Bexarotene

Bexarotene is a synthetic retinoid that acts by selectively binding to and activating the three retinoid X receptors (RXR-alpha, RXR-beta and RXR-gamma). These receptors have biological activity distinct from that of the retinoic acid receptors (RARs). The exact mechanism of action in cutaneous T-cell lymphoma (CTCL) is unknown.

Mechanism of Action

• Receptor activation: once activated, RXRs act as transcription factors that regulate cellular differentiation and proliferation, apoptosis and insulin sensitisation.
• Heterodimer partners: RXRs can pair with other receptors important in cell function (DrugBank names the retinoic acid receptors, vitamin D receptor, thyroid receptor and peroxisome proliferator-activated receptors), so the biological activities of bexarotene are more diverse than those of compounds that activate RARs.
• Laboratory antitumour effects: in vitro, bexarotene inhibits the growth of tumour cell lines of haematopoietic and squamous cell origin; in vivo, it caused tumour regression in some animal models and prevented tumour induction in others.
• Clinical response: bexarotene capsules were studied in 193 patients with CTCL, 93 of whom had advanced stage disease refractory to prior systemic therapy. Among 61 patients given an initial dose of 300 mg/m²/day, the overall response rate by the physician’s global assessment was 51 % (31/61), with a clinical complete response rate of 3 %; by a composite score of five clinical signs it was 31 % (19/61), with a clinical complete response rate of 7 % (4/61).

Pharmacokinetics

• Absorption: pharmacokinetics are linear up to 650 mg/m². Plasma exposure (AUC and Cmax) was substantially higher after a fat-containing meal than after a glucose solution, which is why the capsules are taken with food. No prolonged accumulation was seen, and at the recommended initial dose single-dose and repeated-dose parameters were similar.
• Distribution: more than 99 % bound to plasma proteins; uptake by organs and tissues has not been evaluated.
• Metabolism: plasma metabolites include 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro, glucuronidation is a metabolic pathway and CYP3A4 is the main cytochrome P450 enzyme forming the oxidative metabolites. The metabolites have little effect on the retinoid receptor activation profile.
• Elimination: the terminal elimination half-life is generally between one and three hours. Neither bexarotene nor its metabolites appear in urine in appreciable amounts (estimated renal clearance below 1 mL/minute; urinary elimination below 1 % of the dose).
• Special populations: in population analyses age and sex had no statistically significant effect on exposure; apparent clearance rises with body weight (patients weighing 26 to 145 kg); pharmacokinetics were similar in Black and Caucasian patients, and data are insufficient for other races.

• Cutaneous T-cell lymphoma (CTCL): treatment of the skin manifestations of advanced stage CTCL in adult patients who are refractory to at least one systemic treatment.

A generic bexarotene 75 mg soft capsule authorised in Spain carries the same indication.

• Hypersensitivity to bexarotene or to any of the excipients.
• Pregnancy and lactation.
• Women of childbearing potential without effective birth-control measures.
• History of pancreatitis.
• Uncontrolled hypercholesterolaemia or uncontrolled hypertriglyceridaemia.
• Hypervitaminosis A.
• Uncontrolled thyroid disease.
• Hepatic insufficiency.
• Ongoing systemic infection.

Safety was examined in 193 patients with CTCL who took bexarotene for up to 118 weeks and in 420 patients with other cancers. In 109 CTCL patients treated at the recommended initial dose of 300 mg/m²/day, the most commonly reported reactions were hyperlipaemia (mainly raised triglycerides, 74 %), hypothyroidism (29 %), hypercholesterolaemia (28 %), headache (27 %), leucopenia (20 %), pruritus (20 %), asthenia (19 %), rash (16 %), exfoliative dermatitis (15 %) and pain (12 %). The lists below follow the SmPC table, which groups reactions as very common, common or uncommon.

Very common (≥1/10): leucopenia; hypothyroidism; hyperlipaemia, hypercholesterolaemia; exfoliative dermatitis, pruritus, rash; pain, headache, asthenia.

Common (≥1/100 to <1/10): lymphoma-like reaction, lymphadenopathy, hypochromic anaemia; thyroid disorder; weight gain, raised AST (SGOT), ALT (SGPT), lactate dehydrogenase and creatinine, hypoproteinaemia; dizziness, hypoaesthesia, insomnia; dry eyes, eye disorder; deafness; peripheral oedema; vomiting, diarrhoea, nausea, anorexia, abnormal liver function tests, cheilitis, dry mouth, constipation, flatulence; skin ulcer, alopecia, skin hypertrophy, skin nodule, acne, sweating, dry skin, skin disorder; bone pain, arthralgia, myalgia; allergic reaction, infection, chills, abdominal pain, altered hormone level.

