Targretin

Mechanism of Action

Retinoid X receptor activator, regulates genes that control cell differentiation; induces tumor regression

Pharmacokinetics

Half-Life: 7 hr

Peak Plasma Time: 2 hr

Protein Bound: >99%

Metabolism: Liver (CYP3A4)

Metabolites: 6- & 7- hydroxy- bexarotene, 6- & 7- oxo- bexarotene

Excretion: Feces (primarily); urine (<1%)

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsule):
  • For cutaneous T-cell lymphoma:
    • Adults—Dose is based on body size and must be determined by your doctor. The usual dose is 300 milligrams (mg) for each square meter of body surface area taken once a day with a meal. Your dose may then be adjusted by your doctor.
    • Children—Use and dose must be determined by your doctor.

The exact way bexarotene works is unknown, but it is believed to inhibit the growth of tumor cells.

Bexarotene is used to treat skin lesions of cutaneous T-cell lymphoma (CTCL) in patients who have not responded to or not tolerated other therapies.

Bexarotene may also be used for purposes other than those listed in this medication guide.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.
The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Oral:

• The recommended dose range is 100 to 400 mg/m²/day. Targretin capsules should be taken as a single daily dose with a meal.

Topical:

• Targretin gel should be initially applied once every other day for the first week.
• The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to tolerance.
• Sufficient gel should be applied to cover the lesion with a generous coating.

Take the missed dose with food as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Many drugs can interact with bexarotene. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with bexarotene, especially:

• atorvastatin;

• gemfibrozil;

• an antibiotic--clarithromycin, erythromycin, telithromycin;

• birth control pills or hormone replacement therapy;

• antifungal medicine--itraconazole, ketoconazole, voriconazole;

• other cancer medications--paclitaxel, tamoxifen; or

• seizure medication--carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone.

This list is not complete and many other drugs can interact with bexarotene. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Contraindications

• Known or suspected pregnancy.1 2 3

• Known hypersensitivity to bexarotene or any ingredient in the formulation.1 2

Warnings/Precautions

Warnings

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 2 2

Exclude pregnancy 1 week prior to initiation of therapy.1 Initiate therapy on second or third day of normal menstrual period.1 Repeat pregnancy tests monthly during therapy.1 To facilitate pregnancy test assessment and counseling, dispense no more than 1 month supply.1 2

Use contraception (2 reliable forms, including at least 1 nonhormonal method) for 1 month before, during, and for 1 month after administration.1 2 Male patients should use condoms during sexual intercourse with women who are or may become pregnant.1 2

If pregnancy occurs, immediately discontinue and apprise of potential fetal hazard.1 2

Lipid abnormalities (e.g., hyperlipidemia, elevated fasting triglycerides and cholesterol, decreased HDL-cholesterol) occur in most patients; usually develop within 2–4 weeks and are reversible with cessation of therapy.1

If fasting triglycerides are or become elevated, institute antilipemic therapy and reduce bexarotene dosage or suspend therapy.1 Gemfibrozil is not recommended.1 (See Specific Drugs and Foods under Interactions.) Monitor fasting blood lipid levels weekly until lipid response is established, then at 8 week intervals.1

Possible acute pancreatitis; possibly fatal.1 2 Patients with risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia or diabetes mellitus, excessive alcohol consumption, biliary tract disease, or therapy with drugs associated with pancreatic toxicity or known to increase triglyceride concentrations) generally should not receive bexarotene.1 2

Possible elevations in AST and ALT; usually resolve within 1 month following decrease in dosage or discontinuance.1 2

Monitor liver function tests at baseline; after 1, 2, and 4 weeks of treatment; and at least every 8 weeks thereafter.1 Consider discontinuance if transaminases or bilirubin increase to 3 times ULN.1 2

Possible hypothyroidism.1 2 Consider thyroid supplementation in patients with laboratory evidence of hypothyroidism.1 Monitoring of thyroid function tests recommended.1

Leukopenia (generally neutropenia) possible, rarely associated with serious adverse events;1 2 time to onset usually 4–8 weeks, with resolution occurring within 30 days of dosage reduction or discontinuance of the drug in most patients.1 2 Obtain WBC with differential at baseline and periodically during therapy.1

New cataracts or worsening of existing cataracts possible.1 2 Ophthalmologic evaluation recommended if visual difficulties occur.1 2

