PRINCIPIOS DE FARMACOLOGIA

Description: Bexarotene (LGD1069) is a synthetic retinoid, also called a rexinoid due to its selectivity for the retinoid X-receptor. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. As opposed to all-trans-retinoic acid, which only binds to retinoic acid receptors (RARs), and 9-cis-retinoic acid, which binds to RARs and retinoid X receptors (RXRs), bexarotene is highly selective for RXRs with a low affinity for RARs. Bexarotene has been studied in patients with cutaneous T cell lymphoma (CTCL), breast cancer, advanced head and neck cancer, lung cancer, Kaposi's sarcoma, and renal cell cancer. Bexarotene has also been studied for the prevention of breast cancer in preclinical models, even if tamoxifen resistance is present.[2714] A phase II trial has begun to assess the effectiveness of bexarotene in the treatment of advanced breast cancer. The use of bexarotene in diabetes mellitus is no longer under investigation due to bexarotene's unfavorable affect on lipids. In August 1999, bexarotene received orphan drug designation for the treatment of CTCL and was accepted for priority review by the FDA. In December 1999, the FDA approved bexarotene for the treatment of CTCL in patients who are refractory to at least one prior systemic therapy. In June 2000, the FDA approved bexarotene gel 1% for the treatment of CTCL in patients with early stage disease who have not tolerated other therapies or who have refractory or persistent disease. Mechanism of Action: Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoids exert their effects through binding to specific nuclear retinoid receptors, which are members of the steroid-thyroid superfamily of nuclear receptors. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Bexarotene selectively binds to and activates RXRs with a low affinity for RARs. RXRs are located primarily in visceral organs such as the liver and kidney. Activated RXRs form homodimers (RXR/RXR) or heterodimers with RARs, vitamin D receptors, thyroid receptors, or peroxisome proliferator activator receptors. RXR agonists may activate any RXR-dependent heterodimers. Once activated, retinoid receptor dimers bind to DNA at retinoic acid response elements and act as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Retinoid agonists can activate the expression of retinoid-regulated genes by removing negative transcription control or by facilitating positive transcriptional activity. The exact mechanism of bexarotene in cutaneous T cell lymphoma is not known. The role of retinoids in fetal development is to specify positional information for cells in developing limbs and possibly in the nervous system. In all age groups, retinoids are required for normal growth and proliferation of epithelial tissues. Dysregulation of retinoids may contribute to lung, gastric, uterine, bladder, testicular, breast, prostate, pancreatic, and skin cancers. Pharmacokinetics: Bexarotene is administered orally or topically. In general, after topical administration only very low levels of bexarotene are absorbed. Plasma concentrations were mostly < 5 ng/ml and did not exceed 55 ng/ml. However, more frequent application and larger treated body surface area are associated with increased systemic levels. In patients receiving low to moderate topical doses, there is a low potential for significant bexarotene plasma concentrations following repeated administration. Following oral administration, bexarotene reaches its Tmax within 2 hours. Plasma bexarotene AUC and Cmax values following a 300 mg PO dose were 35% and 48% higher, respectively, following a fat-containing meal than after a glucose solution. Bexarotene is highly protein bound (> 99%). The plasma proteins to which bexarotene binds have not been determined, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene have not been studied. The terminal half-life of bexarotene is 7 hours. Bexarotene undergoes oxidative metabolism via cytochrome P450 (CYP) 3A4. The oxidative metabolites are then glucuronidated. Four bexarotene metabolites have been identified in plasma: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. The oxidative metabolites are active in vitro, but the relative contribution of the parent or bexarotene metabolites to the efficacy and safety of therapy is not known. Agents that affect CYP3A4 may alter the metabolism of bexarotene (see Drug Interactions). Bexarotene and its metabolites are eliminated primarily through the hepatobiliary system. Less than 1% of the dose is excreted in the urine unchanged. No specific studies have been performed in patients with renal or hepatic impairment. Although renal elimination is insignificant, protein binding changes due to renal impairment may alter the pharmacokinetics of bexarotene in patients with renal insufficiency. Hepatic impairment would be expected to greatly decrease the clearance of bexarotene.