Uncommon (≥1/1,000 to <1/100): blood dyscrasia, purpura, coagulation disorder, increased coagulation time, anaemia, thrombocytopenia, thrombocythaemia, eosinophilia, leucocytosis, lymphocytosis; hyperthyroidism; gout, bilirubinaemia, raised blood urea nitrogen, decreased high-density lipoproteins; ataxia, neuropathy, vertigo, hyperaesthesia, depression, agitation; cataract, amblyopia, visual field defect, corneal lesion, abnormal vision, blepharitis, conjunctivitis; ear disorder; tachycardia; haemorrhage, hypertension, oedema, vasodilatation, varicose vein; pancreatitis, hepatic disorder, gastrointestinal disorder; serous discharge, herpes simplex, pustular rash, skin discolouration, hair disorder, nail disorder; myasthenia; albuminuria, abnormal kidney function; neoplasm, fever, cellulitis, parasitic infection, mucous membrane disorder, back pain, abnormal laboratory test.

Most reactions were seen more often at doses above 300 mg/m²/day and generally resolved without sequelae when the dose was reduced or the medicine stopped. Among 810 patients treated with bexarotene, including patients without cancer, three serious reactions had a fatal outcome: acute pancreatitis, subdural haematoma and hepatic failure. The SmPC also lists further reactions reported at higher doses or in cancers other than CTCL.

No formal interaction studies have been conducted. Bexarotene is metabolised by CYP3A4 and may itself induce CYP3A4, including its own metabolism.

• Gemfibrozil: substantially raises plasma bexarotene concentrations by an unknown mechanism; the combination is not recommended. Atorvastatin and levothyroxine did not change bexarotene concentrations.
• CYP3A4 inhibitors (ketoconazole, itraconazole, protease inhibitors, clarithromycin, erythromycin): may in theory raise bexarotene concentrations. Grapefruit juice may do the same.
• CYP3A4 inducers (rifampicin, phenytoin, dexamethasone, phenobarbital): may in theory lower bexarotene concentrations.
• CYP3A4 substrates with a narrow therapeutic margin: caution with immunosuppressants (ciclosporin, tacrolimus, sirolimus) and with CYP3A4-metabolised medicines such as cyclophosphamide, etoposide, finasteride, ifosfamide, tamoxifen and vinca alkaloids. Particularly above 300 mg/m²/day, bexarotene may lower plasma concentrations of other CYP3A4 substrates such as tamoxifen.
• Hormonal contraceptives: bexarotene may reduce the efficacy of oral contraceptives, so a reliable non-hormonal method is also required.
• Antidiabetic medicines: bexarotene may enhance the action of insulin, insulin secretagogues (sulfonylureas) and insulin sensitisers (thiazolidinediones), causing hypoglycaemia.
• Vitamin A: because of the relationship to vitamin A, vitamin A supplements should be limited to 15,000 IU/day.
• Laboratory tests: CA125 values in patients with ovarian cancer may be raised during bexarotene treatment.
• Food: take the capsules with food, as in the clinical trials.

Bexarotene therapy should only be initiated and maintained by physicians experienced in the treatment of patients with CTCL. The capsules are taken as a single oral daily dose with a meal and must not be chewed.

Recommended Dose

The initial dose is 300 mg/m² per day. The number of 75 mg capsules by body surface area (BSA) is:

• BSA 0.88–1.12 m²: 300 mg/day (4 capsules)
• BSA 1.13–1.37 m²: 375 mg/day (5 capsules)
• BSA 1.38–1.62 m²: 450 mg/day (6 capsules)
• BSA 1.63–1.87 m²: 525 mg/day (7 capsules)
• BSA 1.88–2.12 m²: 600 mg/day (8 capsules)
• BSA 2.13–2.37 m²: 675 mg/day (9 capsules)
• BSA 2.38–2.62 m²: 750 mg/day (10 capsules)

Dose Adjustments

• The dose may be lowered from 300 mg/m²/day to 200 mg/m²/day, then to 100 mg/m²/day, or temporarily suspended, if toxicity requires. When toxicity is controlled, the dose may be carefully raised again.
• With appropriate clinical monitoring, individual patients may benefit from doses above 300 mg/m²/day; doses above 650 mg/m²/day have not been evaluated in CTCL.
• Raised fasting triglycerides call for antilipaemic therapy and, if necessary, the same step-wise dose reductions or discontinuation.
• Suspension or discontinuation should be considered if AST, ALT or bilirubin rise above three times the upper limit of normal.
• In clinical trials bexarotene was given for up to 118 weeks. Treatment continues for as long as the patient benefits.

Special Populations

• Elderly: use the standard dose. About 61 % of the CTCL patients studied were 60 or older and 30 % were 70 or older; no overall difference in safety was seen between patients 70 or older and younger patients, although greater sensitivity in some older people cannot be ruled out.
• Renal impairment: no formal studies; patients should be monitored carefully.
• Hepatic impairment: contraindicated in hepatic insufficiency.
• Children and adolescents: not recommended below 18 years; safety and efficacy have not been established.