Sensitivity Reactions

Use with caution in patients with known hypersensitivity to retinoids.1 2

Sunburn and skin sensitivity to sunlight possible in patients exposed to direct sunlight.1 2 Minimize exposure to sunlight and artificial UV light.1 2

Specific Populations

Category X.1 2 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)

Not known whether bexarotene is distributed into milk.1 2 Discontinue nursing or the drug.1 2

Safety and efficacy not established in children <18 years of age.1 2

No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.1 2

Use only with great caution.1 (See Hepatic Effects under Cautions and also Elimination: Special Populations under Pharmacokinetics.)

Common Adverse Effects

Lipid abnormalities, hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, dry skin.1 2

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1

• Importance of women and men taking measures to avoid pregnancy because of risk to fetus.1 2

• Importance of men using condoms during sexual intercourse while receiving the drug and for at least 1 month after discontinuing the drug.1 2

• Importance of monthly pregnancy tests.1 2

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 2

• Importance of taking bexarotene with, or immediately following, a meal.1 2

• Risk of photosensitivity reactions.1 2

• Risk of hypoglycemia in patients being treated for diabetes mellitus.1 2

• Importance of adhering to laboratory appointment schedules.1 2

• Importance of informing patients of other important precautionary information. (See Cautions.)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies of this medicine have been done only in adult patients, and there is no specific information comparing the use of bexarotene in children with use in other age groups.

Geriatric

This medicine has been tested in patients 60 years of age or older and has not been shown to cause different side effects or problems in older people than it does in younger adults. However, elderly patients may be more sensitive to the effects of bexarotene.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Chlortetracycline
• Demeclocycline
• Doxycycline
• Efavirenz
• Gemfibrozil
• Lymecycline
• Meclocycline
• Methacycline
• Minocycline
• Oxytetracycline
• Paclitaxel
• Rolitetracycline
• Tetracycline

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atorvastatin
• Desogestrel
• Dienogest
• Drospirenone
• Erythromycin
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Fosphenytoin
• Ketoconazole
• Levonorgestrel
• Medroxyprogesterone Acetate
• Mestranol
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Phenobarbital
• Phenytoin
• Rifampin
• Tamoxifen
• Vitamin A

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow depression, existing or
• Infection—There may be an increased risk of infections or worsening of infections because of the body's reduced ability to fight them
• Cataracts—May cause new cataracts or worsen previous cataracts
• Chickenpox (including recent exposure) or
• Herpes zoster (shingles)—Risk of severe disease affecting other parts of the body
• Diabetes mellitus—May be more likely to experience low blood sugar (hypoglycemia).
• High cholesterol—Bexarotene can cause an increase in cholesterol levels.
• Kidney disease—May increase the chance of side effects

• Liver disease—Effects of bexarotene may be increased because of slower removal from the body.

• Pancreatitis or
• Risk factors for pancreatitis, such as:
  • Drinking large quantities of alcohol or
  • Problems with your gallbladder or biliary tract or
  • Type 2 diabetes mellitus that is not well-controlled or
  • High cholesterol that is not well-controlled or
  • Taking medicines that cause high levels of triglycerides (fat-like substances) or
  • Taking medicines that are toxic to the pancreas or
  • Prior pancreatitis—Bexarotene can cause an increase in triglyceride levels which can cause inflammation of the pancreas.
• Photosensitivity—Bexarotene may cause increased sensitivity of the skin to sunlight

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Since this medication is given in varying doses, the actual frequency of side effects may vary. In general, side effects are less common with lower doses than with higher doses.

Check with your doctor as soon as possible if any of the following side effects occur:

• Unusual tiredness or weakness
• skin rash or other skin and mucous membrane lesions
• fever
• increase in lipid or cholesterol levels
• coldness, dry, puffy skin or weight gain
• chills, cough, hoarseness, lower back or side pain or painful or difficult urination
• swelling of the arms, feet, hands, or legs

• Severe stomach pain with nausea or vomiting
• shortness of breath
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal pain
• hair loss
• loss of appetite
• loss of strength or energy, tiredness or weakness
• back pain
• diarrhea
• dry skin
• general feeling of discomfort or illness
• trouble in sleeping
• headache
• nausea or vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Targretin® (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.