Indications...Dosage For the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (mycosis fungoides): NOTE: Bexarotene has been designated an orphan drug by the FDA for this indication. .for patients who are refractory to at least one prior systemic therapy for cutaneous T-cell lymphoma (CTCL): Oral dosage: Adults: 300 mg/m2 PO once daily with meals. Dosage should be rounded to the nearest 75 mg. The dose of bexarotene may reduced to 200 mg/m2/day PO then to 100 mg/m2/day PO, or temporarily suspended, if clinical toxicity occurs. When toxicity is controlled, doses may be restarted and carefully increased. If there is no tumor response after 8 weeks of treatment and the initial 300 mg/m2/day dose is well tolerated, the dose may be escalated to 400 mg/m2/day PO with careful monitoring. Bexarotene therapy should be continued as long as the patient is deriving benefit. NOTE: In clinical trials, bexarotene was administered for up to 97 weeks. In patients with advanced CTCL, 49% of patients achieved an objective response (complete and partial responses) to treatment with any dose of bexarotene. Patient response rates were 45% at a dose of 300 mg/m2/day PO and 55% at doses > 300 mg/m2/day PO. Responses were seen in patients with erythrodermic CTCL (mycosis fungoides) and Sezary syndrome. Median time to best response was 180 days and these responses were durable for a median of 159 days at bexarotene doses of 300 mg/m2/day PO. Median time to response was shorter and the duration of response was longer with doses > 300 mg/m2/day PO but the incidence of side effects increased substantially at the higher doses. In patients with early stage CTCL, 54% of patients achieved an objective response at bexarotene 300 mg/m2/day PO and the objective response rate was 67% in patients receiving bexarotene > 300 mg/m2/day PO. .for patients with stage IA or IB cutaneous T-cell lymphoma (CTCL) who have refractory or persistent disease after other therapies or who have not tolerated other therapies: Topical dosage: Adults: Apply to affected areas once every other day for the first week. The frequency of application should be increased at weekly intervals to once daily, then twice daily, then 3 times daily, and finally to 4 times daily according to individual tolerance. Generally, most patients are able to maintain a dosing frequency of 2-4 times daily. Most responses were seen at dosing frequencies of 2 times per day and higher. A response may be seen as soon as 4 weeks after starting therapy, but most patients require longer treatment. If application site toxicity occurs, the frequency of application can be reduced. In cases of severe irritation, temporarily discontinue treatment until the symptoms subside. Therapy should be continued as long as the patient is deriving benefit. In a phase III trial, bexarotene 1% gel was applied every other day, then escalated to 4 times a day as tolerated to all affected areas in patients with Stage IA-IIA CTCL who were intolerant to, refractory to, or had persistant disease with at least 2 prior treatments. The response to treatment was 44% with 4 complete responses (8%). Maximum Dosage Limits: .Adults: 400 mg/m2/day PO. In phase III studies, patients with cutaneous T cell lymphoma did not tolerate doses of 500 mg/m2/day PO or 650 mg/m2/day PO. .Elderly: 400 mg/m2/day PO. .Adolescents: No maximum dosage information available. .Children: No maximum dosage information available. Patients with hepatic impairment: No specific studies of bexarotene in patients with hepatic impairment have been conducted. The clearance of systemic bexarotene would be expected to be greatly decreased in patients with hepatic impairment; however, no specific dosage adjustment guidelines are available. Patients with renal impairment: Less than 1% of the bexarotene dose is eliminated renally, but because systemic bexarotene is extensively protein bound,

