Bexarotene: Package Insert and Label Information

BEXAROTENE- bexarotene capsule, liquid filled
Mylan Pharmaceuticals Inc.

WARNING: BIRTH DEFECTS

Bexarotene is a member of the retinoid class of drugs that is associated with birth defects in humans. Bexarotene also caused birth defects when administered orally to pregnant rats. Bexarotene must not be administered to a pregnant woman. (8.1)

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.

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of bexarotene capsules is 300 mg/m2 /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/m2 /day)

Number of 75 mg

Bexarotene Capsules

Body Surface Area

(m2)

Total Daily Dose

(mg/day)

0.88 to 1.12

300

4

1.13 to 1.37

375

5

1.38 to 1.62

450

6

1.63 to 1.87

525

7

1.88 to 2.12

600

8

2.13 to 2.37

675

9

2.38 to 2.62

750

10

Dose Modification Guidelines: The 300 mg/m2 /day dose level of bexarotene capsules may be adjusted to 200 mg/m2 /day then to 100 mg/m2 /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/m2 /day is well tolerated, the dose may be escalated to 400 mg/m2 /day with careful monitoring.

Duration of Therapy: In clinical trials in CTCL, bexarotene was administered for up to 97 weeks.

Bexarotene capsules should be continued as long as the patient is deriving benefit.

3 DOSAGE FORMS AND STRENGTHS

Capsules: 75 mg, white to off-white, oblong soft gelatin capsules printed with B75 in black ink.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 Hyperlipidemia

Bexarotene induces substantial elevations in lipids in most patients. About 70% of patients with CTCL who received an initial dose of ≥300 mg/m2 /day of bexarotene had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% had values over 800 mg/dL with a median of about 1,200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m2 /day or greater than 300 mg/m2 /day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m2 /day or greater than 300 mg/m2 /day, respectively, of bexarotene. Monitor lipid changes and treat abnormalities during therapy. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction and/or concomitant antilipemic therapy.

Perform fasting blood lipid determinations before bexarotene therapy is initiated and weekly until the lipid response to bexarotene is established, which usually occurs within two to four weeks, and monitor at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating bexarotene therapy. Maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae [see Warnings and Precautions (5.2) ]. If fasting triglycerides are elevated or become elevated during treatment, institute antilipemic therapy, and if necessary, reduce or interrupt the dose of bexarotene. In the 300 mg/m2 /day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction, avoid gemfibrozil use with bexarotene [see Drug Interactions (7) ].

5.2 Pancreatitis

Acute pancreatitis, including a fatal case, has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with bexarotene; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non‑CTCL cancer died of pancreatitis. Interrupt bexarotene and evaluate if pancreatitis is suspected. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) may be at greater risk for pancreatitis associated with bexarotene [see Warnings and Precautions (5.1) ].

5.3 Hepatotoxicity, cholestasis, and hepatic failure

Bexarotene caused elevations in liver chemistry tests (LFTs) in 5% (AST), 2% (ALT), and 0% (bilirubin) in patients with CTCL receiving an initial dose of 300 mg/m2 /day. In contrast, with an initial dose greater than 300 mg/m2 /day of bexarotene, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure. In clinical trials, elevated LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Obtain baseline LFTs and monitor LFTs after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Interrupt or discontinue bexarotene if test results exceed three times the upper limit of normal values for AST, ALT, or bilirubin.

5.4 Hypothyroidism

Bexarotene induces hypothyroidism in about half of all patients treated by causing a reversible reduction in levels of thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH). The incidence of decreases in TSH and total T4 were about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m2 /day. Hypothyroidism was reported as an adverse event in 29% of patients. Consider treatment with thyroid hormone supplementation in patients with hypothyroidism. In the 300 mg/m2 /day initial dose group, 37% of patients were treated with thyroid hormone replacement. Obtain baseline thyroid function tests and monitor patients during treatment.

5.5 Neutropenia

Leukopenia in the range of 1,000 to <3,000 WBC x 106 /L occurred in 18% of patients with CTCL receiving an initial dose of 300 mg/m2 /day of bexarotene. Patients receiving an initial dose greater than 300 mg/m2 /day of bexarotene had an incidence of leukopenia of 43%. No patient with CTCL treated with bexarotene developed leukopenia of less than 1,000 WBC x 106 /L. The usual time to onset of leukopenia was four to eight weeks after initiating bexarotene. The leukopenia observed in most patients was predominately neutropenia. In the 300 mg/m2 /day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during bexarotene therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Obtain complete blood counts (CBC) at baseline and periodically during treatment.

