Targretin

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



2

1. NAME OF THE MEDICINAL PRODUCT

Targretin 75 mg soft capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 75 mg of bexarotene.

Excipient(s) with known effect: sorbitol

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Soft capsule. 

Off-white capsule, containing a liquid suspension and imprinted with “Targretin”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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. 

4.2 Posology and method of administration

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. Initial dose calculations according to body surface 
area are as follows:

Table 1 Recommended initial dose
Initial dose level (300 mg/m2/day) Number of 75 mg Targretin 

capsulesBody Surface Area (m2) Total daily dose (mg/day)
0.88 – 1.12 300 4
1.13 - 1.37 375 5
1.38 - 1.62 450 6
1.63 - 1.87 525 7
1.88 - 2.12 600 8
2.13 - 2.37 675 9
2.38 - 2.62 750 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.

4.3 Contraindications

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.

4.4 Special warnings and precautions for use

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 



4

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 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.

Thyroid function test alterations
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. 

Leucopenia
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
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.

Psychiatric disorders
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.

Lens opacities
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.



5

Vitamin A supplementation
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. 

Patients with diabetes mellitus
Caution should be exercised when administering bexarotene in patients using insulin, agents 
enhancing insulin secretion (e.g. sulfonylureas), or insulin-sensitisers (e.g. thiazolidinediones). Based 
on the known mechanism of action, bexarotene may potentially enhance the action of these agents, 
resulting in hypoglycaemia. No cases of hypoglycaemia associated with the use of bexarotene as 
monotherapy have been reported.

Photosensitivity
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. 

Oral contraceptives
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.

Paediatric population
Targretin is not recommended in children (aged below 18 years).

Targretin contains a small amount of sorbitol, therefore patients with rare hereditary problems of 
fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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).



6

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 
following the administration of a fat-containing meal versus those following the administration of a 
glucose solution. Because safety and efficacy data from clinical trials are based upon administration 
with food, it is recommended that Targretin capsules be administered with food.

On the basis of the oxidative metabolism of bexarotene by cytochrome P450 3A4, grapefruit juice may 
theoretically lead to an increase in plasma bexarotene concentrations.

4.6 Fertility, pregnancy and lactation

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.  

4.7 Effects on ability to drive and use machines

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 Targretin. Patients who 
experience dizziness or visual difficulties during therapy must not drive or operate machinery.



7

4.8 Undesirable effects

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.
2: adverse reactions noted with increased frequency when bexarotene was administered at a dose of 300 

mg/m2/day in non-CTCL cancer patients.
3: adverse reactions noted with increased frequency when bexarotene was administered at a dose of >300 

mg/m2/day (compared to administration to CTCL patients at 300 mg/m2/day) in non-CTCL cancer 
patients.

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):



9

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.

Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No clinical experience with an overdose of Targretin has been reported. Any overdose should be 
treated with supportive care for the signs and symptoms exhibited by the patient.

Doses up to 1000 mg/m2/day of bexarotene have been administered in clinical studies with no acute 
toxic effects. Single doses of 1500 mg/kg (9000 mg/m2) and 720 mg/kg (14,400 mg/m2) were tolerated 
without significant toxicity in rats and dogs, respectively.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


10

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XX25

Mechanism of action

Bexarotene is a synthetic compound that exerts its biological action through selective binding and 
activation of the three RXRs: , , and . Once activated, these receptors function as transcription 
factors that regulate processes such as cellular differentiation and proliferation, apoptosis, and insulin 
sensitisation. The ability of the RXRs to form heterodimers with various receptor partners that are 
important in cellular function and in physiology indicates that the biological activities of bexarotene 
are more diverse than those of compounds that activate the RARs. 

In vitro, bexarotene inhibits the growth of tumour cell lines of haematopoietic and squamous cell 
origin. In vivo, bexarotene causes tumour regression in some animal models and prevents tumour 
induction in others.  However, the exact mechanism of action of bexarotene in the treatment of 
cutaneous T-cell lymphoma (CTCL) is unknown.

Clinical results

Bexarotene capsules were evaluated in clinical trials of 193 patients with CTCL of whom 93 had 
advanced stage disease refractory to prior systemic therapy. Among the 61 patients treated at an initial 
dose of 300 mg/m2/day, the overall response rate, according to a global assessment by the physician, 
was 51% (31/61) with a clinical complete response rate of 3%. Responses were also determined by a 
composite score of five clinical signs (surface area, erythema, plaque elevation, scaling and 
hypo/hyperpigmentation) which also considered all extracutaneous CTCL manifestations. The overall 
response rate according to this composite assessment was 31% (19/61) with a clinical complete 
response rate of 7% (4/61).

5.2 Pharmacokinetic properties

Absorption

Absorption/dose proportionality: pharmacokinetics were linear up to a dose of 650 mg/m2. Terminal 
elimination half-life values were generally between one and three hours. Following repeat once daily 
dose administration at dose levels  230 mg/m2, Cmax and AUC in some patients were less than 
respective single dose values. No evidence of prolonged accumulation was observed. At the 
recommended initial daily-dose level (300 mg/m2), single-dose and repeated daily-dose bexarotene 
pharmacokinetic parameters were similar. 

