Bexarotene

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, weight increased, and amylase increased. Musculoskeletal: arthralgia, myalgia, bone pain, myasthenia, and arthrosis. Nervous: depression, agitation, ataxia, cerebrovascular accident, confusion, dizziness, hyperesthesia, hypesthesia, and neuropathy. Respiratory: pharyngitis, rhinitis, dyspnea, pleural effusion, bronchitis, cough increased, lung edema, hemoptysis, and hypoxia. Skin and Appendages: skin ulcer, acne, alopecia, skin nodule, macular papular rash, pustular rash, serous drainage, and vesicular bullous rash. Special Senses: dry eyes, conjunctivitis, ear pain, blepharitis, corneal lesion, keratitis, otitis externa, and visual field defect. Urogenital: albuminuria, hematuria, urinary incontinence, urinary tract infection, urinary urgency, dysuria, and kidney function abnormal. Table 2: Adverse Events with Incidence ≥10% in CTCL Trials Initial Assigned Dose Group (mg/m 2 /day) 300 >300 Body System N=84 N=53 Adverse Event (AE) Preferred English term coded according to Ligand-modified COSTART 5 Dictionary. , Patients are counted at most once in each AE category. N (%) N (%) METABOLIC AND NUTRITIONAL DISORDERS Hyperlipemia 66 (79) 42 (79) Hypercholesteremia 27 (32) 33 (62) Lactic dehydrogenase increased 6 (7) 7 (13) BODY AS A WHOLE Headache 25 (30) 22 (42) Asthenia 17 (20) 24 (45) Infection 11 (13) 12 (23) Abdominal pain 9 (11) 2 (4) Chills 8 (10) 7 (13) Fever 4 (5) 9 (17) Flu syndrome 3 (4) 7 (13) Back pain 2 (2) 6 (11) Infection bacterial 1 (1) 7 (13) ENDOCRINE Hypothyroidism 24 (29) 28 (53) SKIN AND APPENDAGES Rash 14 (17) 12 (23) Dry skin 9 (17) 5 (9) Exfoliative dermatitis 8 (10) 15 (28) Alopecia 3 (4) 6 (11) HEMIC AND LYMPHATIC SYSTEM Leukopenia 14 (17) 25 (47) Anemia 5 (6) 13 (25) Hypochromic anemia 3 (4) 7 (13) DIGESTIVE SYSTEM Nausea 13 (16) 4 (8) Diarrhea 6 (7) 22 (42) Vomiting 3 (4) 7 (13) Anorexia 2 (2) 12 (23) CARDIOVASCULAR SYSTEM Peripheral edema 11 (13) 6 (11) NERVOUS SYSTEM Insomnia 4 (5) 6 (11) Table 3 : Incidence of Moderately Severe and Severe Adverse Events Reported in at Least Two Patients (CTCL Trials) Initial Assigned Dose Group (mg/m 2 /day) 300 (N=84) >300 (N=53) Mod Sev Severe Mod Sev Severe Body System Adverse Event (AE) Preferred English term coded according to Ligand-modified COSTART 5 Dictionary. , Patients are counted at most once in each AE category. Patients are classified by the highest severity within each row. N (%) N (%) N (%) N (%) BODY AS A WHOLE Asthenia 1 (1) 0 (0) 11 (21) 0 (0) Headache 3 (4) 0 (0) 5 (9) 1 (2) Infection bacterial 1 (1) 0 (0) 0 (0) 2 (4) CARDIOVASCULAR SYSTEM Peripheral edema 2 (2) 1 (1) 0 (0) 0 (0) DIGESTIVE SYSTEM Anorexia 0 (0) 0 (0) 3 (6) 0 (0) Diarrhea 1 (1) 1 (1) 2 (4) 1 (2) Pancreatitis 1 (1) 0 (0) 3 (6) 0 (0) Vomiting 0 (0) 0 (0) 2 (4) 0 (0) ENDOCRINE Hypothyroidism 1 (1) 1 (1) 2 (4) 0 (0) HEMIC AND LYMPHATIC SYSTEM Leukopenia 3 (4) 0 (0) 6 (11) 1 (2) METABOLIC AND NUTRITIONAL DISORDERS Bilirubinemia 0 (0) 1 (1) 2 (4) 0 (0) Hypercholesteremia 2 (2) 0 (0) 5 (9) 0 (0) Hyperlipemia 16 (19) 6 (7) 17 (32) 5 (9) SGOT/AST increased 0 (0) 0 (0) 2 (4) 0 (0) SGPT/ALT increased 0 (0) 0 (0) 2 (4) 0 (0) RESPIRATORY SYSTEM Pneumonia 0 (0) 0 (0) 2 (4) 2 (4) SKIN AND APPENDAGES Exfoliative dermatitis 0 (0) 1 (1) 3 (6) 1 (2) Rash 1 (1) 2 (2) 1 (2) 0 (0) Table 4 : Treatment-Emergent Abnormal Laboratory Values in CTCL Trials Initial Assigned Dose (mg/m 2 /day) 300 >300 N=83 Number of patients with at least one analyte value post-baseline. N=53 Analyte Grade 3 Adapted from NCI Common Toxicity Criteria, Grade 3 and 4, Version 2.0. Patients are considered to have had a Grade 3 or 4 value if either of the following occurred: a) Value becomes Grade 3 or 4 during the study; b) Value is abnormal at baseline and worsens to Grade 3 or 4 on study, including all values beyond study drug discontinuation, as defined in data handling conventions. (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Triglycerides The denominator used to calculate the incidence rates for fasting Total Cholesterol and Triglycerides were N=75 for the 300 mg/m 2 /day initial dose group and N=44 for the >300 mg/m 2 /day initial dose group. 