Administration Oral Administration .Bexarotene should be taken with meals. .For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to treatment with bexarotene. Negative pregnancy results must be confirmed monthly before dispensing of additional prescriptions of bexarotene. No more than a one month supply of bexarotene capsules should be dispensed at any time. Effective contraception must be used by both men and women during bexarotene therapy (see Contraindications/Precautions). .Bexarotene capsules may be stored at 2-25 degrees C (36-77 degrees F). Avoid exposing to high temperatures and humidity after the bottle is opened. Protect from light. Topical Administration .For external application only. Do not apply the gel near mucosal areas of the body. .Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing. Do not use occlusive dressings with bexarotene gel. .Avoid application of the gel to normal skin around the lesions to prevent irritation. .Wait 20 minutes after showering or bathing before applying the gel. Avoid bathing, showering, or swimming for at least 3 hours after any application, if possible. .For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to treatment with bexarotene. Negative pregnancy results must be confirmed monthly before dispensing of additional prescriptions of bexarotene. No more than a one month supply of bexarotene gel should be dispensed at any time. Effective contraception must be used by both men and women during bexarotene therapy (see Contraindications/Precautions). .Store at room temperature 25 degrees C (77 degrees F) with excursions permitted to 15-30 degrees C (59-86 degrees F). Avoid exposing to high temperatures and humidity after the tube is opened. Protect from light.

Contraindications Bexarotene should be used cautiously in patients who experience retinoid hypersensitivity reactions to retinoid derivatives such as vitamin A, isotretinoin, and etretinate because cross-sensitivity between agents is possible. Bexarotene, both capsules and gel, is contraindicated during pregnancy (FDA pregnancy category X) and may cause fetal harm when administered to a pregnant woman. Bexarotene must not be given to a pregnant woman or to a woman who plans on becoming pregnant. If a woman becomes pregnant while taking bexarotene, therapy must be stopped immediately and the woman given appropriate counseling. In animal studies, bexarotene caused malformations during days 7-17 of gestation. Development abnormalities included incomplete ossification, cleft palate, depressed eye bulge/microphthalmia, and small ears. For females of childbearing potential, a negative pregnancy test (e.g., serum beta-human chrorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mIU/L should be obtained within one week prior to beginning bexarotene therapy and then monthly during treatment. Bexarotene therapy should be initiated on the second or third day of a normal menstrual cycle. Effective contraception must be used for one month prior to the initiation of therapy, during therapy, and for at least one month following discontinuation of therapy. It is recommended that 2 forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients with sexual partners who are pregnant, possibly pregnant, or could become pregnant, must use condoms during sexual intercourse while taking bexarotene and for at least one month after the last dose. No more than a one-month supply of bexarotene should be dispensed to a patient so that results of pregnancy testing can be confirmed and counseling regarding avoidance of pregnancy and birth defects can be reinforced. Systemic bexarotene may enhance the effects of antidiabetic agents, resulting in hypoglycemia. Patients with diabetes mellitus who are receiving these agents should be closely monitored and counseled regarding the possibility of hypoglycemia. Systemic bexarotene therapy causes hypertriglyceridemia and hypercholesterolemia in most patients. During long-term treatment oral treatment, fasting blood lipid determinations should be performed prior to starting bexarotene therapy and weekly until the lipid response to bexarotene is established, usually within 2-4 weeks, and then at 8-week intervals. Fasting triglyceride levels should be normal or normalized with appropriate interventions prior to beginning bexarotene. Attempts should be made to maintain triglycerides < 400 mg/dl to reduce the risk of clinical sequelae, including acute pancreatitis. If fasting triglycerides become elevated, antilipemic therapy should be started, and if necessary, the dose of oral bexarotene reduced or suspended. Due to a potential drug interaction, gemfibrozil is not recommended for use with bexarotene (see Drug Interactions). Patients who have risk factors for pancreatitis, including prior pancreatitis, uncontrolled hyperlipidemia, alcoholism, uncontrolled diabetes mellitus, biliary tract disease, and treatment with