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The safety of Targretin® (bexarotene) capsules has been evaluated in clinical studies of 152 patients with CTCL who received Targretin® (bexarotene) capsules for up to 97 weeks and in 352 patients in other studies. 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 Targretin® (bexarotene) capsules are shown in Table 1. 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 higher incidence in patients treated at starting doses of greater than 300 mg/m2/day (see Table 1).

Adverse events leading to dose reduction or study drug 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 moderately severe (NCI Grade 3) and severe (NCI Grade 4) adverse events reported in two or more patients with CTCL treated at an initial dose of 300 mg/m2/day of Targretin® (bexarotene) capsules (see Table 2) 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.

As shown in Table 3, 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. 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 studies, 352 patients received Targretin® (bexarotene) capsules as monotherapy for various advanced malignancies at doses from 5 mg/m2/day to 1000 mg/m2/day. The common adverse events (incidence greater than 10%) were similar to those seen in CTCL.

In the 504 patients (CTCL and non-CTCL) who received Targretin® (bexarotene) capsules as monotherapy, drug-related serious adverse events 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 Targretin® (bexarotene) capsules, adverse events reported at an incidence of less than 10%, and not included in Tables 1-3 or discussed in other parts of labeling and possibly related to treatment were as follows:

Body as a Whole: chills, cellulitis, chest pain, sepsis, and monilia.

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.

Hematic 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, kidney function abnormal, and breast pain.

Table 1. Adverse Events with Incidence ≥ 10% in CTCL Trials

Body System
  Adverse Event1,2
Initial Assigned Dose Group (mg/m2/day)
300 >300
N=84
N(%)
N=53
N(%)
METABOLIC AND NUTRITIONAL DISORDERS
  Hyperlipemia 66(78.6) 42(79.2)
  Hypercholesteremia 27(32.1) 33(62.3)
  Lactic dehydrogenase increased 6(7.1) 7(13.2)
BODY AS A WHOLE
  Headache 25(29.8) 22(41.5)
  Asthenia 17(20.2) 24(45.3)
  Infection 11(13.1) 12(22.6)
  Abdominal pain 9(10.7) 2(3.8)
  Chills 8(9.5) 7(13.2)
  Fever 4(4.8) 9(17.0)
  Flu syndrome 3(3.6) 7(13.2)
  Back pain 2(2.4) 6(11.3)
  Infection bacterial 1(1.2) 7(13.2)
ENDOCRINE
  Hypothyroidism 24(28.6) 28(52.8)
SKIN AND APPENDAGES
  Rash 14(16.7) 12(22.6)
  Dry skin 9(10.7) 5(9.4)
  Exfoliative dermatitis 8(9.5) 15(28.3)
  Alopecia 3(3.6) 6(11.3)
HEMIC AND LYMPHATIC SYSTEM
  Leukopenia 14(16.7) 25(47.2)
  Anemia 5(6.0) 13(24.5)
  Hypochromic anemia 3(3.6) 7(13.2)
DIGESTIVE SYSTEM
  Nausea 13(15.5) 4(7.5)
  Diarrhea 6(7.1) 22(41.5)
  Vomiting 3(3.6) 7(13.2)
  Anorexia 2(2.4) 12(22.6)
CARDIOVASCULAR SYSTEM
  Peripheral edema 11(13.1) 6(11.3)
NERVOUS SYSTEM
  Insomnia 4(4.8) 6(11.3)
1Preferred English term coded according to Ligand-modified COSTART 5 Dictionary.
2Patients are counted at most once in each AE category.

Table 2. Incidence of Moderately Severe and Severe Adverse Events Reported in at Least Two Patients (CTCL Trials)

Body System
  Adverse Event1,2
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(1.2) 0(0.0) 11(20.8) 0(0.0)
  Headache 3(3.6) 0(0.0) 5(9.4) 1(1.9)
  Infection bacterial 1(1.2) 0(0.0) 0(0.0) 2(3.8)
CARDIOVASCULAR SYSTEM
  Peripheral edema 2(2.4) 1(1.2) 0(0.0) 0(0.0)
DIGESTIVE SYSTEM
  Anorexia 0(0.0) 0(0.0) 3(5.7) 0(0.0)
  Diarrhea 1(1.2) 1(1.2) 2(3.8) 1(1.9)
  Pancreatitis 1(1.2) 0(0.0) 3(5.7) 0(0.0)
  Vomiting 0(0.0) 0(0.0) 2(3.8) 0(0.0)
ENDOCRINE
  Hypothyroidism 1(1.2) 1(1.2) 2(3.8) 0(0.0)
HEM. & LYMPH. SYS.
  Leukopenia 3(3.6) 0(0.0) 6(11.3) 1(1.9)
META. AND NUTR. DIS.
  Bilirubinemia 0(0.0) 1(1.2) 2(3.8) 0(0.0)
  Hypercholesteremia 2(2.4) 0(0.0) 5(9.4) 0(0.0)
  Hyperlipemia 16(19.0) 6(7.1) 17(32.1) 5(9.4)
  SGOT/AST increased 0(0.0) 0(0.0) 2(3.8) 0(0.0)
  SGPT/ALT increased 0(0.0) 0(0.0) 2(3.8) 0(0.0)
RESPIRATORY SYSTEM
  Pneumonia 0(0.0) 0(0.0) 2(3.8) 2(3.8)
SKIN AND APPENDAGES
  Exfoliative dermatitis 0(0.0) 1(1.2) 3(5.7) 1(1.9)
  Rash 1(1.2) 2(2.4) 1(1.9) 0(0.0)
1Preferred English term coded according to Ligand-modified COSTART 5 Dictionary.
2Patients are counted at most once in each A Ecategory. Patients are classified by the highest severity within each row.

Table 3. Treatment-Emergent Abnormal Laboratory Values in CTCL Trials

Analyte Initial Assigned Dose (mg/m2/day)
300 >300
N=831 N=531
Grade 32 Grade 42 Grade 3 Grade 4
(%) (%) (%) (%)
Triglycerides3 21.3 6.7 31.8 13.6
Total Cholesterol3 18.7 6.7 15.9 29.5
Alkaline Phosphatase 1.2 0.0 0.0 1.9
Hyperglycemia 1.2 0.0 5.7 0.0
Hypocalcemia 1.2 0.0 0.0 0.0
Hyponatremia 1.2 0.0 9.4 0.0
SGPT/ALT 1.2 0.0 1.9 1.9
Hyperkalemia 0.0 0.0 1.9 0.0
Hypernatremia 0.0 1.2 0.0 0.0
SGOT/AST 0.0 0.0 1.9 1.9
Total Bilirubin 0.0 0.0 0.0 1.9
ANC 12.0 3.6 18.9 7.5
ALC 7.2 0.0 15.1 0.0
WBC 3.6 0.0 11.3 0.0
Hemoglobin 0.0 0.0 1.9 0.0
1Number of patients with at least one analyte value post-baseline.
2Adapted 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.
3The 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/m2/day initial dose group.