# Presentation: 169158

## A New Once-Daily Formulation of IsotretinoinAccutane NF

**John McLane, PhD**Roche Medical Science and Safety **David Young, PharmD, PhD**GloboMax LLC

**Notes:**
Test 1

## Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

- New Formulation Development Program
- Dose/Exposure Response Relationship
- Risk Management of Two Formulations
- Benefit of New Formulation

**Notes:**
Test 2

## Accutane Dose Efficacy Studies

## Variability in Accutane Exposure 

- Dosing without food results in a significant reduction in exposure
- Physician Survey
- 68% of patients instructed to take Accutane with food
- 21% of patients instructed to take Accutane once a day (approximately 1 mg/kg)
- Prescribers report that 33% of patients do not take Accutane consistently with food
- Prescribers report that 22% of patients do not consistently take the second dose in a BID regimen
*** ******Overall Effect: *****significant***** *****patient variability in exposure**

**Notes:**
Efficacy of alternative dosing regimens has not been fully evaluated

## Accutane Dosing Issues

- Inconsistency in dosing recommendations
- once a day or twice a day
- with or without food
- Individual tolerabilityPrescriber survey shows that the principal reasons for patients withdrawing from therapy are:
- mucocutaneous effects (19%)
- triglyceride elevations (17%)
- Compliance
- Noncompliance would result in under/over dosing which may affect efficacy and safety

## The New Formulation (NF) of Isotretinoin is as Safe and Efficacious as Accutane

- Simplifying dosing recommendations
- The NF can be given with or without food
- The NF can be given QD
- Individual tolerability
- The NF has fewer and less intense mucocutaneous events
- The NF has fewer patients with elevated triglycerides
- Compliance with dosing regimen
- More predictable exposure from NF decreases the impact of individual noncompliance

## Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

**New Formulation Development Program**
- Dose/Exposure Response Relationship
- Risk Management of Two Formulations
- Benefit of New Formulation

## Clinical Development Program for NF

- Pivotal Clinical Program
- efficacy and safety trial
- Pharmacokinetic Program
- food effect on bioavailability
- bioequivalence
- dose proportionality
- Hormonal Contraceptive Interaction Program
- in vitro studies
- clinical evaluations

## Clinical Study Objective

-   Compare the efficacy and safety:
- 		_New Formulation_      vs.	_Accutane_
-      	Once per day	Twice per day
-  		No Food	Food
- 		Lower Exposure	Labeled Exposure
- 		182M / 118 F	174M / 126F

## Daily Dosing Regimen

- 12 AM

- 12 Noon

- 12 AM

**Accutane Group 1 mg/kg**

**New Formulation Group 0.4 mg/kg**

- Active

- Active

- Placebo

- Placebo

- Placebo

- Active

**Breakfast**

**Dinner**

## Inclusion Criteria

- Male or non-pregnant and non-nursing female patients, 12 years of age or older
- Diagnosed with severe recalcitrant nodular acne, with 10 or more nodular lesions at least  5 mm in diameter

## Clinical Efficacy Endpoints

- Primary
- number of patients with 90% reduction in nodules
- reduction in total number of nodules from baseline
- Secondary
- global evaluations by both patients and physicians
- reduction in total number of papules and pustules

## Safety Evaluations During Trial 

- Laboratory
- CBC, blood lipids, liver enzymes
- Psychiatric evaluations
- Mood/Depression Questionnaire
- Beck Depression Inventory
- Mucocutaneous adverse events
- Dry or peeling skin
- Dry or bleeding nose
- Dry or irritated eyes
- Chapped lips
- Rash or erythema of face

## Additional Evaluations

- Objective measurements of inflammatory lesions at 8 week and 16 week evaluation points
- Subjective measurement of need for retreatment
- phone call to patients 16 weeks post therapy

