# Presentation: 514436

## Clinical SafetyOral TazaroteneNDA 21-701

**Denise Cook, M.D.**
**Medical Officer**
**Division of Dermatology and Dental Drug Products**

## Safety Data Base

**Safety data base derived from the following trials:**
**2 phase 3 double-blind placebo controlled trials**
**2 open-label phase 3 trials**

## Safety 

**Duration of trials**
**Double-blind placebo controlled**
**12 weeks with 12 week follow-up**
**Open label**
**12 weeks with 12 week follow-up**
**52 weeks with 12 week follow-up**

## SafetyDuration of Exposure

**Tazarotene treated patients – 987**
**Placebo treated patients – 383**
**Tazarotene treated patients with 4.5 mg once daily – 831**
**640 (77.0%) treated ****≥ 12 weeks**
**261 (31.4%) treated ≥ 24 weeks**
**153 (18.4%) treated ≥ 48 weeks**
**101 (12.2%) treated for 52 weeks**

## SafetyDiscontinuations

**Treatment related reasons accounted for the majority of discontinuations – 54% (93/173)**
**Lack of efficacy**
**Adverse events**
**Discontinuations secondary ****to**** adverse events**
**Placebo-controlled trials – 3.4%**
**Short term open-label trial – 6.5% for those taking a 2****nd**** course vs. 3.2% for those taking a 1****st**** course**
**Long term (52 week) open-label trial – 14.4%**

## Adverse Events That Led to Discontinuations in the  Long Term Trial

**Adverse Events in more than 1 patient**
**Arthralgia (10)**
**Myalgia (7)**
**Arthritis (4)**
**Back pain (4)**
**Alopecia(4)**
**Dermatitis (3)**
**Joint Disorder (3)**
**Abnormal liver function tests (3)**
**Cheilitis (2)**
**Asthenia (2)**
**Depression (2)**
**Emotional Liability (2)**

## Safety-Pivotal TrialsAdverse Events

**Overall, tazarotene group had more adverse events than placebo, 90.2% vs. 74.6% (p<0.001)**
**Significant adverse events**
**Cheilitis - 65.5% vs. 16.8% **
**Dry skin - 23.6% vs.14.8% **
**Headache - 18.7% vs. 12.0% **
**Arthralgia - 17.5% vs. 7.3% **

## Adverse Events (con’t)

**Significant adverse events**
**Myalgia - 14.7% vs. 8.4% **
**Joint disorder - 4.0% vs. 1.1% **
**Back pain - 6.6% vs. 2.8%**
**Nasal dryness - 3.7% vs. 1.1% **
**Foot pain - 2.9% vs. 0.8%**
**Rash - 2.9% vs. 0.6% **
**Dermatitis - 1.4% vs. 0% **

## Metabolic and EndocrineAdverse Events

**Hypertriglyceridemia**
**Significant difference between tazarotene and placebo**
**Hypertriglyceridemia leading to pancreatitis**
**One patient in the placebo controlled trials**
**Hyperglycemia**
**The Applicant found  a statistical difference **
**Hypothyroidism – 4 cases diagnosed**
**3 in the placebo controlled trials**
**1 in the long-term trial**
**All patients were on tazarotene**
**Elevated LFTs leading to discontinuation**
**One patient in the placebo controlled trials**

## Elevated Serum Triglycerides

| Study | Tazarotene
N = 166 |  |  |  |  | Placebo
N=171 |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 048P | Mild
2.3-2.79 mmol/L | Moderate
2.8-5.6 mmol/L |  | Severe
>5.61 mmol/L | Total* | Mild
2.3-2.79 mmol/L | Moderate
2.8-5.6 mmol/L |  | Severe
>5.6 mmol/L |  | Total* |
|  | 35 (21.1%) | 32 (19.3%) |  | 8 (4.8%) | 75 (45.2%) | 20 (11.7%) | 30 (17.5%) |  | 8 (4.7%) |  | 58(33.9%) |
| 049P | Tazarotene
N = 182 |  |  |  |  | Placebo
N=187 |  |  |  |  |  |
|  | 22 (12.1%) | 42 (23.1%) | 13 (7.1%) |  | 77 (42.3%) | 30 (16.0%) | 28 (15.0%) | 6 (3.2%) |  | 64 (34.2%) |  |
| *p = 0.0107 for total combined |  |  |  |  |  |  |  |  |  |  |  |

## Post-Treatment PeriodPlacebo Controlled Trials

**Only cheilitis remained a statistically significant event**
**Skin and appendages as a whole but driven primarily by dry skin**
**Serum triglycerides returned to acceptable range in 55% of patients followed in post-treatment period**

## Adverse EventsShort-term Open-label Trial

**Significant adverse events in patients taking 2****nd**** course of tazarotene compared to those taking 1****st**** course**
**Arthralgias – 33.7% vs. 14.1%**
**Back pain – 17.4% vs. 7.7%**
**Alopecia – 5.4% vs. 0.9%**
**Significant laboratory abnormalities**
**Elevated serum triglycerides**
**Elevated alkaline phosphatase levels**

## Adverse EventsLong-term Open-label Safety Trial

**One or more adverse events reported for 98.9% (260/263) patients**
**Adverse events for >5% of patients**
**Cheilitis (64.3%)**
**Arthralgia (36.1%)**
**Myalgia (28.9%)**
**Infection (28.5%)**
**Dry skin (22.8%)**

