Bexarotene

12.1 Mechanism of Action Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRß, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

1 INDICATIONS AND USAGE TARGRETIN ® (bexarotene) Capsules are indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. TARGRETIN (bexarotene) is a retinoid indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended initial dose of TARGRETIN is 300 mg/m 2 /day (see Table 1). TARGRETIN should be taken as a single oral daily dose with a meal. For precautions to prevent pregnancy and birth defects in women of child-bearing potential [ see Use in Specific Populations (8.1) ]. Table 1: TARGRETIN Initial Dose Calculation According to Body Surface Area Initial Dose Level (300 mg/m 2 /day) Number of 75 mg TARGRETIN Capsules Body Surface Area (m 2 ) Total Daily Dose (mg/day) 0.88 – 1.12 300 4 1.13 – 1.37 375 5 1.38 – 1.62 450 6 1.63 – 1.87 525 7 1.88 – 2.12 600 8 2.13 – 2.37 675 9 2.38 – 2.62 750 10 Dose Modification Guidelines: The 300 mg/m 2 /day dose level of TARGRETIN may be adjusted to 200 mg/m 2 /day then to 100 mg/m 2 /day, or temporarily suspended, if necessitated by toxicity. When toxicity is controlled, doses may be carefully readjusted upward. If there is no tumor response after 8 weeks of treatment and if the initial dose of 300 mg/m 2 /day is well tolerated, the dose may be escalated to 400 mg/m 2 /day with careful monitoring. Duration of Therapy: In clinical trials in CTCL, TARGRETIN was administered for up to 97 weeks. TARGRETIN should be continued as long as the patient is deriving benefit. • Recommended initial dose is 300 mg/m 2 /day. ( 2 ) • Take TARGRETIN as a single oral daily dose with a meal. ( 2 ) • Dose Adjustment: May be adjusted to 200 mg/m 2 /day then to 100 mg/m 2 /day. ( 2 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: • Hyperlipidemia [ see Warnings and Precautions (5.1) ] • Pancreatitis [ see Warnings and Precautions (5.2) ] • Hepatotoxicity, Cholestasis, and Hepatic Failure [ see Warnings and Precautions (5.3) ] • Hypothyroidism [ see Warnings and Precautions (5.4) ] • Neutropenia [ see Warnings and Precautions (5.5) ] • Cataracts [ see Warnings and Precautions (5.6) ] • Vitamin A Supplementation Hazard [ see Warnings and Precautions (5.7) ] • Hypoglycemia Risk in Patients with Diabetes Mellitus [ see Warnings and Precautions (5.8) ] • Photosensitivity [ see Warnings and Precautions (5.9) ] • Laboratory Tests [ see Warnings and Precautions (5.10) ] • Drug/Laboratory Test Interactions [ see Warnings and Precautions (5.11) ] The most common adverse reactions (greater than 10%) include: hyperlipidemia, hypercholesteremia, headache, hypothyroidism, asthenia, leukopenia, rash, nausea, infection, peripheral edema, abdominal pain, and dry skin. ( 6.1 ) 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TARGRETIN has been evaluated in two clinical trials of 152 patients with CTCL who received TARGRETIN for up to 97 weeks and in 352 patients in other trials. The mean duration of therapy for the 152 patients with CTCL was 166 days. The most common adverse events reported with an incidence of at least 10% in patients with CTCL treated at an initial dose of 300 mg/m 2 /day of TARGRETIN are shown in Table 2. The events at least possibly related to treatment are lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol and decreased HDL cholesterol), hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, and dry skin. Most adverse events occurred at a greater incidence in patients treated at starting doses of greater than 300 mg/m 2 /day (see Table 2). Adverse reactions leading to TARGRETIN dose reduction or discontinuation in at least two patients were hyperlipemia, neutropenia/leukopenia, diarrhea, fatigue/lethargy, hypothyroidism, headache, liver function test abnormalities, rash, pancreatitis, nausea, anemia, allergic reaction, muscle spasm, pneumonia, and confusion. The NCI Grade 3 and NCI Grade 4 adverse reactions reported in two or more patients with CTCL treated at an initial dose of 300 mg/m 2 /day of TARGRETIN (see Table 3) were hypertriglyceridemia, pruritus, headache, peripheral edema, leukopenia, rash, and hypercholesteremia. Most of these moderately severe or severe adverse events occurred at a higher rate in patients treated at starting doses of greater than 300 mg/m 2 /day than in patients treated at a starting dose of 300 mg/m 2 /day. In patients with CTCL receiving an initial dose of 300 mg/m 2 /day, the incidence of NCI Grade 3 or 4 elevations in triglycerides and total cholesterol was 28% and 25%, respectively (Table 4). In contrast, in patients with CTCL receiving greater than 300 mg/m 2 /day, the incidence of NCI Grade 3 or 4 elevated triglycerides and total cholesterol was 45% and 45%, respectively. Other Grade 3 and 4 laboratory abnormalities are shown in Table 3. In addition to the 152 patients enrolled in the two CTCL trials, 352 patients received TARGRETIN as monotherapy for various advanced malignancies at doses from 5 mg/m 2 /day to 1000 mg/m 2 /day. The common adverse reactions (incidence greater than 10%) were similar to those seen in patients with CTCL. In the 504 patients (CTCL and non-CTCL) who received TARGRETIN as monotherapy, drug-related serious adverse reactions that were fatal, in one patient each, were acute pancreatitis, subdural hematoma, and liver failure. In the patients with CTCL receiving an initial dose of 300 mg/m 2 /day of TARGRETIN, adverse reactions reported at an incidence of less than 10% and not included in Tables 2 through 4 or discussed in other parts of labeling and possibly related to treatment were as follows: Body as a Whole: chills, cellulitis, chest pain, breast pain, sepsis, and monilia infection. Cardiovascular: hemorrhage, hypertension, angina pectoris, right heart failure, syncope, and tachycardia. Digestive: constipation, dry mouth, flatulence, colitis, dyspepsia, cheilitis, gastroenteritis, gingivitis, liver failure, and melena. Hemic and Lymphatic: eosinophilia, thrombocythemia, coagulation time increased, lymphocytosis, and thrombocytopenia. Metabolic and Nutritional: LDH increased, creatinine increased, hypoproteinemia, hyperglycemia, weight decreased, we

7 DRUG INTERACTIONS Effect of Other Drugs on TARGRETIN Gemfibrozil: Concomitant administration of TARGRETIN and gemfibrozil resulted in increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with TARGRETIN is not recommended. Effect of TARGRETIN on Other Drugs TARGRETIN may be an inducer for the CYP3A4 enzymes, and may reduce plasma concentrations of other substrates metabolized by CYP3A4. Drug products which may be affected include oral or other systemic hormonal contraceptives. Thus, if treatment with TARGRETIN is intended for a female with reproductive potential, it is strongly recommended that a non-hormonal contraception be considered. [ see Use in Specific Populations (8.3) , Clinical Pharmacology (12.3) ]. Laboratory Test Interference CA125 assay values in patients with ovarian cancer may be increased by TARGRETIN therapy.