notes:**
Even though the Applicant took substantial efforts in the design of the historical control, all of the inherent potential biases were not adequately controlled.  
Differences in patient populations can impact the success rate of treatment,  if patient care and support differ across countries.
Study 304 was conducted exclusively in Europe, whereas the historical control included both European and US patients.
Satisfactory global response and probability of survival were  lower in the US historical control population. This may be due to the fact that the majority of the US historical control patients had bone marrow transplants or other underlying diseases. Whereas the majority of the European historical control patients and the study 304 voriconazole  patients had hematologic malignancies as their underlying disease. 
When these US HC patients are removed, the difference in global response remains but the difference in survival between the European historical controls and the study 304 voriconazole group become smaller.

## 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

**Notes:**
Additional issues regarding the historical control included:
Differences in the total days of treatment---- with the voriconazole treated group having a longer duration of therapy.
Differences in the inclusion and exclusion criteria --- which could possibly allow for sicker patients to be included in the historical control. 
All in all, these differences in study populations could act to predispose the historical control  to lower success rates and the voriconazole  treated group to have higher success rates----- independent of treatment with voriconazole.

Data review committee was not blinded --look at Judy Staffa’s analysis
Explain this 

## 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 307/602** showed
- Non-inferior Global Response
- Statistically superior
- Survival Benefit

**Notes:**
In summary, the historical control trial, study 1003, was a good effort ---but concerns still persist regarding the comparability of study populations.
Study 304 results are being used to support the randomized controlled study 307/602.
Study 307/602 demonstrated a non-inferior global response and actually met the definition of statistical superiority as well. In addition, voriconazole demonstrated a survival benefit.
We applaud Pfizer’s efforts and success at being able to complete the randomized controlled aspergillosis trial!

## Clinical Safety

- Rosemary Tiernan, MD, MPH

## Clinical Safety

- Focus on 5 specific areas:
- Ocular safety
- Cardiac safety
- Hepatic safety
- Rash
- Drug interactions

**Notes:**
 The safety section of  this presentation will focus on the following 5 areas:
ocular , cardiac  and hepatic safety
 rash and drug interactions.

## Clinical Safety

- Focus on 5 specific areas:
**Ocular  safety**
- Cardiac safety
- Hepatic safety
- Rash
- Drug interactions

## 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

**Notes:**
  In the pre-clinical evaluation of this drug, pharmacology- toxicology studies have demonstrated that voriconazole produced dose-related effects in the ERG of dogs exposed to voriconazole. The voriconazole plasma levels which produced these results in dogs were similar to those plasma levels achieved in human studies.  Histopathology results for female rats who received 50mg/kg voriconazole (equivalent to 8 mg/kg IV) demonstrated mild thinning of the outer layer of retina at 24 months .
During the clinical trials, the incidence of visual symptoms was 1 out of every 3 subjects.
The symptoms included decreased vision, photophobia, altered color perception and ocular discomfort.
The exact mechanism underlying these visual symptoms is unknown.
There is no human histopathology data.
Ocular biomicroscopy has not detected ocular lesions.

## 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

**Notes:**
Results from study 150-1004, a study in which Voriconazole was given to healthy volunteers at a dose of 400 mg q 12 hrs for one day and then 300 mg q 12 hrs for 27 days, are listed as follows:
Effects were noted in the ERG, Farnsworth-Munsell 100 hue test (color vision) and Humphrey Perimetry studies (visual field).
Voriconazole affects both rod and cone function.
Decreased visual function is present on the first day and continued through 28 days of therapy ---at 14 days after the end of therapy the vision returns to normal function.