## Long Term Safety Trial

**Adverse Events (con’t)**
**Back pain (22.1%)**
**Headache (20.9%)**
**Asthenia   (11.4%)**
**Pruritus     (11.4%)**
**Foot pain   (9.9%)**
**Alopecia    (7.6%)**
**Leg Pain    (7.2%)**
**Arthritis     (6.8%)**

## Long Term Safety Trial

**Adverse Events**
**Paresthesia (6.5%)**
**Flu syndrome (6.5%)**
**Nausea (6.1%)**
**Joint disorder (6.1%)**
**Insomnia (6.1%)**
**Rhinitis (5.7%)**
**Bronchitis (5.7%)**
**Most of the events were reported as mild in severity**

## Long Term Safety Trial

**Laboratory adverse events**
**Hypertriglyceridemia (41.1%)**
**Abnormal LFTs (22.9%)**
**Elevated CPK (16.3%)**
**Elevated alkaline phosphatase (13.7%)**
**Elevated SGPT (9.1%)**
**Elevated SGOT (6.5%)**
**Abnormalities in hemic and lymphatic system (5.7%)**
**Elevated TSH (5.3%)**

## Alkaline Phosphatase

**Higher elevation compared to placebo controlled trials  - 13.7% vs. 3.4%**
**Remained elevated at end of post-treatment period (12 weeks) in 69.4% (25/36) patients**
**Only 3.7% (2/54) patients with elevated LFTs had abnormalities at  end of post treatment period suggesting a bone origin for the elevated alkaline phosphatase values**

## Effects on Bone Metabolism in the Clinical Trials

**Mean bone mineral density (BMD) decreased over time for the entire set of patients, with some having decreases close to 30%**
**Over 10% had significant decreases >5%**
**4 patients on tazarotene and 1 on placebo had BMD decreases >5% in the placebo-controlled trials**
**One patient had a decrease of 50% in BMD**

## Effects on Bone Metabolism in the Clinical Trials

**Long term study (52 weeks)**
**5.3% (12/226) of patients had significant changes in calcification and/or osteophyte scores of the cervical spine**
**26% had worsening changes in hyperostosis and ligament calcification with each vertebrae of the cervical spine**
**Significant increase in ankle ligament osteophyte formation at weeks 52 and 64**

## Musculoskeletal Adverse Events in Post-treatment Period

**Arthralgia (19.7%)**
**Back pain (17.8%)**
**Myalgia (15.8%)**
**Arthritis (6.6%)**
**6 moderate fractures occurred during the trials in patients on tazarotene reported as “without known cause”**

## Other Adverse EventsPost Treatment Period

**Cheilitis (38.2%)**
**Dry skin (17.1%)**
**Asthenia (7.9%)**
**Pruritus (6.6%)**

## Discontinuations Neuropsychiatric Events

**Placebo controlled trials**
**Emotional lability**
**Tazarotene – 3 patients**
**Placebo – 3 patients**
**Depression**
**Tazarotene – 1 patient**
**Placebo - none**
**Open-label trials**
**Depression – 2 patients**
**Emotional lability – 5 patients**
**Paranoid reaction – 1 patient**

## Conclusions Neuropsychiatric Events

**No difference between tazarotene and placebo in the controlled trials**
**Due to limitations of the metrics employed and the statistical power, an association cannot be ruled out, given the existing concerns about such effects from other retinoids.**

## Ophthalmologic Conclusion

**Several metrics employed during trials**
**Visual acuity**
**Biomicroscopy**
**Ophthalmoscopy**
**No signal detected **

## Pregnancies

**4 pregnancies in trials thus far on oral tazarotene – 1 in psoriasis trial and 3 in acne trials**
**Two elective abortions**
**One spontaneous abortion**
**One term delivery at 38 weeks gestation **
**At 16.5 months of age, no evidence of complications**

## Phase 3 Pivotal Efficacy Trials

**2 phase 3 efficacy trials exactly alike in design**
**Multicentered, randomized, double-blind and placebo controlled**
**Patients took either tazarotene as a 4.5 mg capsule or its placebo once a day for 12 weeks**
**There was a 12-week post-treatment follow-up**

## Phase 3 Pivotal Efficacy Trials

**Key inclusion criteria**
**Age 21 years or older**
**Severity score ****≥ 3 (moderate) on the Overall Lesional Assessment Scale**
**A minimum body surface area involvement of 10%**

## Phase 3 Pivotal Efficacy Trials

**Key Exclusion Criteria**
**Spontaneously improving or rapidly deteriorating plaque psoriasis**
**Previous fracture, anomaly, or artifact of the ankles or cervical spine **
**Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene) within 8 weeks prior to study entry**
**Use of  systemic medications (other than corticosteroids) known to affect bone (e.g., alendronate sodium) within 12 months prior to study entry)**

## Phase 3 Pivotal Trials

**Key Exclusion Criteria**
**Patients with active suicidal ideation **
**Female of childbearing potential who was unable or unwilling to use 2 birth control methods at the same time during the 28 days prior to the week 0 visit and during the treatment and post-treatment periods of the study. **
**Male and was unwilling to wear a condom when having sexual intercourse with a female of childbearing potential during the study**

## Efficacy Variables

**Primary**
**Overall Lesional Assessment Score **
**0 – none**
**5 – very severe**
**Secondary**
**Clinical Signs of Psoriatic Lesions**
**Erythema**
**Scale**
**Plaque Elevation**
**Overall Global Response**

## Treatment Success for Efficacy in Pivotal Trials

**Success was defined as a score of 0 or 1 (none or minimal disease) on the OLA scale at week 12 (end of treatment)**