medications known to increase triglycerides or to be associated with pancreatitis, should generally not be treated with oral bexarotene. No specific studies of bexarotene in patients with hepatic disease have been conducted. However, since the majority of the bexarotene undergoes extensive hepatic metabolism, systemic bexarotene should be used with extreme caution in this patient population. Baseline liver function tests (LFTs) should be obtained, and LFTs should be carefully monitored one, two and four weeks after initiating oral bexarotene therapy, and if stable, at least every 8 weeks thereafter during treatment. Discontinuation of oral bexarotene therapy should be considered if LFTs (i.e., AST, ALT, or bilirubin) reach > 3-times the upper limit of normal values or if jaundice occurs. Patients who develop symptoms of thyroid disease while receiving oral bexarotene should be carefully evaluated. Systemic bexarotene induce biochemical evidence of clinical hypothyroidism in about half of all patients treated. Baseline thyroid function tests should be obtained and patients should be monitored during treatment. Bone marrow suppression (i.e., leukopenia or neutropenia) may occur during systemic bexarotene treatment of cutaneous T cell lymphoma; however, it was rarely associated with severe sequelae or serious adverse events. Determination of WBC with differential should be obtained at baseline and periodically during bexarotene treatment. In preclinical studies, oral bexarotene was associated with new cataract formation or worsening of previous cataracts. Because of the high prevalence and rate of cataract formation in older patients, the relationship of systemic bexarotene and cataracts cannot be determined without an appropriate control group. Patients treated with bexarotene who experience visual difficulties should have an appropriate ophthalmologic exam. Patients should minimize their sunlight (UV) exposure and exposure to artificial ultraviolet light during bexarotene therapy. Mild photosensitivity may occur in patients exposed to direct sunlight while receiving bexarotene capsules or gel. It is not known if bexarotene is excreted into breast milk. Because many drugs are excreted into breast milk and there is a potential for serious adverse reactions from bexarotene in infants who are nursing, a decision to discontinue breast-feeding or to discontinue the drug must be made, taking into consideration the importance of the drug to the mother. The safety and effectiveness of bexarotene capsules or gel in children have not been established. Avoid occlusive dressings when using bexarotene gel.

Interactions No specific drug interaction studies with bexarotene have been conducted. Concomitant administration of bexarotene capsules and gemfibrozil is not recommended. Concurrent administration of oral bexarotene and gemfibrozil results in substantially increased bexarotene plasma concentrations. This is probably due to inhibition of hepatic cytochrome P450 3A4 by gemfibrozil. Bexarotene serum concentrations were not affected by concurrent administration with atorvastatin. Bexarotene is metabolized by cytochrome P450 (CYP) 3A4. Inhibitors of CYP3A4 such as cimetidine, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, mibefradil, nefazodone, or troleandomycin would be expected to lead to an increase in bexarotene plasma concentrations following oral administration. However, due to low systemic exposure to bexarotene after low to moderate intense gel regimens, clinically significant drug interactions are unlikely with bexarotene gel. This list may not be inclusive of all CYP3A4 inhibitors. Inducers of cytochrome P450 (CYP) 3A4 may cause a reduction in bexarotene plasma concentrations following oral administration. Agents that induce CYP3A4 include phenobarbital, phenytoin, rifabutin, and rifampin. However, due to low systemic exposure to bexarotene after low to moderate intense gel regimens, clinically significant drug interactions are unlikely with bexarotene gel. This list may not be inclusive of all agents that induce CYP3A4. Plasma bexarotene AUC and Cmax values were substantially higher when bexarotene capsules were administered following a fat-containing meal versus those following a glucose solution. Because safety and efficacy data are based upon administration with food, it is recommended that bexarotene capsules be administered with