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.

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.

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.

Bexarotene may potentially enhance the action of insulin, agents enhancing insulin secretion (e.g. sulfonylureas), or insulin-sensitisers (e.g. thiazolidinediones), resulting in hypoglycaemia.

Bexarotene can potentially induce metabolic enzymes and thereby theoretically reduce the efficacy of oestroprogestive contraceptives. Thus, if treatment with bexarotene is intended in a woman of childbearing potential, a reliable, non-hormonal form of contraception is also required, because bexarotene belongs to a therapeutic class for which the human malformative risk is high.

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.

Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to ≤15,000 IU/day to avoid potential additive toxic effects.

Changes in thyroid function tests have been observed in patients receiving bexarotene, most often noted as a reversible reduction in thyroid hormone (total thyroxine [total T₄]) and thyroid-stimulating hormone (TSH) levels. Baseline thyroid function tests should be obtained and then monitored at least monthly during treatment and as indicated by the emergence of symptoms consistent with hypothyroidism. Patients with symptomatic hypothyroidism on bexarotene therapy have been treated with thyroid hormone supplements with resolution of symptoms.

LFT elevations associated with the use of bexarotene have been reported. Based on data from ongoing clinical trials, elevation of LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Baseline LFTs should be obtained, and LFTs should be carefully monitored weekly during the first month and then monthly thereafter. Consideration should be given to a suspension or discontinuation of bexarotene if test results reach greater than three times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin.

Depression, depression aggravated, anxiety, and mood alterations have been reported in patients treated with systemic retinoids, including bexarotene. Particular care should be taken in patients with a history of depression. Patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Awareness by family or friends may be useful to detect mental health deterioration.

Following bexarotene treatment, some patients were observed to have previously undetected lens opacities or a change in pre-existing lens opacities unrelated to treatment duration or dose level of exposure. Given the high prevalence and natural rate of cataract formation in the older patient population represented in the clinical studies, there was no apparent association between the incidence of lens opacity formation and bexarotene administration. However, an adverse effect of long-term bexarotene treatment on lens opacity formation in humans has not been excluded. Any patient treated with bexarotene who experiences visual difficulties should have an appropriate ophthalmologic examination.

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.

Leucopenia associated with bexarotene therapy has been reported in clinical studies. The majority of cases resolved after dose reduction or discontinuation of treatment. Determination of white blood cell count with differential count should be obtained at baseline, weekly during the first month and then monthly thereafter.

Anaemia associated with bexarotene therapy has been reported in clinical studies. Determination of haemoglobin should be obtained at baseline, weekly during the first month and then monthly thereafter. Decreases of haemoglobin should be managed according to current medical practice.

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 gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene and therefore, concomitant administration of gemfibrozil with bexarotene is not recommended. Elevations of serum cholesterol should be managed according to current medical practice.

The use of some retinoids has been associated with photosensitivity. Patients should be advised to minimise exposure to sunlight and avoid sun lamps during therapy with bexarotene, as in vitro data indicate that bexarotene may potentially have a photosensitising effect.

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. Bexarotene is contraindicated in pregnancy.

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.

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. Effects on fertility cannot be excluded.

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. 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.

No studies on the effects on the ability to drive and use machines have been performed. However, dizziness and visual difficulties have been reported in patients taking bexarotene. Patients who experience dizziness or visual difficulties during therapy must not drive or operate machinery.

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 bexarotene 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%).

List of adverse reactions

The following bexarotene-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.

Adverse reactions reported in patients in clinical trials:

Blood and lymphatic system disorders

Very Common: Leucopenia

Common: Lymphoma Like Reaction, Lymphadenopathy, Hypochromic Anaemia^1,2,3

Uncommon: Blood Dyscrasia, Purpura, Coagulation Disorder, Coagulation Time Increased^2,3, Anaemia¹, Thrombocytopenia³, Thrombocythemia, Eosinophilia¹, Leukocytosis², Lymphocytosis

Endocrine disorders

Very Common: Hypothyroidism

Common: Thyroid Disorder

Uncommon: Hyperthyroidism

Metabolism and nutrition disorders

Very Common: Hyperlipaemia, Hypercholesterolaemia

Common: Weight Gain, SGOT Increased, SGPT Increased, Lactic Dehydrogenase Increased, Creatinine Increased, Hypoproteinaemia

Uncommon: Gout, Bilirubinemia^1,3, BUN Increased1, High Density Lipoprotein, Decreased

Nervous system disorders

Common: Dizziness, Hypesthesia, Insomnia

Uncommon: Ataxia, Neuropathy, Vertigo, Hyperaesthesia, Depression^1,2,3, Agitation

Eye disorders

Common: Dry Eyes, Eye Disorder

Uncommon: Cataract Specified^1,2,3, Amblyopia³, Visual Field Defect, Corneal Lesion, Abnormal Vision^1,2,3, Blepharitis, Conjunctivitis³