21 7 32 14 Total cholesterol 19 7 16 30 Alkaline phosphatase 1 0 0 2 Hyperglycemia 1 0 6 0 Hypocalcemia 1 0 0 0 Hyponatremia 1 0 9 0 SGPT/ALT 1 0 2 2 Hyperkalemia 0 0 2 0 Hypernatremia 0 1 0 0 SGOT/AST 0 0 2 2 Total bilirubin 0 0 0 2 ANC decreased 12 4 19 8 ALC decreased 7 0 15 0 WBC decreased 4 0 11 0 Hemoglobin decreased 0 0 2 0 The safety profile from the one post-approval trial with 59 subjects was generally comparable to that of the pivotal trials with the exception of serious adverse events hypertriglyceridemia, neutropenia and bone marrow failure which were observed more frequently in the TARGRETIN 300 mg/m 2 /day group than in the TARGRETIN 150 mg/m 2 /day group. Severe hypertriglyceridemia (≥800 mg/dL) was not seen in any subject in the lower dosage arm. The most common AEs by preferred term in either the TARGRETIN 300 or 150 mg/m 2 /day treatment group were as follows: hypertriglyceridemia (18 subjects [62.1%] and 17 subjects [56.7%], respectively); hypothyroidism (15 subjects [51.7%] and 13 subjects [43.3%], respectively); headache (9 subjects [31.0%] and 7 subjects [23.3%], respectively); hypercholesterolemia (8 subjects [27.6%] and 7 subjects [23.3%], respectively); neutropenia (7 subjects [24.1%] and 2 subjects [6.7%], respectively); and skin exfoliation (5 subjects [17.2%] and 5 subjects [16.7%], respectively). Higher percentage of subjects in the TARGRETIN 300 mg/m 2 /day group than in the TARGRETIN 150 mg/m 2 /day group experienced SAEs (13 subjects [44.8%] vs 11 subjects [36.7%], respectively. Of the SAEs of special interest, there were more events in the TARGRETIN 300 mg/m 2 /day group than in TARGRETIN 150 mg/m 2 /day group of bone marrow failure (3 [10.3%] vs 1 [3.3%, respectively]), neutropenia (3 [10.3%] vs 0 [0%], respectively), and hypertriglyceridemia (9 [31%] vs 2 [6.7%], respectively).

12.3 Pharmacokinetics Terminal half-life of bexarotene is approximately 7 hours. Studies in patients with advanced malignancies show approximate single dose linearity within the therapeutic range. Absorption After oral administration of TARGRETIN, bexarotene is absorbed with a T max of about 2 hours. Plasma bexarotene AUC and C max values resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, after a fat-containing meal than after a glucose solution. Distribution Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied. Elimination Metabolism Four bexarotene metabolites have been identified in plasma: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of TARGRETIN is unknown. Excretion The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose). Pharmacokinetics in Specific Populations Age: Based on the population pharmacokinetic analysis of data for 232 patients aged ≥65 years and 343 patients aged <65 years, age has no statistically significant effect on bexarotene pharmacokinetics. Body Weight and Gender: Based on the population pharmacokinetics analysis of data for 614 patients with a weight range of 26 to 145 kg, the bexarotene apparent clearance increases with increasing body weight. Gender has no statistically significant effect on bexarotene pharmacokinetics. Race: Based on the population pharmacokinetic analysis of data for 540 Caucasian and 44 Black patients, bexarotene pharmacokinetics are similar in Blacks and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of bexarotene for other races. Renal Impairment: No formal studies have been conducted with TARGRETIN in patients with renal impairment. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose), but because renal impairment can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal impairment. Hepatic Impairment: No specific studies have been conducted with TARGRETIN in patients with hepatic impairment. Because less than 1% of the dose is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. Drug Interactions Effect of Other Drugs on TARGRETIN CYP3A4 Inhibitors/Inducers: In a clinical study, concomitant administration of multiple doses of ketoconazole with TARGRETIN did not alter bexarotene plasma concentrations. This suggests that bexarotene elimination is not dependent on CYP3A4 metabolism. Paclitaxel plus Carboplatin: The co-administration of paclitaxel (200 mg/m 2 IV dose over 3 hours) plus carboplatin (at a dose expected to achieve an AUC of 6 mg●min/mL) with TARGRETIN (400 mg/m 2 orally once daily) increased the exposure to bexarotene (AUC 0-24 and C max ) by 2-fold compared to TARGRETIN alone. Atorvastatin: Bexarotene concentrations were not affected by concomitant atorvastatin administration. Effect of TARGRETIN on Other Drugs Bexarotene did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. In vitro data suggested a potential for bexarotene to inhibit CYP2C8 and induce CYP3A4. Atorvastatin: The exposure (AUC) to atorvastatin (a substrate for CYP3A4) decreased by half when atorvastatin was co-administered with TARGRETIN (400 mg/m 2 orally once daily). Tamoxifen: Based on interim data, concomitant administration of TARGRETIN and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen, possibly through induction of CYP3A4 by bexarotene. Paclitaxel: The exposure (AUC) to paclitaxel (a substrate for CYP3A4 and CYP2C8) decreased by 19% when paclitaxel (200 mg/m 2 IV dose over 3 hours) was co-administered with TARGRETIN (400 mg/m 2 orally once daily). Carboplatin: The co-administration of TARGRETIN (400 mg/m 2 orally once daily) had no effect on the exposure to free or total carboplatin.