Targretin

ADVERSE REACTIONS The safety of Targretin gel has been assessed in clinical studies of 117 patients with CTCL who received Targretin gel for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received Targretin gel for up to 98 weeks. The mean duration of therapy for these 50 patients was 199 days. The most common adverse events reported with an incidence at the application site of at least 10% in patients with CTCL were rash, pruritus, skin disorder, and pain. Adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus. Of the 49 patients (98%) who experienced any adverse event, most experienced events categorized as mild (9 patients, 18%) or moderate (27 patients, 54%). There were 12 patients (24%) who experienced at least one moderately severe adverse event. The most common moderately severe events were rash (7 patients, 14%) and pruritus (3 patients, 6%). Only one patient (2%) experienced a severe adverse event (rash). In the patients with CTCL receiving Targretin gel, adverse events reported regardless of relationship to study drug at an incidence of ≥5% are presented in Table 1. A similar safety profile for Targretin gel was demonstrated in the Phase I-II program. For the 67 patients enrolled in the Phase I-II program, the mean duration of treatment was 436 days (range 12-1203 days). As in the multicenter study, the most common adverse events regardless of relationship to study drug in the Phase I-II program were rash (78%), pain (40%), and pruritus (40%). Table 1. Incidence of All Adverse Events* and Application Site Adverse Events with Incidence ≥5% for All Application Frequencies of Targretin Gel in the Multicenter CTCL Study * Regardless of association with treatment Includes Investigator terms such as: 1 Contact dermatitis, irritant contact dermatitis, irritant dermatitis 2 Pruritus, itching, itching of lesion 3 Erythema, scaling, irritation, redness, rash, dermatitis 4 Skin inflammation, excoriation, sticky or tacky sensation of skin; NOS = Not Otherwise Specified To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. All Adverse Events Application Site Adverse Events COSTART 5 Body System/Preferred Term N = 50 n (%) N = 50 n (%) Skin and Appendages Contact Dermatitis 1 7 (14) 4 (8) Exfoliative Dermatitis 3 (6) 0 Pruritus 2 18 (36) 9 (18) Rash 3 36 (72) 28 (56) Maculopapular Rash 3 (6) 0 Skin Disorder (NOS) 4 13 (26) 9 (18) Sweating 3 (6) 0 Body as a Whole Asthenia 3 (6) 0 Headache 7 (14) 0 Infection 9 (18) 0 Pain 15 (30) 9 (18) Cardiovascular Edema 5 (10) 0 Peripheral Edema 3 (6) 0 Hemic and Lymphatic Leukopenia 3 (6) 0 Lymphadenopathy 3 (6) 0 WBC Abnormal 3 (6) 0 Metabolic and Nutritional Hyperlipemia 5 (10) 0 Nervous Paresthesia 3 (6) 3 (6) Respiratory Cough Increased 3 (6) 0 Pharyngitis 3 (6) 0

<table ID="_RefID0EOAAE" width="100%"><caption>Table 1. Incidence of All Adverse Events* and Application Site Adverse Events with Incidence &#x2265;5% for All Application Frequencies of Targretin Gel in the Multicenter CTCL Study </caption><col width="50%"/><col width="25%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" styleCode="Botrule" valign="top"> * Regardless of association with treatment Includes Investigator terms such as: ¹ Contact dermatitis, irritant contact dermatitis, irritant dermatitis ² Pruritus, itching, itching of lesion ³ Erythema, scaling, irritation, redness, rash, dermatitis ⁴ Skin inflammation, excoriation, sticky or tacky sensation of skin; NOS = Not Otherwise Specified </td></tr><tr><td align="left" colspan="3" styleCode="Botrule" valign="top"><content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.</content></td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">All Adverse Events</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Application Site Adverse Events</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">COSTART 5</content> <content styleCode="bold">Body System/Preferred Term</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N = 50</content> <content styleCode="bold">n (%)</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N = 50</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Skin and Appendages </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Contact Dermatitis¹</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 7 (14) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 4 (8) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Exfoliative Dermatitis </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus²</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 18 (36) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 9 (18) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash³</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 36 (72) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 28 (56) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Maculopapular Rash </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Skin Disorder (NOS)⁴</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 13 (26) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 9 (18) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Sweating </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Body as a Whole </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenia </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 7 (14) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 9 (18) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 15 (30) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 9 (18) </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cardiovascular </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 5 (10) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hemic and Lymphatic </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lymphadenopathy </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> WBC Abnormal </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Metabolic and Nutritional </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipemia </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 5 (10) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nervous </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Respiratory </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough Increased </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pharyngitis </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> 3 (6) </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> 0 </paragraph></td></tr></tbody></table>