1. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 1 Clinical Safety Oral Tazarotene NDA 21-701 Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products

2. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 2 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 data base derived from the following trials: –2 phase 3 double-blind placebo controlled trials –2 open-label phase 3 trials

3. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 3 SafetySafety 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 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

4. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 4 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 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

5. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 5 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% 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%

6. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 6 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) 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)

7. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 7 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% 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%

8. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 8 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% 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%

9. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 9 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 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

10. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 10 Elevated Serum Triglycerides StudyTazarotene N = 166 Placebo N=171 048PMild 2.3-2.79 mmol/ L Moderate 2.8-5.6 mmol/L Severe >5.61 mm ol/ L Total*Mild 2.3-2.79 mmol/ L Moderate 2.8-5.6 mmol/L Severe >5.6 mm ol/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%) 049PTazarotene 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

11. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 11 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 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

12. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 12 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 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

13. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 13 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%) 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%)

14. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 14 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%) 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%)

15. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 15 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 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

16. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 16 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%) 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%)

17. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 17 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 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

18. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 18 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 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

19. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 19 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 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

20. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 20 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” 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”

21. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 21 Other Adverse Events Post Treatment Period Cheilitis (38.2%) Dry skin (17.1%) Asthenia (7.9%) Pruritus (6.6%) Cheilitis (38.2%) Dry skin (17.1%) Asthenia (7.9%) Pruritus (6.6%)

22. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 22 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 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

23. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 23 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. 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.

24. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 24 Ophthalmologic Conclusion Several metrics employed during trials –Visual acuity –Biomicroscopy –Ophthalmoscopy No signal detected Several metrics employed during trials –Visual acuity –Biomicroscopy –Ophthalmoscopy No signal detected

25. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 25 PregnanciesPregnancies 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 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

26. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 26 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 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

27. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 27 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% 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%

28. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 28 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) 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)

29. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 29 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 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

30. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 30 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 Primary –Overall Lesional Assessment Score 0 – none 5 – very severe Secondary –Clinical Signs of Psoriatic Lesions Erythema Scale Plaque Elevation –Overall Global Response

31. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 31 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)