## 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

**Notes:**
Additional issues regarding the use of  this drug include:
--there is insufficient information to  predict what the ophthalmologic effects will be in patients who are either re-challenged or re-treated with voriconazole
--ultimately, if this drug is considered for use in children less than 9 years of age, we do not have sufficient data to predict the effect of voriconazole on the eye which is not yet fully developed.
A careful risk/benefit assessment will have to be made when considering the use of voriconazole in patients with underlying eye disease such as CMV retinitis .
We can not predict that visual changes will resolve--- if this drug is used beyond 28 days of therapy.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
**Cardiac safety**
- Hepatic safety
- Rash
- Drug interactions

## Cardiac Safety

***In vitro***** data**
***In vivo***** data**
**Clinical data**
- One sudden death

**Notes:**
 In vitro studies of this drug,  demonstrated no major effects for voriconazole in HERG channel studies or in the dofetilide studies when compared to ketoconazole. In vivo data demonstrated that, in dogs, high doses of voriconazole produced arrhythmia, PVC’s and prolonged QT interval. 
As already discussed by the Applicant, there was one sudden death in the phase 3 clinical trials for which a role for voriconazole could not be excluded.  In response to this event investigators were asked to monitor patients with telemetry if the patient had underlying heart disease and was to receive intravenous voriconazole. The Applicant planned to further investigate the effect of  3 intravenous doses of voriconazole (4 mg/kg, 8 mg/kg and 12 mg/kg) on QTc interval in healthy subjects aged 18-65 years. However,  this study was terminated because of anaphylactoid reactions.  The Applicant has conducted a thorough investigation and no causative factor has been found for these anaphylactoid reactions. The Applicant has committed to complete a similar study but utilizing the oral preparation of voriconazole.

## Cardiac Safety

**Clinical data**
- Adverse Events
- Cardiac arrhthymias, CHF, cardiac arrests
- Discontinuations

**Notes:**
In the controlled clinical trials, studies 307/602, 603 and 305, no major differences between voriconazole and controls  have been detected in the adverse event reporting or rate of discontinuations for cardiac events such as arrhythmias and congestive heart failure. However, the voriconazole arm in study 307/602 did have more grade 3 cardiac adverse events (27/ 196  vs 13/185 ) and a role for the drug could not be excluded. It is important to note that these clinical studies were not specifically designed to assess the risk to develop an arrhythmia in a population who may be on multiple medications, have underlying heart disease and may also be on anti-arrhythmic drugs.
Consequently, warnings may be necessary regarding the use of this drug in patients with underlying heart disease or in patients on concomitant anti-arrhythmic drugs. When this drug is used in patients with underlying heart disease, consideration should be given to employ cardiac monitoring during the period when the patient is receiving intravenous medication.
However, the voriconazole arm did have more cardiac arrests and episodes of syncope  noted in trial 307/602 (6/196 3.1% vs 2/185 1.1% and 5/196 2.6% to 1/185  0.5%).  A role for the drug could not be excluded.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
**Hepatic safety**
- Rash
- Drug interactions

## 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.

**Notes:**
Pfizer has already presented information on the hepatic safety of voriconazole.  In general, we are in agreement with the information as presented by Pfizer.
Our conclusions are similar, in that the data from the Phase I/II studies support that there is a positive dose or exposure response relationship between  voriconazole and transaminase increases and a possible association with alkaline phosphatase increases.  In the phase III comparative studies, hepatic adverse events and abnormalities of transaminases and alkaline phosphatase  were more frequent among patients taking voriconazole than fluconazole.  The hepatic adverse events were similar between voriconazole and its amphotericin B comparators with the exception of bilirubin elevations which were more frequent among those treated with amphotericin B formulations. While the numbers are small, serious adverse events were reported more frequently among patients receiving voriconazole in the phase III comparative studies.  Regarding hepatic failure deaths---Pfizer has already described  the findings of the expert panel of hepatologists who reviewed those specific deaths.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
- Hepatic safety
**Rash**
- Drug interactions

## 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

**Notes:**
We agree with the Applicant that rash is a potential hazard associated with the use of this drug.
Patients in the clinical studies were often on concomitant medications that could either cause rash themselves or concomitant medications such as antihistamines and steroids that might affect the type and severity of skin symptoms observed.Conditions such as GVHD can also make it difficult to completely assess a causative role for study drug in the development of rash.
GVHD incidence :
Voriconazole	4.1 % in 307/602 	and 	2.9% in 603
Comparator	2.2 % in 307/602 	and 	1.4% in 603
Only 4 skin biopsy results submitted
Grade 3 rashes
307/602	Vori 5/196	Ampho B	1/185
305	Vori 3/200	Flu	1/191
603	Vori 12/421	Ampho B	15/428