## Results - STD Efficacy Analyses

## Overall Comparison of Safety

_**Accutane NF**_

**Patients with adverse event**
**Total adverse events****Adverse events leading to treatment discontinuation****Serious adverse events**
**Withdrawals (non AEs)**

_**Variable**_

**296 **
**1362****16 **
**2 **
**22**

**293 **
**1450****16 **
**4 **
**30**

**Overall Comparison of Safety**

## Adverse Events Leading to Treatment Discontinuation

**Appendicitis****	****Depression (3)****	**
**Chapped lips, dry skin****	****Dizziness/Blurred vision****	**
**Headache (3)****	****General body weakness****	**
**Irritated eyes****	****Hair loss****	**
**LFT (3)****	****Headache****	**
**Low white cell count****	****LFT (3)****	**
**Triglyceride elev (6)****	****Mood swings ****	**
**	****Pregnancy****	**
**	****Pustular eruption****	**
**	****Triglyceride elev (3) ****	**

**Adverse Events Leading to Treatment Discontinuation**

## Comparison of Total Adverse Events (>5%)

## Lipid Profile During Treatment

**Abnormal triglyceride levels were observed in**
**48/300 patients on Accutane NF **
**75/300 patients on Accutane **
**Mean triglyceride levels increased by**
**0.57 ****±**** 0.87 mmol/L for Accutane NF**
**0.99 ± 1.44 mmol/L for Accutane**
**Mean cholesterol levels increased by**
**0.4 ****±**** 0.56 mmol/L for Accutane NF**
**0.6 ± 0.69 mmol/L for Accutane**

## Comparison of Psychiatric Events

**Comparison of Psychiatric Events**

**	****Accutane NF ****	**** Accutane **** ****	****N = 300 ****	****N =300**

**Patients reporting AEs****	****11****	****1**
**Positive Mood Assessments****	****37****	****38**
**Patients with BDI >13 (not BL)     ****	****9****	****10**
**      ****Pts with Baseline BDI********13****1****     ****	****6****	****     7 **
**Prior history (medications)****	****13****	****15**
**      ****Additional BDI****1****	****2****	****2**

- 1. Subgroup of prior category

## Mucocutaneous Adverse Events (MAEs)

- MAEs were fewer and less intense in Accutane NF-treated patients
- At several time points, differences were statistically significant
- Subgroup analysis showed no imbalance among age, sex, race, or body weight categories

## Mucocutaneous Event:Dry or Bleeding Nose

- *

- *

- *

- *

- *

## Mucocutaneous Event:  Dry or Irritated Eyes

- *

- *

- *

- *

- *

## Isotretinoin / Hormonal Contraceptives Program

- To assure that isotretinoin does not alter the clinical pharmacology of hormonal contraceptives
- Two components of program:
- in vitro studies with hepatocytes and microsomes
- clinical program

## In Vitro Human Hepatocytes ExperimentsExperiment Completion Dates

***Initiated January 2000:  5-6 months to complete each study**

**†****Initiated January 2000:  11 months to complete each study**

## Oral Contraceptive Clinical Studies

- Two studies to determine if isotretinoin affects oral contraceptives (Ortho-Novum 7/7/7)
- pharmacokinetics (ethinyl estradiol and norethindrone)
- pharmacodynamics (LH/FSH/progesterone)
- Females with severe recalcitrant nodular acne
- Accutane 1.0 mg/kg/day in two divided doseswith  food
- Accutane NF 0.4 mg/kg/day as a single dailydose fasted

## Oral Contraceptive Studies:  Pharmacokinetic (PK) and Pharmacodynamic (PD) Assessments

**Study Month 1**

**Study Month 2**

**OC Stabilization**

**OC Pill Cycle 2**

**Study Month 3**

**OC Pill Cycle 3 + Isotretinoin**

**Day 6**

**Day 6**

**Day 20**

**Day 20**

**PK and PD**

**Assessments**

**Study Month 4**

**Isotretinoin**
**Initiated**

**OC Pill Cycle 4 + Isotretinoin**

## Oral Contraceptive StudiesCurrent Status

- No pregnancies
- No serious or unexpected adverse events
**Timelines:**
- September 2000:  last patient visit scheduled for both studies
- 1st Quarter 2001:  final study reports to FDA

## Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

- New Formulation Development Program
**Dose/Exposure Response Relationship**
- Risk Management of Two Formulations
- Benefit of New Formulation

## Isotretinoin Dose Efficacy Studies

## Plasma Concentrations of Isotretinoin After Single Dose of Accutane (80 mg), Accutane NF (30 mg)  Under Fed or Fasted Conditions  (n=74)

**Isotretinoin****ng/mL**

**Time, (hrs)**

## Effect of Food on Exposure

- Accutane has a significant food effect:
- 2.5 : 1 ratio between Accutane (fed) and Accutane (fasted)
- inconsistent eating habits lead to large within subject variability
- between subject variability is less when administered with food
- Taking Accutane without food significantly increases the risk of under exposure to isotretinoin, which could result in sub-optimal therapy (decreased efficacy)

## Effect of Food on Exposure (cont’d)

- Accutane NF has minimal food effect
- 30% greater exposure when administered with food
- between subject variability is similar when administered with or without food
- reduced within subject variability (versus Accutane)  even with inconsistent eating habits
- Risk of sub-optimal therapy is minimized with Accutane NF

## Method for Simulating the Steady State Plasma Concentrations of Isotretinoin

- Data from the Fed/Fasted PK Accutane - NF  study were used
- Principle of superpositioning for linear pharmacokinetics was used to simulate  plasma concentrations of isotretinoin for different dosage regimens of NF and Accutane under fed or fasted conditions

## Figure 1 - Simulated Steady-State Exposure to Isotretinoin Following Administration of Accutane* & Accutane NF†

**Nominal Time, hr**

***1.0 mg/kg and 0.5 mg/kg**

**†****0.4 mg/kg**

- NF 414, 9/17/00

**Isotretinoin****ng/mL**

**Nominal Time, hr**

## Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions 

**Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions**** **

## Isotretinoin Dose Efficacy Studies

## AUC Exposure to Isotretinoin for Accutane and Accutane NF

_***Dose***__***	***__***	***_***   ***_***AUC***__***	***__***	***__***Condition***_
**0.1****	****	****	****     921****	****	****Fed**
**0.2****	****	****	****  1,842****	****	****Fed**
**0.4NF****	****	****  4,161****	****	****Fasted**
**0.5****	****	****	****  4,605****	****	****Fed**
**1.0****	****	****	****  9,209****	****	****Fed**
**2.0****	****	****	****  7,310****	****	****Fasted**

## Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

- New Formulation Development Program
- Dose/Exposure Response Relationship
**Risk Management of Two Formulations**
- Benefit of New Formulation

## Risk of Confusion with Two Formulations

- Taking Accutane with or without food
- Misunderstanding about QD administration for NF and BID for Accutane
- Concurrent administration of NF and Accutane
- Potential for substitution at the pharmacy

## Simulated Steady State Exposure to IsotretinoinFollowing Administration of Accutane and Accutane NFUnder Fed and Fasted Conditions 

**Simulated Steady State Exposure to Isotretinoin****Following Administration of Accutane and Accutane NF****Under Fed and Fasted Conditions **

## Simulated Steady State Exposure to IsotretinoinFollowing Administration of Accutane and Accutane NFUnder Fed and Fasted Conditions 

**Simulated Steady State Exposure to Isotretinoin****Following Administration of Accutane and Accutane NF****Under Fed and Fasted Conditions **

## Simulated Steady-State Exposure to Isotretinoin Following Administration of Accutane (1.0 mg/kg) Given As Divided Doses & As a Single Daily Dose Compared With Accutane NF (0.4 mg/kg)