Ear and labyrinth disorders

Common: Deafness

Uncommon: Ear disorder

Cardiac disorders

Uncommon: Tachycardia

Vascular disorders

Common: Peripheral Oedema

Uncommon: Haemorrhage, Hypertension, Oedema³, Vasodilatation^1,2,3, Varicose Vein

Gastrointestinal disorders

Common: Vomiting, Diarrhoea^1,3, Nausea³, Anorexia¹, Liver Function Tests Abnormal, Cheilitis², Dry Mouth^2,3, Constipation, Flatulence

Uncommon: Pancreatitis^1,3, Hepatic Failure, Gastrointestinal Disorder¹

Skin and subcutaneous tissue disorders

Very Common: Exfoliative Dermatitis, Pruritus, Rash

Common: Skin Ulcer, Alopecia¹, Skin Hypertrophy, Skin Nodule, Acne, Sweating, Dry Skin^2,3, Skin Disorder

Uncommon: Serous Drainage¹, Herpes Simplex, Pustular Rash, Skin Discoloration³, Hair Disorder¹, Nail Disorder^1,3

Musculoskeletal and connective tissue disorders

Common: Bone Pain, Arthralgia, Myalgia

Uncommon: Myasthaenia¹

Renal and urinary disorders

Uncommon: Albuminuria^1,3, Kidney Function Abnormal

General disorders and administration site conditions

Very Common: Pain, Headache, Asthaenia

Common: Allergic Reaction, Infection, Chills¹, Abdominal Pain, Hormone Level Altered¹

Uncommon: Neoplasm, Fever^1,2,3, Cellulitis, Infection Parasitic, Mucous Membrane Disorder³, Back Pain^1,2,3, Lab Test Abnormal

Additional adverse reactions observed when used outside of the recommended dose and indication (i.e. used in CTCL at an initial dose >300mg/m²/day or in non-CTCL cancer indications):

Newly observed adverse reactions: Ecchymosis, petechia, abnormal white blood cells, thromboplastin decreased, abnormal erythrocytes, dehydration, increased gonadotrophic luteinizing hormone, weight loss, increased alkaline phosphatase, increased creatinine phosphokinase, lipase increased, hypercalcaemia, migraine, peripheral neuritis, paraesthesia, hypertonia, confusion, anxiety, emotional lability, somnolence, decreased libido, nervousness, night blindness, nystagmus, lacrimation disorder, tinnitus, taste perversion, chest pain, arrhythmia, peripheral vascular disorder, generalized oedema, haemoptysis, dyspnoea, increased cough, sinusitis, pharyngitis, dysphagia, mouth ulceration, oral moniliasis, stomatitis, dyspepsia, thirst, abnormal stools, eructation, vesicobullous rash, maculopapular rash, leg cramps, haematuria, flu syndrome, pelvic pain, and body odour.

Single observations of the following were also reported: bone marrow depression, decreased prothrombin, decreased gonadotrophic luteinizing hormone, increased amylase, hyponatraemia, hypokalaemia, hyperuricaemia, hypocholesterolaemia, hypolipaemia, hypomagnesaemia, abnormal gait, stupor, circumoral paraesthesia, abnormal thinking, eye pain, hypovolaemia, subdural haematoma, congestive heart failure, palpitation, epistaxis, vascular anomaly, vascular disorder, pallor, pneumonia, respiratory disorder, lung disorder, pleural disorder, cholecystitis, liver damage, jaundice, cholestatic jaundice, melaena, vomiting, laryngismus, tenesmus, rhinitis, increased appetite, gingivitis, herpes zoster, psoriasis, furunculosis, contact dermatitis, seborrhoea, lichenoid dermatitis, arthritis, joint disorder, urinary retention, impaired urination, polyuria, nocturia, impotence, urine abnormality, breast enlargement, carcinoma, photosensitivity reaction, face oedema, malaise, viral infection, enlarged abdomen.

The majority of adverse reactions were noted at a higher incidence at doses greater than 300 mg/m²/day. Generally, these resolved without sequelae on dose reduction or withdrawal of treatment. However, among a total of 810 patients, including those without malignancy, treated with bexarotene, there were three serious adverse reactions with fatal outcome (acute pancreatitis, subdural haematoma and liver failure). Of these, liver failure, subsequently determined to be not related to bexarotene, was the only one to occur in a CTCL patient.

Hypothyroidism generally occurs 4-8 weeks after commencement of therapy. It may be asymptomatic and responds to treatment with thyroxine and resolves upon withdrawal of treatment.

Bexarotene has a different adverse reaction profile to other oral, non-retinoid X receptor (RXR)-selective retinoids. Owing to its primarily RXR-binding activity, bexarotene is less likely to cause mucocutaneous, nail, and hair toxicities; arthralgia; and myalgia; which are frequently reported with retinoic acid receptor (RAR)-binding agents.