Bexarotene
Generic: BEXAROTENE
Basic Information
Manufacturer
Upsher-Smith Laboratories, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
7437a43f-172a-4f4e-8132-fe23b00224f9
Indications & Usage
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 )
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 )
Adverse Reactions
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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 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 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 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 (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 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 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/m 2 /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 Initial Assigned Dose Group (mg/m 2 /day) 300 >300 Body System N=84 N=53 Adverse Event 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 Severe Severe Mod Severe Severe Body System Adverse Event 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 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 Analyte (%) (%) (%) (%) 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
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 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 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 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 (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 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 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/m 2 /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 Initial Assigned Dose Group (mg/m 2 /day) 300 >300 Body System N=84 N=53 Adverse Event 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 Severe Severe Mod Severe Severe Body System Adverse Event 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 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 Analyte (%) (%) (%) (%) 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