# Presentation: 516426

## Allergan, Inc.NDA 21-701tazarotene 1.5 and 4.5 mg capsules

**Backup slides presented**
**FDA Advisory Committee**** ***July 12, 2004*

- Allergan, Inc. - Backup Files Presented

## Prior and Concomitant Therapy

**Patients were not to have used: **
**Systemic medications (other than corticosteroids) known to affect bone (eg, alendronate sodium) in ****the 12 months before study entry**
**Systemic retinoids (eg, isotretinoin, acitretin, bexarotene) or oral or injectable systemic corticosteroids in the 8 weeks before study entry**
**PUVA, methotrexate, or cyclosporine in the 4 weeks before study entry**
**UVB treatment or topical therapies (eg, topical corticosteroids, topical retinoids, topical calcipotriene) that may have altered the course of psoriasis in the ****2 weeks before study entry**
**Daily vitamin A supplements > 5,000 IU, vitamin D supplements > 400 IU, or calcium supplements ****> 1,300 mg in the 7 days before study entry**

- C-028

- Allergan, Inc. - Backup Files Presented

## Prior and Concomitant Therapy(cont.)

**During their participation in the study, other than the use of study medication, patients were not to use any medications that could alter the course of their psoriasis or could interfere with the evaluation of the study medication**
**Therapies considered necessary for the patient’s welfare could be given at the discretion of the investigator**
**If the decision was made to administer a medication that may have affected the outcome of the study, the medication was to be administered in constant doses throughout the study**

- C-029

- Allergan, Inc. - Backup Files Presented

## Liver Function TestsNot Elevated Compared With Placebo

|   | Placebo | 12 Week Tx | 24 Week Tx | 52 Week Tx |
| --- | --- | --- | --- | --- |
| ALT | 25.3%* | 19.1% | 26.1% | 17.9% |
| AST | 14.9% | 15.3% | 29.3% | 23.6% |
| GGT | 17.1% | 17.9% | 28.3% | 21.3% |
| LDH | 3.1% | 3.2% | 6.5% | 4.9% |
| Total Bili | 3.4%* | 0.9% | 1.1% | 3.0% |
| Direct Bili | 0.3% | 0.0% | 0.0% | 0.0% |
| Indirect Bili | 1.7% | 0.6% | 1.1% | 1.9% |
| Alk Phos | 4.2% | 3.8% | 4.3% | 14.1%^ |
| Adverse Events (LFTs) | 1.1% | 1.1% | 1.1% | 5.7% |

***Placebo higher than tazarotene in 12 weeks tx study**
**^ Higher than placebo and higher with long term tx**

- S-035

- Allergan, Inc. - Backup Files Presented

## Patients Treated with Oral Tazarotene Had Greater Satisfaction with Their Study Medication(Study 048P/049P)

**Mean satisfaction scores indicate statistically significant greater satisfaction with oral tazarotene than with placebo (*****p*****<0.001).**

**Patients Treated with Oral Tazarotene Had ****Greater Satisfaction with Their Study Medication****(Study**** ****048P/049P)**

**Oral Tazarotene 4.5 mg**
**79.5%**were satisfied with their study medication

**Placebo**
**52.3%**were satisfied with their study medication

- E-134

- Allergan, Inc. - Backup Files Presented

## Improvement in PQOL-12 is Correlated to Improvement in OLA (048P/049P)and Greater Than Placebo

**OLA Improvement at Week 12****Relative to PQOL-12 Change Scores**

**Mean PQOL-12 Change Score**

- MID=1.24

**Improvement in PQOL-12 is Correlated to Improvement in OLA (048P/049P)*****and Greater Than Placebo***

- [-2.08, -1.65]*

- [-2.79, -2.07]*

- [-3.42, -2.50]*

- [-1.05, -0.62]

*** 95% confidence interval of the mean**

**1 grade OLA Improvement**

**2 grade OLA Improvement**

**Placebo**

**OLA of****min or none**

- E-141

- Allergan, Inc. - Backup Files Presented

## Bone Mineral Density Issue

**Bone Mineral Density Issue**

**Femoral Neck BMD Data, 95% Tolerance Region, **
**and +/-5% Straight-Line Tolerance Region**

- 94% of points in TR
- 83% in “slice” (vs. 81% expected)
- 11% below “slice” (vs. 13% exp.)
- 6% above “slice” (vs. 5% exp.)
- Mean shift: -0.01 (0.943 vs 0.933)
- Median shift: -0.003