Hyperlipidemia

Targretin induces substantial elevations in lipids in most patients. About 70% of patients with CTCL who received an initial dose of >300 mg/m2/day of Targretin had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% had values over 800 mg/dL with a median of about 1200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively, of Targretin. Monitor lipid changes and treat abnormalities during therapy. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction and/or concomitant antilipemic therapy.

Perform fasting blood lipid determinations before Targretin therapy is initiated and weekly until the lipid response to Targretin is established, which usually occurs within two to four weeks, and monitor at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating Targretin therapy. Maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae [see Warnings and Precautions (5.2)]. If fasting triglycerides are elevated or become elevated during treatment, institute antilipemic therapy, and if necessary, reduce or interrupt the dose of Targretin. In the 300 mg/m2/day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction, avoid gemfibrozil use with Targretin [see Drug Interactions (7)].

Pancreatitis

Acute pancreatitis, including a fatal case, has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with Targretin; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non-CTCL cancer died of pancreatitis. Interrupt Targretin and evaluate if pancreatitis is suspected. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) may be at greater risk for pancreatitis associated with Targretin [see Warnings and Precautions (5.1)].

Hepatotoxicity, cholestasis, and hepatic failure

Targretin caused elevations in liver chemistry tests (LFTs) in 5% (AST), 2% (ALT), and 0% (bilirubin) in patients with CTCL receiving an initial dose of 300 mg/m2/day. In contrast, with an initial dose greater than 300 mg/m2/day of Targretin, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure. In clinical trials, elevated LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Obtain baseline LFTs and monitor LFTs after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Interrupt or discontinue Targretin if test results exceed three times the upper limit of normal values for AST, ALT, or bilirubin.

Hypothyroidism

Targretin induces hypothyroidism in about half of all patients treated by causing a reversible reduction in levels of thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH). The incidence of decreases in TSH and total T4 were about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m2/day. Hypothyroidism was reported as an adverse event in 29% of patients. Consider treatment with thyroid hormone supplementation in patients with hypothyroidism. In the 300 mg/m2/day initial dose group, 37% of patients were treated with thyroid hormone replacement. Obtain baseline thyroid function tests and patients monitor during treatment.

Neutropenia

Leukopenia in the range of 1000 to <3000 WBC x 106/L occurred in 18% of patients with CTCL receiving an initial dose of 300 mg/m2/day of Targretin. Patients receiving an initial dose greater than 300 mg/m2/day of Targretin had an incidence of leukopenia of 43%. No patient with CTCL treated with Targretin developed leukopenia of less than 1000 WBC x 106/L. The usual time to onset of leukopenia was four to eight weeks after initiating Targretin. The leukopenia observed in most patients was predominately neutropenia. In the 300 mg/m2/day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during Targretin therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Obtain complete blood counts (CBC) at baseline and periodically during treatment.

Cataracts

Posterior subcapsular cataracts occurred in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. New cataracts or worsening of previous cataracts occurred in 15 of 79 patients who were monitored with serial slit lamp examinations. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of Targretin and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with Targretin who experience visual difficulties should have an appropriate ophthalmologic evaluation.

Vitamin A Supplementation Hazard

In clinical studies, patients were advised to limit vitamin A intake to <15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

Hypoglycemia Risk in Patients with Diabetes Mellitus

In patients using insulin, agents enhancing insulin secretion (e.g., sulfonylureas), or insulin-sensitizers (e.g., thiazolidinedione class), based on the mechanism of action, Targretin could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of Targretin as monotherapy.

Photosensitivity

Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Phototoxicity manifested as sunburn and skin sensitivity to sunlight occurred in patients who were exposed to direct sunlight while receiving Targretin. Advise patients to minimize exposure to sunlight and artificial ultraviolet light while receiving Targretin.

Laboratory Tests

Before initiating Targretin therapy, obtain a CBC, fasting lipid profile, liver function tests, and a thyroid profile. Fasting triglycerides should be normal or normalized with appropriate intervention prior to therapy. Monitor lab tests during Targretin therapy as described above.

Hyperlipidemia usually occurs within the initial two to four weeks. Therefore, weekly lipid determinations are recommended during this interval. Subsequently, in patients not hyperlipidemic, determinations can be performed less frequently [see Warnings and Precautions (5.1)].