## 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

**Notes:**
In the controlled clinical trials, rash was observed in voriconazole study patients at a rate similar to that of its comparators.  Overall, rash develops  in 18.6% of patients receiving voriconazole. 
The applicant has already presented several descriptions of the various types of skin exanthems observed. No specific rash  is characteristic of voriconazole exposure. There is insufficient information at this time to conclude that the rash is due to photosensitivity.
Most rashes were of mild to moderate severity.
There were no major differences in the discontinuations for rash between voriconazole and its comparators.
However, the Applicant has already described  4 non-fatal cases of Stevens Johnson  syndrome which were noted in patients on voriconazole. Two of these cases  developed rash, discontinued drug and then re-exacerbated  upon  re-challenge (304- 01370816 and 604-10346186)
TEN ampho B on 603-90441462

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
- Hepatic safety
- Rash
**Drug interactions**

## Drug Interactions with VoriconazoleIn 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

**Notes:**
Finally, we will address the safety implications of drug interactions with voriconazole.  In vitro metabolism studies performed with human hepatic microsomes and genetically engineered cell lines indicate that:
- voriconazole is both a substrate and an inhibitor of three cytochrome P450 enzymes:  CYP2C19, CYP2C9, and CYP3A4.
	Rose’s Notes:
	CYP2C19  omeprazole
	CYP2C9  phenytoin, warfarin
	CYP3A4  tacrolimus, cyclosporine, PI, NNRTI
-  the substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4.
	- for comparison, the potency of voriconazole as an in vitro 	inhibitor of CYP3A4 appears to be weaker than ketoconazole 	and itraconazole
- the in vitro potency of voriconazole to inhibit the metabolism of CYP3A4 substrates (and for CYP3A4 substrates to inhibit voriconazole) varies among classes of drugs, including:
	- HIV protease inhibitors
	- non-nucleoside reverse transcriptase inhibitors
	and immunosuppressant drugs

-

## Drug Interactions with VoriconazoleIn 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

**Notes:**
The Applicant has evaluated representative substrates/inhibitors/inducers of the three CYP enzymes both in vitro and in vivo.  However, it is not possible to evaluate every potential drug interaction.
To illustrate, representative protease inhibitors and non-nucleoside reverse transcriptase inhibitors were studied in vitro, but not in vivo.  The exception is indinavir which was studied under both conditions and found not to interact with voriconazole.  However, other protease inhibitors and non-nucleoside reverse transcriptase inhibitors are known inhibitors and/or inducers of CYP3A4 and the clinical significance of an in vivo interaction with voriconazole is currently unknown. Therefore, the potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber, when attempting to manage patients on multiple concomitant medications. The Applicant states that these drug interactions are  “manageable” but please keep in mind that this is predicated on experience within the setting of a carefully monitored clinical trial. We look to the Advisory committee for advice regarding additional drug interactions that may need to be explored.

## Clinical Safety

- Rosemary Tiernan, MD, MPH

## Clinical Safety

- Focus on 5 specific areas:
- Ocular safety
- Cardiac safety
- Hepatic safety
- Rash
- Drug interactions

**Notes:**
 The safety section of  this presentation will focus on the following 5 areas:
ocular , cardiac  and hepatic safety
 rash and drug interactions.

## Clinical Safety

- Focus on 5 specific areas:
**Ocular  safety**
- Cardiac safety
- Hepatic safety
- Rash
- Drug interactions

## 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

**Notes:**
  In the pre-clinical evaluation of this drug, pharmacology- toxicology studies have demonstrated that voriconazole produced dose-related effects in the ERG of dogs exposed to voriconazole. The voriconazole plasma levels which produced these results in dogs were similar to those plasma levels achieved in human studies.  Histopathology results for female rats who received 50mg/kg voriconazole (equivalent to 8 mg/kg IV) demonstrated mild thinning of the outer layer of retina at 24 months .
During the clinical trials, the incidence of visual symptoms was 1 out of every 3 subjects.
The symptoms included decreased vision, photophobia, altered color perception and ocular discomfort.
The exact mechanism underlying these visual symptoms is unknown.
There is no human histopathology data.
Ocular biomicroscopy has not detected ocular lesions.