- Allergan, Inc. - Backup Files Presented

## Bone Fractures Reported in 9 Patients in 048P, 049P, 052P, and 050P Trials

| Patient | Duration Tx when reported | Study day of onset | Duration, d | Location | Age, y | Gender |
| --- | --- | --- | --- | --- | --- | --- |
| 1088 | 61 days placebo | 61 | 54 | Hand | 34 | Male |
| 1101 | 0 days taz | -6 | 41 | Toe | 35 | Female |
| 1099 | 87 days taz | 130
(post-Tx) | 39 | Toe | 37 | Male |
| 2382 | 80 days taz         | 98
(post-Tx) |  ? | Ankle | 30 | Female |
| 3915 | 5 days taz | 5 |  2 | Small toe | 44 | Male |
| 3758 | 59 days taz | 59 |  72 | Toe | 47 | Male |
| 3457 | 174 days taz | 174 |  78 | Lower leg | 28 | Male |
| 3564 | 277 days taz | 277 | 147 | Ribs | 74 | Male |
| 3553 | 286 days taz | 286 |  93 | Hand | 40 | Male |

- S-086

- Allergan, Inc. - Backup Files Presented

## No Apparent Association Between Fractures and BMD

***LS = lumbar spine, H = total hip, FN = femoral neck***

- S-087

| Patient | Duration Tx when fracture reported | Location | Age, y | Gender | ∆ BMDnext scan |
| --- | --- | --- | --- | --- | --- |
| 1101 | 0 days tazarotene | Toe | 35 | Female | LS:   -1.9%
H:     +2.2%
FN:   -1.1% |
| 1099 | 87 days tazarotene
(post-Tx) | Toe | 37 | Male | LS:   +0.6%
H:      -3.8%
FN:   -1.8% |
| 2382 | 80 days tazarotene
(post-Tx) | Ankle | 30 | Female | LS:   -3.0%
H:     +2.4%
FN:   +0.2% |
| 3915 | 5 days tazarotene | Toe | 44 | Male | LS:   +4.2%
H:      -0.2%
FN:   +0.9% |
| 3564 | 277 days tazarotene | Ribs | 74 | Male | LS:   +5.2%
H:     +1.2%
FN:    -6.5% |
| 3553 | 286 days tazarotene | Hand | 40  | Male | LS:   +2.3%
H:      -1.2%
FN:   +0.7% |

- Allergan, Inc. - Backup Files Presented

## Patient 1115 (Apparent Loss of >50% Hip BMD Due to Scan of Unacceptable Quality)

|  |  | Bone Density (g/cm2) | Change in Bone Density (%) |
| --- | --- | --- | --- |
| Lumbar spine | Screening
Wk 12
Wk 24 | 1.417
1.353
1.294 | 
 -4.52%
 -8.68% |
| Total hip | Screening
Wk 12
Wk 24 | 1.150
0.535
1.126 | 
[-53.48%]*
  -2.09% |
| Femoral neck | Screening
Wk 12
Wk 24 | 0.979
0.836
0.931 | 
[-14.61%]*
 -4.90% |

***Unacceptable quality scan**

- S-183

- Allergan, Inc. - Backup Files Presented

## Apparent Loss of ≥ 20% BMD from Baseline (Patient 3409)

|  | Bone Density(g/cm2) | Change in Bone Density (%) |  |  |
| --- | --- | --- | --- | --- |
|  | Screening | Wk 24 | Wk 52 | Wk 64 |
| Lumbar spine | 1.420 | -6.7% | -9.3% | -5.8% |
| Total hip | 1.287 | -6.6% | -8.2% | -10.6% |
| Femoral neck | 1.259 | -8.5% | -9.8% | -28.3% |

- S-206

**50-year old male with obesity (151 kg), diabetes, and sleep apnea **
**BMD assessment at limits of capability of BMD technology due to obesity **
**Patient started with high BMD/T score**
**Concomitant meds: aspirin, Glucovance, benazepril, amfebutamone, sertraline, pramipexole, saw palmetto**

