Targretin

Bexarotene therapy should only be initiated and maintained by physicians experienced in the treatment of patients with CTCL. Posology The recommended initial dose is 300 mg/m2/day. 62 750 10 Dose modification guidelines The 300 mg/m2/day dose level may be adjusted to 200 mg/m2/day then to 100 mg/m2/day, or temporarily suspended, if necessitated by toxicity.

When toxicity is controlled, doses may be carefully readjusted upward. With appropriate clinical monitoring, individual patients may benefit from doses above 300 mg/m2/day. Doses greater than 650 mg/m2/day have not been evaluated in patients with CTCL.

In clinical trials, bexarotene was administered for up to 118 weeks to patients with CTCL. Treatment should be continued as long as the patient is deriving benefit. 3 Paediatric population The safety and efficacy of bexarotene in children (aged below 18 years) have not been established.

No data are available. Elderly patients Of the total number of patients with CTCL in clinical studies, 61% were 60 years or older, while 30% were 70 years or older. No overall differences in safety were observed between patients 70 years or older and younger patients, but greater sensitivity of some older individuals to bexarotene cannot be ruled out.

The standard dose should be used in the elderly. Patients with renal impairment No formal studies have been conducted in patients with renal insufficiency. Clinical pharmacokinetic data indicate that urinary elimination of bexarotene and its metabolites is a minor excretory pathway for bexarotene.

In all evaluated patients, the estimated renal clearance of bexarotene was less than 1 ml/minute. In view of the limited data, patients with renal insufficiency should be monitored carefully while on bexarotene therapy. Method of administration For oral use.

Targretin capsules should be taken as a single oral daily dose with a meal. The capsule should not be chewed.

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 (MedDRA terminology*) Very Common Common Uncommon Blood and lymphatic system disorders Leucopenia Lymphoma Like Reaction Lymphadenopathy Hypochromic Anaemia1,2,3 Blood Dyscrasia Purpura Coagulation Disorder Coagulation Time Increased2,3 Anaemia1 Thrombocytopenia3 Thrombocythemia Eosinophilia1 Leukocytosis2 Lymphocytosis Endocrine disorders Hypothyroidism Thyroid Disorder Hyperthyroidism Metabolism and nutrition disorders Hyperlipaemia Hypercholesterolaemia Weight Gain SGOT Increased SGPT Increased Lactic Dehydrogenase Increased Creatinine Increased Hypoproteinaemia Gout Bilirubinemia1,3 BUN Increased1 High Density Lipoprotein Decreased Nervous system disorders Dizziness Hypesthesia Insomnia Ataxia Neuropathy Vertigo Hyperaesthesia Depression1,2,3 Agitation Eye disorders Dry Eyes Eye Disorder Cataract Specified1,2,3 Amblyopia3 Visual Field Defect Corneal Lesion Abnormal Vision1,2,3 Blepharitis Conjunctivitis3 8 System Organ Class (MedDRA terminology*) Very Common Common Uncommon Ear and labyrinth disorders Deafness Ear disorder Cardiac disorders Tachycardia Vascular disorders Peripheral Oedema Haemorrhage Hypertension Oedema3 Vasodilatation1,2,3 Varicose Vein Gastrointestinal disorders Vomiting Diarrhoea1,3 Nausea3 Anorexia1 Liver Function Tests Abnormal Cheilitis2 Dry Mouth2,3 Constipation Flatulence Pancreatitis1,3 Hepatic Failure Gastrointestinal Disorder1 Skin and subcutaneous tissue disorders Exfoliative Dermatitis Pruritus Rash Skin Ulcer Alopecia1 Skin Hypertrophy Skin Nodule Acne Sweating Dry Skin2,3 Skin Disorder Serous Drainage1 Herpes Simplex Pustular Rash Skin Discoloration3 Hair Disorder1 Nail Disorder1,3 Musculoskeletal and connective tissue disorders Bone Pain Arthralgia Myalgia Myasthaenia1 Renal and urinary disorders Albuminuria1,3 Kidney Function Abnormal General disorders and administration site conditions Pain Headache Asthaenia Allergic Reaction Infection Chills1 Abdominal Pain Hormone Level Altered1 Neoplasm Fever1,2,3 Cellulitis Infection Parasitic Mucous Membrane Disorder3 Back Pain1,2,3 Lab Test Abnormal 1: adverse reactions noted with increased frequency when bexarotene was administered at a dose >300mg/m2/day.

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. 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. 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.

, 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.

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.