Pregnancy Tests and Contraception

This is a condition of treatment for every woman of childbearing potential.

• Teratogenic risk: bexarotene is contraindicated in pregnancy. Animal studies show reproductive toxicity, a margin of safety for human teratogenicity has not been demonstrated, and bexarotene belongs to a class for which the human malformative risk is high.
• Before treatment: a negative, sensitive pregnancy test (for example serum beta-hCG) must be obtained within one week before bexarotene is started.
• During treatment: effective contraception must be used from the time of the negative pregnancy test, through the start of therapy and throughout treatment, and for at least one month after it stops. Two reliable forms of contraception used together are recommended. The SmPC sections consulted set no schedule for repeat pregnancy tests during treatment; follow the prescriber’s instructions. If a patient becomes pregnant while taking bexarotene, or it is used inadvertently in pregnancy, she must be told of the potential hazard to the foetus.
• Hormonal contraceptives: bexarotene may induce metabolic enzymes and in theory reduce the efficacy of combined (oestroprogestative) contraceptives, so a reliable non-hormonal method is also required.
• Men: male patients whose partners are pregnant, possibly pregnant or able to become pregnant must use condoms during intercourse while taking bexarotene and for at least one month after the last dose.

Lipids and Pancreatitis

Hyperlipidaemia is a recognised effect. Fasting triglycerides and cholesterol should be measured before starting, weekly until the lipid response is established (usually within two to four weeks), and then at least monthly. Fasting triglycerides should be normal, or normalised with treatment, before bexarotene is started, and every attempt should be made to keep them below 4.52 mmol/L. Acute pancreatitis associated with raised fasting triglycerides has been reported; patients with risk factors (earlier pancreatitis, uncontrolled hyperlipidaemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, or medicines that raise triglycerides or are toxic to the pancreas) should not be treated unless the benefit outweighs the risk.

Liver, Thyroid and Blood Tests

• Liver function: baseline tests, weekly in the first month, then monthly. Elevations resolved within one month in 80 % of patients after dose reduction or discontinuation.
• Thyroid function: baseline tests, then at least monthly and whenever symptoms of hypothyroidism appear. Reduced total thyroxine and TSH are the usual changes and are reversible; symptomatic hypothyroidism has responded to thyroid hormone supplements.
• Leucopenia and anaemia: white blood cell count with differential and haemoglobin at baseline, weekly in the first month, then monthly. Most cases of leucopenia resolved after dose reduction or discontinuation.

Psychiatric Disorders

Depression, aggravated depression, anxiety and mood changes have been reported with systemic retinoids, including bexarotene. Take particular care in patients with a history of depression, monitor for signs of depression and refer for treatment if needed; family or friends may help notice any decline in mental health.

Other Precautions

• Eyes: some patients had previously undetected lens opacities or a change in existing ones, with no clear link to bexarotene; an effect of long-term use has not been excluded. Patients with visual difficulties should have an ophthalmological examination.
• Sunlight: bexarotene may be photosensitising; minimise sun exposure and avoid sun lamps.
• Retinoid hypersensitivity and blood donation: use with caution in patients with known hypersensitivity to retinoids (no clinical instances of cross-reactivity have been noted). Patients receiving bexarotene should not donate blood for transfusion.
• Capsules: butylated hydroxyanisole in the capsule may irritate mucous membranes, so capsules must be swallowed whole.

Breastfeeding and Fertility

Bexarotene is contraindicated during lactation; it is not known whether it passes into human milk. There are no human data on fertility; effects were documented in male dogs and an effect on fertility cannot be excluded.

Sorbitol

Targretin contains a small amount of sorbitol; patients with rare hereditary fructose intolerance should not take it. The generic Spanish SmPC states 122.198 mg of sorbitol per capsule.

Effect on Driving

Dizziness and visual difficulties have been reported. Patients who experience them must not drive or operate machinery.

Targretin: do not store above 30 °C and keep the bottle tightly closed. It comes in high-density polyethylene bottles with child-resistant closures holding 100 capsules. A generic bexarotene 75 mg soft capsule authorised in Spain is stored below 25 °C, also in a tightly closed bottle. Keep out of the sight and reach of children.

Targretin: 3 years. The generic bexarotene 75 mg soft capsule authorised in Spain: 2 years.

Prescription only (Rx). Bexarotene therapy is initiated and maintained only by physicians experienced in treating patients with CTCL. Bexarotene is taken at home, so it is supplied to the patient or the treating clinic on prescription.

Pregnancy test condition: for a woman of childbearing potential, a negative, sensitive pregnancy test (for example serum beta-hCG) must have been obtained within one week before treatment starts, and effective contraception must be used from that test, throughout treatment and for at least one month after the last dose. The SmPC sets no schedule for repeat tests during treatment; follow the prescriber’s instructions (see Special Instructions).