- Allergan, Inc. - Backup Files Presented

## Risk of Osteopenia and Osteoporosis In Patients with ≥ 5% Loss in BMD (050P)

**Of 32 patients with ****≥ 5% loss in BMD at any time:**
**14 (44%) had normal BMD throughout the study **
**12 (38%) had osteopenia at baseline and never became osteoporotic**
**5 (16%) developed osteopenia (from normal at baseline) **
**None developed osteoporosis; 1 (3%) had osteoporosis at baseline *****and***** follow-up**
**No greater risk of osteoporosis in patients with  ****≥ 5% loss vs. patients who do not have ≥ 5% loss**

- S-196

- Allergan, Inc. - Backup Files Presented

## Minimal Effects on Thyroid Function

- S-188

| 048P & 049P combined (12 weeks treatment) | Tazarotene | Placebo | P-value |
| --- | --- | --- | --- |
| Hypothyroidism | 2/348 (0.6%) | 0/358 (0.0%)  | p = 0.243 |
| TSH > ULN | 23/346 (6.6%) | 23/356 (6.5%) | p = 0.920 |
| Thyroxine | 4/346 (1.2%) | 9/356 (2.5%) | p = 0.178 |

| 052P | Taz → Taz(24 weeks) | Placebo(12 weeks) |
| --- | --- | --- |
| Hypothyroidism | 2/92 (2.2%) | 0/220 (0.0%)  |
| TSH > ULN | 8/92 (8.7%) | 16/220 (7.3%) |
| Thyroxine | 1/92 (1.1%) | 7/220 (3.2%) |

| 050P
(52 weeks treatment) | 0-24 weeks | 24-52 weeks | 0-52 weeks |
| --- | --- | --- | --- |
| Hypothyroidism | 1/263 (0.4%) | 1/199 (0.5%)  | 1/263 (0.4%) |
| TSH > ULN |  |  | 20/263 (7.6%) |
| Thyroxine |  |  | 4/263 (1.5%) |

- Allergan, Inc. - Backup Files Presented

## Education Materials for Physicians

***What Prescribers Need to Know***** Brochure**
**Prescriber Introduction Letter**
**Prescriber certification test**
**Medication Guide**

- R-052

- Allergan, Inc. - Backup Files Presented

## RiskMAP Roll-out

- R-055

**Broad target audience**
**Registration kits for physicians and pharmacies**
**Educational seminars**
**Professional meetings**
**Field force participation**

- Allergan, Inc. - Backup Files Presented

## Body Weight, Gender, and Age Have No Effects on PK  

**Body Weight, Gender, and Age ****Have No Effects on PK  **

***Study 048P***

***Study 049P***

- PC-017

- Allergan, Inc. - Backup Files Presented

## Logistic Regression: Clinical Success* Versus Possible CovariatesStudies 048P/049P(N = 689)

| Variable | Parameter
Estimate | Wald
Chi-Square | p-value |
| --- | --- | --- | --- |
| Treatment | 	1.883 | 	30.225 | 	< 0.001 |
| Age | 	0.018 | 	3.048 | 	0.081 |
| Sex | 	-0.791 | 	7.699 | 	0.006 |
| Race | 	0.221 | 	0.486 | 	0.486 |
| Baseline OLA | 	-0.489 | 	2.613 | 	0.106 |
| Weight (kgs) | 	-0.006 | 	0.722 | 	0.396 |
| Baseline Body Surface Area | 	0.010 | 	1.654 | 	0.199 |

- C-136

*** Clinical success = None/Minimal OLA at Week 12**

- Allergan, Inc. - Backup Files Presented

## Incidence of Hyperglycemia

- S-189

| 048P & 049P(12 Weeks) | Tazarotene | Placebo | P-value |
| --- | --- | --- | --- |
| Hyperglycemia (AEs) | 7/348 (2.0%) | 0/358 (0.0%) | p = 0.007 |
| Incidence > ULN | 51/346 (14.7%) | 64/356 (18.0%) | p = 0.247 |

| 052P | Taz → Taz
(24 weeks) | Plac → Taz
(12 weeks) |
| --- | --- | --- |
| Hyperglycemia (AEs) | 1/92 (1.1%) | 4/220 (1.8%) |
| Incidence > ULN | 31/92 (33.7%) | 53/220 (24.1%) |

| 050P(52 Weeks) | 0-24 weeks | 24-52 weeks | 0-52 weeks |
| --- | --- | --- | --- |
| Hyperglycemia (AEs) | 3/263 (1.1%) | 3/199 (1.5%) |  |
| Incidence > ULN |  |  | 61/263 (23.2%) |

- Allergan, Inc. - Backup Files Presented