food. Grapefruit juice may increase the serum concentrations of bexarotene by inhibiting the metabolism of bexarotene. Patients should avoid supplementation with vitamin A during treatment with bexarotene capsules or gel to avoid potential additive toxic effects. During clinical trials, patients were advised to limit vitamin A intake to <= 15,000 IU/day. Systemic bexarotene may enhance the action of insulin, sulfonylureas, or insulin-sensitizers (e.g., pioglitazone, rosiglitazone, or troglitazone) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents. Hypoglycemia has not been associated with bexarotene monotherapy. Concurrent use of bexarotene and sulfonylureas may result in additive phototoxicity. Retinoids, vitamin A analogs, may increase the effects of photosensitizing agents used during photodynamic therapy. Administer with caution to patients who are also taking drugs known to be photosensitizers such as quinolones (particularly sparfloxacin), phenothiazines, sulfonamides, tetracyclines, and thiazide diuretics. Patients using bexarotene gel should not use insect-repellant products containing diethyltoluamide, DEET. Animal studies show increased toxicity to DEET when these products were used in combination with bexarotene gel. Due the effect of orlistat on fat absorbtion and lower levels of fat-soluble vitamins during clinical trials, the bioavailability of orally administered retinoids may also be decreased. Close monitoring of paitents receiving bexarotene with orlistat is recommended. Cholestyramine and colestipol can bind with and possibly decrease the oral absorption of orally administered bexarotene.

Adverse Reactions Systemic bexarotene therapy induces hyperlipidemia, including hypercholesterolemia and hypertriglyceridemia, in approximately 80% of patients treated with an initial dose of >= 300 mg/m2/day. Elevations in serum lipids lead to discontinuation of bexarotene treatment in some patients. Fasting triglycerides were > 2.5-times the upper limit of normal in 70% of patients and > 800 mg/dl (median of 1200 mg/dl) in 55% of patients treated. Cholesterol elevations above 300 mg/dl occurred in approximately 60% and 75% of patients who received an initial bexarotene dose of 300 mg/m2/day or > 300 mg/m2/day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to < 25 mg/dl were seen in about 55% and 90% of patients who received an initial bexarotene dose of 300 mg/m2/day or > 300 mg/m2/day, respectively. Hyperlipimic effects are reversible upon discontinuation of bexarotene therapy and can be controlled by reducing the dose of bexarotene or adding antilipemic therapy. Fasting blood lipid determinations should be performed prior to starting bexarotene therapy and weekly until the lipid response to bexarotene is established, usually within 2-4 weeks, and then at 8-week intervals. Fasting triglyceride levels should be normal or normalized with appropriate interventions prior to beginning bexarotene. Attempts should be made to maintain triglycerides < 400 mg/dl to reduce the risk of clinical sequelae. In patients receiving an initial bexarotene dose of 300 mg/m2/day, 60% of patients were given lipid-lowering agents. Atorvastatin was used in 48% of patients with cutaneous T cell lymphoma receiving bexarotene. Gemfibrozil is not recommended for use with bexarotene (see Drug Interactions). Acute pancreatitis has been reported in who have been treated with systemic bexarotene. The cases of pancreatitis have been associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dl in one patient. One patient with advanced cancer died of pancreatitis. In general, patients with risk factors for pancreatitis should not be treated with bexarotene (see Contraindications). Elevated hepatic enzymes have been observed in 5% patients receiving an initial dose of 300 mg/m2/day PO of bexarotene. The incidence is higher in patients receiving initial bexarotene doses > 300 mg/m2/day PO. Two patients developed cholestasis, including one patient who died of hepatic failure. In clinical trials, elevations of hepatic enzymes resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Baseline liver function tests (LFTs) should be obtained, and LFTs should be carefully monitored one, two and four weeks after initiating systemic therapy, and if stable, at least every 8 weeks thereafter during treatment. Discontinuation of systemic bexarotene therapy should be