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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
  Hyperlipemia 66(78.6) 42(79.2)
  Hypercholesteremia 27(32.1) 33(62.3)
  Lactic dehydrogenase increased 6(7.1) 7(13.2)
  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)
  Hypothyroidism 24(28.6) 28(52.8)
  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)
  Leukopenia 14(16.7) 25(47.2)
  Anemia 5(6.0) 13(24.5)
  Hypochromic anemia 3(3.6) 7(13.2)
  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)
  Peripheral edema 11(13.1) 6(11.3)
  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(%)
  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)
  Peripheral edema 2(2.4) 1(1.2) 0(0.0) 0(0.0)
  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)
  Hypothyroidism 1(1.2) 1(1.2) 2(3.8) 0(0.0)
  Leukopenia 3(3.6) 0(0.0) 6(11.3) 1(1.9)
  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)
  Pneumonia 0(0.0) 0(0.0) 2(3.8) 2(3.8)
  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 nolvadex tamoxifen 10 mg astrazeneca canada 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.


Drug-Food Interaction

In all clinical trials, patients were instructed to take Targretin® (bexarotene) capsules with or immediately following a meal. In one clinical study, plasma bexarotene AUC and Cmax values were substantially higher following a fat-containing meal versus those following the administration of a glucose solution. Because safety and efficacy data are based upon administration with food, it is recommended that Targretin® (bexarotene) capsules be administered with food (see CLINICAL PHARMACOLOGY: Food Effects and DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

No formal studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed by cytochrome P450 3A4.

On the basis of the metabolism of bexarotene by cytochrome P450 3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of cytochrome P450 3A4 would be expected to lead to an increase in plasma bexarotene concentrations. Furthermore, rifampin, phenytoin, phenobarbital, and other inducers of cytochrome P450 3A4 may cause a reduction in plasma bexarotene concentrations.

Concomitant administration of Targretin® (bexarotene) capsules and gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene, probably at least partially related to cytochrome P450 3A4 inhibition by gemfibrozil. Under similar conditions, bexarotene concentrations were not affected by concomitant atorvastatin administration. Concomitant administration of gemfibrozil with Targretin® (bexarotene) capsules is not recommended.

Based on interim data, concomitant administration of Targretin® (bexarotene) capsules and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen, possibly through an induction of cytochrome P450 3A4. Based on this known interaction, bexarotene may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by cytochrome P450 3A4, including oral or other systemic hormone contraceptives (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions and CONTRAINDICATIONS: Pregnancy: Category X). Thus, if treatment with Targretin® (bexarotene) capsules is intended in woman with child-bearing potential, it is strongly recommended that two reliable forms of contraception be used concurrently, one of which should be non-hormonal.

Renal Insufficiency

No formal studies have been conducted with Targretin® (bexarotene) capsules in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (<1% of administered dose), but because renal insufficiency can result in significant protein binding changes, and bexarotene is >99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency.

Protein Binding

Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied.

Drug/Laboratory Test Interactions

CA125 assay values in patients with ovarian cancer may be increased by Targretin® (bexarotene) capsule therapy.


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