5.6 Cataracts

Posterior subcapsular cataracts occurred in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. New cataracts or worsening of previous cataracts occurred in 15 of 79 patients who were monitored with serial slit lamp examinations. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of bexarotene and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with bexarotene who experience visual difficulties should have an appropriate ophthalmologic evaluation.

5.7 Vitamin A Supplementation Hazard

In clinical studies, patients were advised to limit vitamin A intake to ≤15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

5.8 Hypoglycemia Risk in Patients with Diabetes Mellitus

In patients using insulin, agents enhancing insulin secretion (e.g., sulfonylureas), or insulin-sensitizers (e.g., thiazolidinedione class), based on the mechanism of action, bexarotene could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of bexarotene as monotherapy.

5.9 Photosensitivity

Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Phototoxicity manifested as sunburn and skin sensitivity to sunlight occurred in patients who were exposed to direct sunlight while receiving bexarotene. Advise patients to minimize exposure to sunlight and artificial ultraviolet light while receiving bexarotene.

5.10 Laboratory Tests

Before initiating bexarotene therapy, obtain a CBC, fasting lipid profile, liver function tests, and a thyroid profile. Fasting triglycerides should be normal or normalized with appropriate intervention prior to therapy. Monitor lab tests during bexarotene therapy as described above.

Hyperlipidemia usually occurs within the initial two to four weeks. Therefore, weekly lipid determinations are recommended during this interval. Subsequently, in patients not hyperlipidemic, determinations can be performed less frequently [see Warnings and Precautions (5.1) ].

A white blood cell count with differential should be obtained at baseline and periodically during treatment. Baseline liver function tests should be obtained and should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, periodically thereafter during treatment. Baseline thyroid function tests should be obtained and then monitored during treatment as indicated [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6)].

5.11 Drug/Laboratory Test Interactions

CA125 assay values in patients with ovarian cancer may be increased by bexarotene therapy.

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) ]

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 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/m2 /day of bexarotene 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/m2 /day (see Table 2).

Adverse reactions leading to bexarotene 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/m2 /day of bexarotene (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/m2 /day than in patients treated at a starting dose of 300 mg/m2 /day.

In patients with CTCL receiving an initial dose of 300 mg/m2 /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/m2 /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 as monotherapy for various advanced malignancies at doses from 5 mg/m2 /day to 1,000 mg/m2 /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 bexarotene 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/m2 /day of bexarotene, adverse reactions reported at an incidence of less than 10% and not included in Tables 2 to 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
Body System Adverse Event *, Initial Assigned Dose Group (mg/m2/day)
300 >300
N=84N (%) N=53N (%)
*
Preferred English term coded according to Ligand-modified COSTART 5 Dictionary.
Patients are counted at most once in each AE category.

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)
*
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.

Body System

Adverse Event *

Initial Assigned Dose Group (mg/m2 /day)

300 (N=84)

>300 (N=53)

Mod Sev

Severe

Mod Sev

Severe

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 SYS.

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)

HEM. & LYMPH. SYS.

Leukopenia

3 (4)

0 (0)

6 (11)

1 (2)

META. AND NUTR. DIS.

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
*
Number of patients with at least one analyte value post-baseline.
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.
The denominator used to calculate the incidence rates for fasting Total Cholesterol and Triglycerides were N=75 for the 300 mg/m2 /day initial dose group and N=44 for the >300 mg/m2 /day initial dose group.

Analyte

Initial Assigned Dose (mg/m2 /day)

300

>300

N=83*

N=53*

Grade 3

(%)

Grade 4

(%)

Grade 3

(%)

Grade 4

(%)

Triglycerides

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 bexarotene 300 mg/m2 /day group than in the bexarotene 150 mg/m2 /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 bexarotene 300 or 150 mg/m2 /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 bexarotene 300 mg/m2 /day group than in the bexarotene 150 mg/m2 /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 bexarotene 300 mg/m2 /day group than in bexarotene 150 mg/m2 /day group of bone marrow failure (3 [10.3%] vs 1 [3.3%, respectively]), neutropenia (3 [10.3%] vs 0 [0%], respectively), and of hypertriglyceridemia (9 [31%] vs 2 [6.7%], respectively).

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