## 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

**Notes:**
Results from study 150-1004, a study in which Voriconazole was given to healthy volunteers at a dose of 400 mg q 12 hrs for one day and then 300 mg q 12 hrs for 27 days, are listed as follows:
Effects were noted in the ERG, Farnsworth-Munsell 100 hue test (color vision) and Humphrey Perimetry studies (visual field).
Voriconazole affects both rod and cone function.
Decreased visual function is present on the first day and continued through 28 days of therapy ---at 14 days after the end of therapy the vision returns to normal function.

## 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

**Notes:**
Additional issues regarding the use of  this drug include:
--there is insufficient information to  predict what the ophthalmologic effects will be in patients who are either re-challenged or re-treated with voriconazole
--ultimately, if this drug is considered for use in children less than 9 years of age, we do not have sufficient data to predict the effect of voriconazole on the eye which is not yet fully developed.
A careful risk/benefit assessment will have to be made when considering the use of voriconazole in patients with underlying eye disease such as CMV retinitis .
We can not predict that visual changes will resolve--- if this drug is used beyond 28 days of therapy.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
**Cardiac safety**
- Hepatic safety
- Rash
- Drug interactions

## Cardiac Safety

***In vitro***** data**
***In vivo***** data**
**Clinical data**
- One sudden death

**Notes:**
 In vitro studies of this drug,  demonstrated no major effects for voriconazole in HERG channel studies or in the dofetilide studies when compared to ketoconazole. In vivo data demonstrated that, in dogs, high doses of voriconazole produced arrhythmia, PVC’s and prolonged QT interval. 
As already discussed by the Applicant, there was one sudden death in the phase 3 clinical trials for which a role for voriconazole could not be excluded.  In response to this event investigators were asked to monitor patients with telemetry if the patient had underlying heart disease and was to receive intravenous voriconazole. The Applicant planned to further investigate the effect of  3 intravenous doses of voriconazole (4 mg/kg, 8 mg/kg and 12 mg/kg) on QTc interval in healthy subjects aged 18-65 years. However,  this study was terminated because of anaphylactoid reactions.  The Applicant has conducted a thorough investigation and no causative factor has been found for these anaphylactoid reactions. The Applicant has committed to complete a similar study but utilizing the oral preparation of voriconazole.

## Cardiac Safety

**Clinical data**
- Adverse Events
- Cardiac arrhthymias, CHF, cardiac arrests
- Discontinuations

**Notes:**
In the controlled clinical trials, studies 307/602, 603 and 305, no major differences between voriconazole and controls  have been detected in the adverse event reporting or rate of discontinuations for cardiac events such as arrhythmias and congestive heart failure. However, the voriconazole arm in study 307/602 did have more grade 3 cardiac adverse events (27/ 196  vs 13/185 ) and a role for the drug could not be excluded. It is important to note that these clinical studies were not specifically designed to assess the risk to develop an arrhythmia in a population who may be on multiple medications, have underlying heart disease and may also be on anti-arrhythmic drugs.
Consequently, warnings may be necessary regarding the use of this drug in patients with underlying heart disease or in patients on concomitant anti-arrhythmic drugs. When this drug is used in patients with underlying heart disease, consideration should be given to employ cardiac monitoring during the period when the patient is receiving intravenous medication.
However, the voriconazole arm did have more cardiac arrests and episodes of syncope  noted in trial 307/602 (6/196 3.1% vs 2/185 1.1% and 5/196 2.6% to 1/185  0.5%).  A role for the drug could not be excluded.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
**Hepatic safety**
- Rash
- Drug interactions

## 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.

**Notes:**
Pfizer has already presented information on the hepatic safety of voriconazole.  In general, we are in agreement with the information as presented by Pfizer.
Our conclusions are similar, in that the data from the Phase I/II studies support that there is a positive dose or exposure response relationship between  voriconazole and transaminase increases and a possible association with alkaline phosphatase increases.  In the phase III comparative studies, hepatic adverse events and abnormalities of transaminases and alkaline phosphatase  were more frequent among patients taking voriconazole than fluconazole.  The hepatic adverse events were similar between voriconazole and its amphotericin B comparators with the exception of bilirubin elevations which were more frequent among those treated with amphotericin B formulations. While the numbers are small, serious adverse events were reported more frequently among patients receiving voriconazole in the phase III comparative studies.  Regarding hepatic failure deaths---Pfizer has already described  the findings of the expert panel of hepatologists who reviewed those specific deaths.

