Leitlinien & Arzneimittelsicherheit

HOS-084356 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The safety of bexarotene has been examined in clinical studies of 193 patients with CTCL who received bexarotene for up to 118 weeks and in 420 non-CTCL cancer patients in other studies. In 109 patients with CTCL treated at the recommended initial dose of 300 mg/m2/day, the most commonly reported adverse reactions to Targretin were hyperlipaemia ((primarily elevated triglycerides) 74%), hypothyroidism (29%), hypercholesterolaemia (28%), headache (27%), leucopenia (20%), pruritus (20%), asthenia (19%), rash (16%), exfoliative dermatitis (15%), and pain (12%). Tabulated list of adverse reactions The following Targretin-related adverse reactions were reported during clinical studies in patients with CTCL (N=109) treated at the recommended initial dose of 300 mg/m2/day. The frequencies of adverse reactions are classified as very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 2 Adverse reactions reported in patients in clinical trials System Organ Class Very Common Common Uncommon (MedDRA terminology*) Blood Dyscrasia Purpura Coagulation Disorder Blood and Coagulation Time Increased2,3 Lymphoma Like Reaction lymphatic Anaemia1 Leucopenia Lymphadenopathy system Thrombocytopenia3 Hypochromic Anaemia1,2,3 disorders Thrombocythemia Eosinophilia1 Leukocytosis2 Lymphocytosis

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HOS-084352 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy and lactation. Women of child-bearing potential without effective birth-control measures. History of pancreatitis. Uncontrolled hypercholesterolaemia. Uncontrolled hypertriglyceridaemia. Hypervitaminosis A. Uncontrolled thyroid disease. Hepatic insufficiency. Ongoing systemic infection.

HOS-084351 · has-indication-information · PDF-Seite 2

Targretin is indicated for the treatment of skin manifestations of advanced stage cutaneous T-cell lymphoma (CTCL) in adult patients refractory to at least one systemic treatment.

HOS-084354 · has-interaction-information · PDF-Seite 5

Effects of other substances on bexarotene No formal studies to evaluate interactions with bexarotene have been conducted. On the basis of the oxidative metabolism of bexarotene by cytochrome P450 3A4 (CYP3A4), coadministration with other CYP3A4 substrates such as ketoconazole, itraconazole, protease inhibitors, clarithromycin and erythromycin may theoretically lead to an increase in plasma bexarotene concentrations. Furthermore, co-administration with CYP3A4 inducers such as rifampicin, phenytoin, dexamethasone or phenobarbital may theoretically cause a reduction in plasma bexarotene concentrations. Caution is advised in case of combination with CYP3A4 substrates having a narrow therapeutic margin i.e. immunosuppressive agents (cyclosporine, tacrolimus, sirolimus) as well as CYP3A4-metabolised cytotoxics, i.e. cyclophosphamide, etoposide, finasteride, ifosfamide, tamoxifen, vinca-alcaloids. A population analysis of plasma bexarotene concentrations in patients with CTCL indicated that concomitant administration of gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene. The mechanism of this interaction is unknown. Under similar conditions, bexarotene concentrations were not affected by concomitant administration of atorvastatin or levothyroxine. Concomitant administration of gemfibrozil with bexarotene is not recommended. Effects of bexarotene on other substances There are indications that bexarotene may induce CYP3A4. Therefore, repeated administration of bexarotene may result in an auto-induction of its own metabolism and, particularly at dose levels greater than 300 mg/m2/day, may increase the rate of metabolism and reduce plasma concentrations of other substances metabolised by cytochrome P450 3A4, such as tamoxifen. For example bexarotene may reduce the efficacy of oral contraceptives (see sections 4.4 and 4.6). 5 Bexarotene may potentially enhance the action of insulin, agents enhancing insulin secretion (e.g. sulfonylureas), or insulin-sensitisers (e.g. thiazolidinediones), resulting in hypoglycaemia (see section 4.4). Laboratory test interactions CA125 assay values in patients with ovarian cancer may be accentuated with bexarotene therapy. Food interactions In all clinical trials, patients were instructed to take Targretin capsules with or immediately following a meal. In one clinical study, plasma bexarotene AUC and Cmax values were substantially higher follo

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HOS-084355 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data from the use of bexarotene in pregnant women. Studies in animals have shown reproductive toxicity. Based on the comparison of animal and patient exposures to bexarotene, a margin of safety for human teratogenicity has not been demonstrated (see section 5.3). Bexarotene is contraindicated in pregnancy (see section 4.3). If this medicinal product is used inadvertently during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be informed of the potential hazard to the foetus. Contraception in males and females Women of childbearing potential must use adequate birth-control measures when bexarotene is used. A negative, sensitive, pregnancy test (e.g. serum beta-human chorionic gonadotropin, beta-HCG) should be obtained within one week prior to bexarotene therapy. Effective contraception must be used from the time of the negative pregnancy test through the initiation of therapy, during therapy and for at least one month following discontinuation of therapy. Whenever contraception is required, it is recommended that two reliable forms of contraception be used simultaneously. Bexarotene can potentially induce metabolic enzymes and thereby theoretically reduce the efficacy of oestroprogestative contraceptives (see section 4.5). Thus, if treatment with bexarotene is intended in a woman with childbearing potential, a reliable, non-hormonal contraceptive method is also recommended. Male patients with sexual partners who are pregnant, possibly pregnant, or may potentially become pregnant must use condoms during sexual intercourse while taking bexarotene and for at least one month after the last dose. Breast-feeding It is unknown whether bexarotene is excreted in human milk. Bexarotene should not be used in breast-feeding mothers. Fertility There are no human data on the effect of bexarotene on fertility. In male dogs, some effects have been documented (see section 5.3). Effects on fertility cannot be excluded.

HOS-084353 · has-warning-information · PDF-Seite 3

General Targretin capsules should be used with caution in patients with a known hypersensitivity to retinoids. No clinical instances of cross-reactivity have been noted. Patients receiving bexarotene should not donate blood for transfusion. Butylated hydroxyanisole, an ingredient in Targretin, may cause irritation to the mucous membranes, therefore the capsules must be swallowed intact and not chewed. Lipids Hyperlipidaemia has been identified as an effect associated with the use of bexarotene in clinical studies. Fasting blood lipid determinations (triglycerides and cholesterol) should be performed before bexarotene therapy is initiated and at weekly intervals until the lipid response to bexarotene is established, which usually occurs within two to four weeks, and then at intervals no less than monthly thereafter. Fasting triglycerides should be normal or normalised with appropriate intervention prior to bexarotene therapy. Every attempt should be made to maintain triglyceride levels below 4.52 mmol/l in order to reduce the risk of clinical sequelae. If fasting triglycerides are elevated or become elevated during treatment, institution of antilipaemic therapy is recommended, and if necessary, dose reductions (from 300 mg/m2/day of bexarotene to 200 mg/m2/day, and if necessary to 100 mg/m2/day) or treatment discontinuation. Data from clinical studies indicate that bexarotene concentrations were not affected by concomitant administration of atorvastatin. However, concomitant administration of 3 gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene and therefore, concomitant administration of gemfibrozil with bexarotene is not recommended (see section 4.5). Elevations of serum cholesterol should be managed according to current medical practice. Pancreatitis Acute pancreatitis associated with elevations of fasting serum triglycerides has been reported in clinical studies. Patients with CTCL having risk factors for pancreatitis (e.g., prior episodes of pancreatitis, uncontrolled hyperlipidaemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) should not be treated with bexarotene, unless the potential benefit outweighs the risk. Liver Function Test (LFT) abnormalities LFT elevations associated with the use of bexarotene have been reporte

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