considered if LFTs reach > 3-times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin. Systemic bexarotene therapy induces biochemical or clinical evidience of hypothyroidism in about 50% of patients treated, causing a reversible reduction in thyroid hormone (total thyroxine [T4]) and thyroid-stimulating hormone (TSH) levels. The secretion of TSH and T4 are regulated by triiodothyroinin which acts at a response element near the transcription site of the thyrotropin gene and also interacts with other nuclear cofactors, including the retinoid X receptor (RXR). It is proposed that bexarotene suppresses TSH and T4 secretion through its interaction with RXR. Decreases in TSH and total T4 occur in about 60% and 45% of patients receiving an initial bexarotene oral dose of 300 mg/m2/day, respectively. Symptomatic hypothyroidism was reported as an adverse event in 29% of patients. Patients who receive high dose bexarotene (> 300 mg/m2/day) or have been previously treated with interferon may experience greater suppression of TSH.[2715] Treatment with thyroid hormone replacement should be considered in patients with laboratory evidence of hypothyroidism. In patients receiving bexarotene 300 mg/m2/day, 37% required thyroid hormone replacement. Baseline thyroid function tests should be obtained and patients monitored during treatment. Reversible leukopenia (1000-2999 WBC/mm3) occurred in 18% of patient with cutaneous T cell lymphoma (CTCL) receiving an initial oral bexarotene dose of 300 mg/m2/day. Patients receiving an initial oral bexarotene dose > 300 mg/m2/day had an incidence of leukopenia of 43%. No patient with CTCL developed leukopenia of < 1000 WBC/mm3. The time to onset of leukopenia was about 4-8 weeks. In patients receiving 300 mg/m2/day the incidence of grade 3 or 4 neutropenia was 12% and 4%, respectively. The leukopenia and neutropenia resolved within 30 days of dose reduction or discontinuation of bexarotene therapy in 93% of patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Determination of WBC with differential should be obtained at baseline and periodically during bexarotene treatment. Teratogenesis is a serious concern with bexarotene; retinoids are well-known teratogens. Teratogenic and embryotoxic effects have been demonstrated in animals receiving bexarotene. It is expected that bexarotene will cause fetal harm when administered to a pregnant woman and that there is a high-risk of producing a severely deformed infant. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Mild phototoxicity manifested as sunburn and skin sensitivity to sunlight was observed in patients who were exposed to direct sunlight while receiving bexarotene capsules. There were no reports of photosensitivity during the clinical trials with bexarotene gel; however, the number of patients in these trials was small. The most common adverse events associated with bexarotene gel include rash (unspecified) (56%) including erythema, pruritus (18%), pain at application site (18%), skin irritation (18%) including skin inflammation, excoriation, and sticky or tacky sensation of the skin, contact dermatitis (8%), and paresthesias (6%). The most common severe adverse reactions to bexarotene gel were rash (14%) and pruritus (6%). Common dermatologic adverse reactions associated with oral bexarotene include rash (unspecified) (17%), dry skin (11%), and exfoliative dermatitis (9%). Exfoliative dermatitis (28%), rash (unspecified) (23%), and alopecia (11%) occurred more commonly at oral doses of bexarotene > 300 mg/m2/day. Other common adverse events associated with oral bexarotene treatment (initial dose 300 mg/m2/day) include headache (30%), asthenia (20%), nausea/vomiting (15%/4%), infection (13%), peripheral edema (13%), abdominal pain (11%), chills (10%), diarrhea (7%), fever (5%), and insomnia (5%). Most adverse events were more severe and occurred at a higher incidence in patients treated at starting doses > 300 mg/m2/day. Adverse events that occurred more commonly at higher doses include headache (41%), asthenia (45%), anemia (24%), anorexia (22%), fever (17%), hypochromic anemia (13%), flu-like symptoms (13%), back pain (11%), bacterial infection (13%), insomnia (11%), hyponatremia (9%), and hyperglycemia (6%). One case of bexarotene-related, fatal subdural hematoma was reported during clinical trials.

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