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
- Hepatic safety
**Rash**
- Drug interactions

## 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

**Notes:**
We agree with the Applicant that rash is a potential hazard associated with the use of this drug.
Patients in the clinical studies were often on concomitant medications that could either cause rash themselves or concomitant medications such as antihistamines and steroids that might affect the type and severity of skin symptoms observed.Conditions such as GVHD can also make it difficult to completely assess a causative role for study drug in the development of rash.
GVHD incidence :
Voriconazole	4.1 % in 307/602 	and 	2.9% in 603
Comparator	2.2 % in 307/602 	and 	1.4% in 603
Only 4 skin biopsy results submitted
Grade 3 rashes
307/602	Vori 5/196	Ampho B	1/185
305	Vori 3/200	Flu	1/191
603	Vori 12/421	Ampho B	15/428

## 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

**Notes:**
In the controlled clinical trials, rash was observed in voriconazole study patients at a rate similar to that of its comparators.  Overall, rash develops  in 18.6% of patients receiving voriconazole. 
The applicant has already presented several descriptions of the various types of skin exanthems observed. No specific rash  is characteristic of voriconazole exposure. There is insufficient information at this time to conclude that the rash is due to photosensitivity.
Most rashes were of mild to moderate severity.
There were no major differences in the discontinuations for rash between voriconazole and its comparators.
However, the Applicant has already described  4 non-fatal cases of Stevens Johnson  syndrome which were noted in patients on voriconazole. Two of these cases  developed rash, discontinued drug and then re-exacerbated  upon  re-challenge (304- 01370816 and 604-10346186)
TEN ampho B on 603-90441462

## Clinical Safety

- Focus on 5 specific areas:
- Ocular  safety
- Cardiac safety
- Hepatic safety
- Rash
**Drug interactions**

## Drug Interactions with VoriconazoleIn 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

**Notes:**
Finally, we will address the safety implications of drug interactions with voriconazole.  In vitro metabolism studies performed with human hepatic microsomes and genetically engineered cell lines indicate that:
- voriconazole is both a substrate and an inhibitor of three cytochrome P450 enzymes:  CYP2C19, CYP2C9, and CYP3A4.
	Rose’s Notes:
	CYP2C19  omeprazole
	CYP2C9  phenytoin, warfarin
	CYP3A4  tacrolimus, cyclosporine, PI, NNRTI
-  the substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4.
	- for comparison, the potency of voriconazole as an in vitro 	inhibitor of CYP3A4 appears to be weaker than ketoconazole 	and itraconazole
- the in vitro potency of voriconazole to inhibit the metabolism of CYP3A4 substrates (and for CYP3A4 substrates to inhibit voriconazole) varies among classes of drugs, including:
	- HIV protease inhibitors
	- non-nucleoside reverse transcriptase inhibitors
	and immunosuppressant drugs

-

## Drug Interactions with VoriconazoleIn 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

**Notes:**
The Applicant has evaluated representative substrates/inhibitors/inducers of the three CYP enzymes both in vitro and in vivo.  However, it is not possible to evaluate every potential drug interaction.
To illustrate, representative protease inhibitors and non-nucleoside reverse transcriptase inhibitors were studied in vitro, but not in vivo.  The exception is indinavir which was studied under both conditions and found not to interact with voriconazole.  However, other protease inhibitors and non-nucleoside reverse transcriptase inhibitors are known inhibitors and/or inducers of CYP3A4 and the clinical significance of an in vivo interaction with voriconazole is currently unknown. Therefore, the potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber, when attempting to manage patients on multiple concomitant medications. The Applicant states that these drug interactions are  “manageable” but please keep in mind that this is predicated on experience within the setting of a carefully monitored clinical trial. We look to the Advisory committee for advice regarding additional drug interactions that may need to be explored.