Bexarotene

1 INDICATIONS AND USAGE 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. Bexarotene capsules are 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 bexarotene capsules is 300 mg/m 2 /day (see Table 1). Bexarotene capsules 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: Bexarotene Capsules Initial Dose Calculation According to Body Surface Area Initial Dose Level (300 mg/m 2 /day) Number of 75 mg Bexarotene 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 bexarotene capsules 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 eight 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, bexarotene capsules were administered for up to 97 weeks. Bexarotene capsules should be continued as long as the patient is deriving benefit. • Recommended initial dose is 300 mg/m 2 /day. ( 2 ) • Take bexarotene capsules 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 )

3 DOSAGE FORMS AND STRENGTHS Capsules: 75 mg, opaque off-white, oblong soft gelatin capsules, imprinted with black ink “A832”. Capsules: 75 mg ( 3 )

4 CONTRAINDICATIONS • Pregnancy (Boxed Warning, 4.1 ) • Known hypersensitivity to bexarotene ( 4.2 ) 4.1 Pregnancy Bexarotene can cause fetal harm when administered to a pregnant female. Bexarotene is a member of the retinoid class of drugs that is associated with birth defects in humans and is contraindicated in females who are pregnant. Bexarotene was also teratogenic and caused developmental mortality when administered orally to pregnant rats. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential risk to a fetus. 4.2 Hypersensitivity Bexarotene capsules are contraindicated in patients with a known serious hypersensitivity to bexarotene or other components of the product.

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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 bexarotene has been evaluated in two clinical trials of 152 patients with CTCL who received bexarotene capsules 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 bexarotene capsules 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 bexarotene capsule 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 bexarotene capsules (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 bexarotene capsules 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 …

7 DRUG INTERACTIONS Effect of Other Drugs on Bexarotene Capsules Gemfibrozil: Concomitant administration of bexarotene capsules and gemfibrozil resulted in increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with bexarotene capsules is not recommended. Effect of Bexarotene Capsules on Other Drugs Bexarotene 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 bexarotene capsules 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 bexarotene capsule therapy.

Drug Interactions Effect of Other Drugs on Bexarotene CYP3A4 Inhibitors/Inducers: In a clinical study, concomitant administration of multiple doses of ketoconazole with bexarotene capsules 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 bexarotene capsules (400 mg/m 2 orally once daily) increased the exposure to bexarotene (AUC 0-24 and C max ) by 2-fold compared to bexarotene capsules alone. Atorvastatin: Bexarotene concentrations were not affected by concomitant atorvastatin administration. Effect of Bexarotene 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 bexarotene capsules (400 mg/m 2 orally once daily). Tamoxifen: Based on interim data, concomitant administration of bexarotene capsules 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 bexarotene capsules (400 mg/m 2 orally once daily). Carboplatin: The co-administration of bexarotene capsules (400 mg/m 2 orally once daily) had no effect on the exposure to free or total carboplatin.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Bexarotene, a retinoid, can cause fetal harm based on findings from animal studies when administered to a pregnant female and is contraindicated during pregnancy. Bexarotene was teratogenic and caused developmental mortality in rats following oral administration during organogenesis [see Data] . Bexarotene capsules must not be given to a pregnant female or a female who intends to become pregnant. If pregnancy does occur during treatment with bexarotene capsules, immediately discontinue the drug and advise the pregnant female of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data Bexarotene caused malformations when administered orally to pregnant rats during days 7-17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. The plasma AUC of bexarotene in rats at 4 mg/kg/day is approximately one third the AUC in humans at the recommended daily dose. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no effect dose for fetal effects in rats was 1 mg/kg/day (producing an AUC approximately one sixth of the AUC at the recommended human daily dose). 8.2 Lactation Risk Summary There is no information regarding the presence of bexarotene in human milk, the effects on the breast fed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bexarotene, discontinue breastfeeding during treatment with bexarotene capsules. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Obtain a negative serum pregnancy test (e.g., serum beta-human chorionic gonadotropin [beta-HCG]) with a sensitivity of at least 50 mIU/L within one week prior to bexarotene capsule therapy. Obtain another pregnancy test at monthly intervals while the patient remains on bexarotene capsules. Contraception Females Bexarotene can cause fetal harm when administered to a pregnant female [ see Use in Specific Populations (8.1) ]. Females of reproductive potential should be advised to avoid becoming pregnant when bexarotene is used. Effective contraception must be used for one month prior to the initiation of therapy, during therapy and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Bexarotene can potentially induce metabolic enzymes and thereby theoretically reduce the plasma concentrations of oral or other systemic hormonal contraceptives [ see Drug Interactions (7) ]. Thus, if treatment with bexarotene capsules is intended in a female with reproductive potential, it is strongly recommended that one of the two reliable forms of contraception should be non-hormonal. Bexarotene capsule therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of bexarotene capsules should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced. Males Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while taking bexarotene capsules and for at least one month after the last dose of drug. 8.4 Pediatric Use Safety and effectiveness of bexarotene in pediatric patients have not been established. 8.5 Geriatric Use Of the total patients with CTCL in clinical trials of bexarotene capsules, 64% were 60 years or older, while 33% we …

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.

11 DESCRIPTION Bexarotene capsules contain bexarotene, a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). The chemical name of bexarotene is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid, and the structural formula is as follows: Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C 24 H 28 O 2 . It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP. Each bexarotene capsule contains 75 mg of bexarotene for oral administration. It also contains the following inactive ingredients: gelatin, nitrogen, butylated hydroxyanisole, glycerin, hydrolyzed gelatin, medium chain triglyceride, Shellac glaze, FD&C red #40, FD&C blue #1, FD&C yellow #6, propylene glycol, simethicone, polyethylene glycol 400, polysorbate 20, povidone, sorbitol, 1,4-sorbitan, mannitol, soy lecithin and titanium dioxide. structure

10 OVERDOSAGE Doses up to 1000 mg/m 2 /day of bexarotene capsules have been administered in short-term trials in patients with advanced cancer without acute toxic effects. Single doses of 1500 mg/kg and 720 mg/kg were tolerated without significant toxicity in rats and dogs, respectively. These doses are approximately 30 and 50 times, respectively, the recommended human dose on a mg/m 2 basis.

16 HOW SUPPLIED/STORAGE AND HANDLING Bexarotene capsules are supplied as 75 mg off-white, opaque, oblong soft gelatin capsules, imprinted with black ink “A78”, in high density polyethylene bottles with child-resistant closures. Bottles of 100 capsules: NDC 43975-315-10 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Avoid exposing to high temperatures and humidity after the bottle is opened. Protect from light.