**Isotretinoin****ng/mL**

**Time, hr**

## New Formulation Product Differentiation

- Differences in dosing
- once per day vs twice per day
- taken with or without food
- Unique packaging
- pouches versus prescription packs
- packaging shape and color
- Capsule appearance
- contrasting capsule color schemes
- different identification marks on capsules
- different capsules strengths (7.5, 15, 22.5 mg for Accutane NF)
- Distinct, unique brand name for NF
- trade name submitted to FDA July 2000

## The New Formulation of Isotretinoin is as Safe and Efficacious as Accutane

- Simplifying dosing recommendations
- The NF can be given with or without food
- The NF can be given QD
- Individual tolerability
- The NF has fewer and less intense mucocutaneous events
- The NF has fewer patients with elevated triglycerides
- Compliance with dosing regimen
- More predictable exposure from NF decreases the impact of individual noncompliance

## Labeling for the New Formulation

- Once per day
- Can be taken with or without food
- All safety issues and programs carried over from Accutane
- Indication remains the same

## End of presentation

## Benefit of New Formulation

- Equivalent clinical efficacy
- Increased tolerability and comparable safety profiles
- mucocutaneous adverse events
- lipid adverse events
- Decreased variability in exposure
- Once daily dosing
- Can be taken with or without food

## Dosing variability issues with Accutane
Rationale for new formulation for isotretinoin
Program for assessing new formulation
efficacy
safety
drug interaction program
pharmacokinetics of dosing
Risk management issues

- Rationale for new formulation for isotretinoin
- Program for assessing new formulation
- efficacy
- safety
- drug interaction program
**pharmacokinetics of dosing**
- Risk management issues

## Slide 51

## The new formulation is designed to address:
acceptability
inconsistency in dosing recommendations
compliance

- acceptability
- inconsistency in dosing recommendations
- compliance

## Psychiatric Adverse Event Reports

- Self-reporting of adverse events
- Other tools to evaluate psychiatric conditions do not demonstrate disparity in formulations
- Not substantiated by BDI-II scores of individuals or population
- Formulation with most AE reports had lowest exposure to isotretinoin

**Notes:**
Based on utility of other tools expected more reports in Accutane arm

## Frequency Distribution of Triglycerides

## Outcomes from Accutane Therapy

**Accutane Treatment**

**Incomplete Therapy**

**Effective** **Therapy**

**Incomplete clearance**

##  Accutane NF

**Weeks**

**Triglyceride Level Categorized at Baseline**

- NF 038, (65), 9/5/00

**mg/dL**

## Improved Safety Profile of Accutane NF Adverse Events

**Improved Safety Profile of Accutane NF Adverse Events**

- Fewer total adverse events
- Fewer moderate or severe adverse events
- Fewer adverse events in most body systems

## In Vitro Human Hepatocytes ProgramExperiment Completion Dates

***Initiated January 2000:  5-6 months to complete each study**

**†****Initiated January 2000:  11 months to complete each study**

## Therapeutic Dose Range for Isotretinoin

**Therapeutic Dose Range for Isotretinoin**

## Rationale for Evaluating Accutane NF

- Provide a new micronized formulation of isotretinoin that reduces variability in exposure
- taken with or without food
- administered once daily
- Retain the efficacy and safety of Accutane
- Enhance patient compliance and convenience
- Achieve a lower but effective exposure

## Psychiatric Adverse Event Reports

**Treatment Group**

**Psychiatric Adverse Event Reports**

**	****Accutane NF ****	**** Accutane ****Adverse Event ****	****N = 300 ****	****N =300**
**Depression NOS ****	****6 (2.0%)****	****-**
**Mood swings****	****2 (0.7%)****	****-**
**Panic reaction ****	****1 (0.3%)****	****1 (0.3%)**
**Anxiety****	****1 (0.3%)****	****-**
**Mood alteration NOS ****	****1 (0.3%)****	****-**

## Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions 

**Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions**** **

## Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions 

**Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions**** **