A white blood cell count with differential should be obtained at baseline and periodically during treatment. Baseline liver function tests should be obtained and should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, periodically thereafter during treatment. Baseline thyroid function tests should be obtained and then monitored during treatment as indicated [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6)].

Drug/Laboratory Test Interactions

CA125 assay values in patients with ovarian cancer may be increased by Targretin therapy.

Targretin was evaluated in two clinical trials in 152 patients with advanced and early stage cutaneous T-cell lymphoma (CTCL) in two multicenter, open-label, historically-controlled clinical trials conducted in the U.S., Canada, Europe, and Australia.

The advanced disease patients had disease refractory to at least one prior systemic therapy (median of two, range one to six prior systemic therapies) and had been treated with a median of five (range 1 to 11) prior systemic, irradiation, and/or topical therapies. Early disease patients were intolerant to, had disease that was refractory to, or had reached a response plateau of six months on, at least two prior therapies. The patients entered had been treated with a median of 3.5 (range 2 to 12) therapies (systemic, irradiation, and/or topical).

The two clinical trials enrolled a total of 152 patients, 102 of whom had disease refractory to at least one prior systemic therapy, 90 with advanced disease and 12 with early disease. This is the patient population for whom Targretin is indicated.

Patients were initially treated with a starting dose of 650 mg/m2/day with a subsequent reduction of starting dose to 500 mg/m2/day. Neither of these starting doses was tolerated, and the starting dose was then reduced to 300 mg/m2/day. If, however, a patient on 300 mg/m2/day of Targretin showed no response after eight or more weeks of therapy, the dose could be increased to 400 mg/m2/day.

Tumor response was assessed in both trials by observation of up to five baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. Also considered in response assessment was the presence or absence of cutaneous tumors and extracutaneous disease manifestations.

All tumor responses required confirmation over at least two assessments separated by at least four weeks. A partial response was defined as an improvement of at least 50% in the index lesions without worsening, or development of new cutaneous tumors or non-cutaneous manifestations. A complete clinical response required complete disappearance of all manifestations of disease, but did not require confirmation by biopsy.

At the initial dose of 300 mg/m2/day, 1/62 (1.6%) of patients had a complete clinical tumor response and 19/62 (30%) of patients had a partial tumor response. The rate of relapse (25% increase in CA or worsening of other aspects of disease) in the 20 patients who had a tumor response was 6/20 (30%) over a median duration of observation of 21 weeks, and the median duration of tumor response had not been reached. Responses were seen as early as 4 weeks and new responses continued to be seen at later visits.

In one post-approval clinical trial with a total of 59 subjects (29 in 300 mg/m2/day dose group and 30 in the 150 mg/m2/day dose), the objective response rate was higher in the Targretin 300 mg/m2/day group than in the Targretin 150 mg/m2/day group with respect to the CA (34.5% vs 23.3%), Physicians Global Assessment (PGA) (37.9% vs 20.0%), and percent BSA involvement (34.5% vs 23.3%).

The median duration of response in the Targretin 300 mg/m2/day group based on the CA, PGA, and percent BSA involvement was 86.5 days, 72.0 days and 60.0 days respectively. While in the Targretin 150 mg/m2/day group the median duration of response based on the CA, PGA, and percent BSA involvement was 55 days, 119.0 days and 118.0 days respectively.

The median time to cutaneous tumor response (the time to cutaneous tumor response for a given subject is defined as the time interval from the first day of Targretin treatment to the time of the first observation when the subject with subsequent confirmation of response meets criteria for CR, CCR or PR) in the Targretin 300 mg/m2/day group based on the CA, PGA, and percent BSA involvement was 85 days, 98 days and 117.5 days respectively. While in the Targretin 150 mg/m2/day group the median time to cutaneous tumor response based on the CA, PGA, and percent BSA involvement was 87 days, 57 days and 57 days respectively. In the Targretin 300 mg/m2/day group, the median time to cutaneous tumor progression based on the CA, PGA, and percent BSA involvement was 77.5, 115.5, and 88.0 days, respectively. In the Targretin 150 mg/m2/day group, the median time to cutaneous tumor progression was 203.0 days based on the CA and 86.0 days based on percent BSA involvement; no subject in this treatment group had cutaneous tumor progression based on the PGA.