TARGRETIN SIDE EFFECTS
- Generic Name: bexarotene
- Brand Name: Targretin
- Drug Class: Antineoplastics, Other
SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:
- Hyperlipidemia
- Pancreatitis
- Hepatotoxicity, Cholestasis, and Hepatic Failure
- Hypothyroidism
- Neutropenia
- Cataracts
- Vitamin A Supplementation Hazard
- Hypoglycemia Risk in Patients with Diabetes Mellitus
- Photosensitivity
- Laboratory Tests
- Drug/Laboratory Test Interactions
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 TARGRETIN has been evaluated in two clinical trials of 152 patients with CTCL who received TARGRETIN 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 TARGRETIN 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 TARGRETIN 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 TARGRETIN (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 TARGRETIN as monotherapy for various advanced malignancies at doses from 5 mg/m2/day to 1000 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 TARGRETIN 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 TARGRETIN, adverse reactions reported at an incidence of less than 10% and not included in Tables 2 through 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 1: Adverse Events with Incidence ≥10% in CTCL Trials
| Initial Assigned Dose Group (mg/m2/day) |
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| 300 | >300 | |
| Body System | N=84 | N=53 |
| Adverse Event (AE)*,† | 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) |
| * Preferred English term coded according to Ligand-modified COSTART 5 Dictionary. † Patients are counted at most once in each AE category. |
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Table 2: Incidence of Moderately Severe and Severe Adverse Events Reported in at Least Two Patients (CTCL Trials)
| Reported in at Least Two Patients (CTCL Trials) | Initial Assigned Dose Group (mg/m2/day) | |||
| 300 (N=84) | >300 (N=53) | |||
| Mod Sev | Severe | Mod Sev | Severe | |
| Body System | ||||
| Adverse Event (AE)*,† | 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) |
| * 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. |
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Table 3: Treatment-Emergent Abnormal Laboratory Values in CTCL Trials
| Initial Assigned Dose (mg/m2/day) | ||||
| 300 | >300 | |||
| N=83* | N=53* | |||
| Analyte | 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 |
| * 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. |
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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 TARGRETIN 300 mg/m2/day group than in the TARGRETIN 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 TARGRETIN 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 TARGRETIN 300 mg/m2/day group than in the TARGRETIN 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 TARGRETIN 300 mg/m2/day group than in TARGRETIN 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 hypertriglyceridemia (9 [31%] vs 2 [6.7%], respectively).
SRC: NLM .