Targretin (Bexarotene) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

The safety of Targretin^® capsules has been evaluated in clinical studies of 152 patients with CTCL who received Targretin^® 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^® 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^® 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^® 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 patients with CTCL.

In the 504 patients (CTCL and non-CTCL) who received Targretin^® 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^® 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.

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, kidney function abnormal, and breast pain.

Preferred English term coded according to Ligand-modified COSTART 5 Dictionary.

Patients are counted at most once in each AE category.

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

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

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.

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

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	Initial Assigned Dose Group (mg/m2/day)
	300 (N=84)			>300 (N=53)
	Mod Sev	Severe		Mod Sev	Severe
Body System     Adverse Event1,2	N (%)	N (%)		N (%)	N (%)
BODY AS A WHOLE     Asthenia     Headache     Infection bacterial	1 (1.2) 3 (3.6) 1 (1.2)	0 (0.0) 0 (0.0) 0 (0.0)		11 (20.8) 5 (9.4) 0 (0.0)	0 (0.0) 1 (1.9) 2 (3.8)
CARDIOVASCULAR SYS.      Peripheral edema	2 (2.4)	1 (1.2)		0 (0.0)	0 (0.0)
DIGESTIVE SYSTEM     Anorexia     Diarrhea     Pancreatitis     Vomiting	0 (0.0) 1 (1.2) 1 (1.2) 0 (0.0)	0 (0.0) 1 (1.2) 0 (0.0) 0 (0.0)		3 (5.7) 2 (3.8) 3 (5.7) 2 (3.8)	0 (0.0) 1 (1.9) 0 (0.0) 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     Hypercholesteremia     Hyperlipemia     SGOT/AST increased     SGPT/ALT increased	0 (0.0) 2 (2.4) 16 (19.0) 0 (0.0) 0 (0.0)	1 (1.2) 0 (0.0) 6 (7.1) 0 (0.0) 0 (0.0)		2 (3.8) 5 (9.4) 17 (32.1) 2 (3.8) 2 (3.8)	0 (0.0) 0 (0.0) 5 (9.4) 0 (0.0) 0 (0.0)
RESPIRATORY SYSTEM     Pneumonia	0 (0.0)	0 (0.0)		2 (3.8)	2 (3.8)
SKIN AND APPENDAGES     Exfoliative dermatitis     Rash	0 (0.0) 1 (1.2)	1 (1.2) 2 (2.4)		3 (5.7) 1 (1.9)	1 (1.9) 0 (0.0)

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.

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

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	Initial Assigned Dose (mg/m2/day)
	300			>300
	N=831			N=531
Analyte	Grade 32 (%)	Grade 42 (%)		Grade 3 (%)	Grade 4 (%)
Triglycerides3 Total Cholesterol3 Alkaline Phosphatase Hyperglycemia Hypocalcemia Hyponatremia SGPT/ALT Hyperkalemia Hypernatremia SGOT/AST Total Bilirubin ANC ALC WBC Hemoglobin	21.3 18.7 1.2 1.2 1.2 1.2 1.2 0.0 0.0 0.0 0.0 12.0 7.2 3.6 0.0	6.7 6.7 0.0 0.0 0.0 0.0 0.0 0.0 1.2 0.0 0.0 3.6 0.0 0.0 0.0		31.8 15.9 0.0 5.7 0.0 9.4 1.9 1.9 0.0 1.9 0.0 18.9 15.1 11.3 1.9	13.6 29.5 1.9 0.0 0.0 0.0 1.9 0.0 0.0 1.9 1.9 7.5 0.0 0.0 0.0