Distribution

Protein binding/distribution: bexarotene is highly bound (>99%) to plasma proteins. The uptake of 
bexarotene by organs or tissues has not been evaluated.

Biotransformation  

Metabolism: bexarotene metabolites in plasma include 6- and 7-hydroxy-bexarotene and 6- and 
7-oxo-bexarotene. In vitro studies suggest glucuronidation as a metabolic pathway, and that 
cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for formation of the 
oxidative metabolites. Based on the in vitro binding and the retinoid receptor activation profile of the 
metabolites, and on the relative amounts of individual metabolites in plasma, the metabolites have 
little impact on the pharmacological profile of retinoid receptor activation by bexarotene.



11

Elimination

Excretion: neither bexarotene nor its metabolites are excreted in urine in any appreciable amounts. 
The estimated renal clearance of bexarotene is less than 1 ml/minute. Renal excretion is not a 
significant elimination pathway for bexarotene.

Pharmacokinetics in Special Populations
Age: Based on the population pharmacokinetic analysis of data for 232 patients aged ≥ 65 years and 
343 patients aged < 65 years, age has no statistically significant effect on bexarotene 
pharmacokinetics.

Body Weight and Gender: Based on the population pharmacokinetics analysis of data for 614 patients 
with a weight range of 26 to 145 kg, the bexarotene apparent clearance increases with increasing body 
weight. Gender has no statistically significant effect on bexarotene pharmacokinetics.

Race: Based on the population pharmacokinetic analysis of data for 540 Caucasian and 44 Black 
patients, bexarotene pharmacokinetics are similar in Blacks and Caucasians.  There are insufficient 
data to evaluate potential differences in the pharmacokinetics of bexarotene for other races.

5.3 Preclinical safety data

Bexarotene is not genotoxic. Carcinogenicity studies have not been conducted. Fertility studies have 
not been conducted; however, in sexually immature male dogs, reversible aspermatogenesis (28-day 
study) and testicular degeneration (91-day study) were seen. When bexarotene was administered for 
six months to sexually mature dogs, no testicular effects were seen. Effects on fertility cannot be 
excluded. Bexarotene, in common with the majority of retinoids, was teratogenic and embryotoxic in 
an animal test species at systemic exposures that are achievable clinically in humans. Irreversible 
cataracts involving the posterior area of the lens occurred in rats and dogs treated with bexarotene at 
systemic exposures that are achievable clinically in humans. The aetiology of this finding is unknown. 
An adverse effect of long-term bexarotene treatment on cataract formation in humans has not been 
excluded. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content:
macrogol
polysorbate 
povidone
butylated hydroxyanisole

Capsule shell:
gelatin
sorbitol special-glycerin blend (glycerin, sorbitol, sorbitol anhydrides (1,4-sorbitan), mannitol and 
water)
titanium dioxide (E171) 
printing ink (SDA 35A alcohol (ethanol & ethyl acetate), propylene glycol (E1520), iron oxide black 
(E172), polyvinyl acetate phthalate, purified water, isopropyl alcohol, macrogol 400, ammonium 
hydroxide 28%)

6.2 Incompatibilities

Not applicable.



12

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30oC.  
Keep the bottle tightly closed.

6.5 Nature and contents of container

High-density polyethylene bottles with child-resistant closures containing 100 capsules.

6.6 Special precautions for disposal and other handling 

No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany
e-mail: medinfo_de@eisai.net 

8. MARKETING AUTHORISATION NUMBER

EU/1/01/178/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 29 March 2001.
Date of latest renewal: 24 April 2006.

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.



13

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



14

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer responsible for batch release
Eisai Manufacturing Limited
European Knowledge Centre
Mosquito Way
Hatfield 
Hertfordshire
AL10 9SN
United Kingdom

Or

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and  published on the European medicines web-
portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

Not applicable.



15

ANNEX III

LABELLING AND PACKAGE LEAFLET



16

A. LABELLING



17

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON TEXT AND BOTTLE LABEL TEXT

1. NAME OF THE MEDICINAL PRODUCT

Targretin 75 mg soft capsules
Bexarotene

2. STATEMENT OF ACTIVE SUBSTANCE

One capsule contains 75 mg of bexarotene.

3. LIST OF EXCIPIENTS

Contains sorbitol. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

100 soft capsules

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use.
To be swallowed whole.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

Do not store above 30C.
Keep the bottle tightly closed.



18

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/01/178/001 

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Targretin 75 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



19

B. PACKAGE LEAFLET



20

Package leaflet: Information for the user

TARGRETIN 75 mg soft capsules
Bexarotene

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet.  You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Targretin is and what it is used for
2. What you need to know before you take Targretin
3. How to take Targretin
4. Possible side effects
5. How to store Targretin
6. Contents of the pack and other information

1. What Targretin is and what it is used for

The active substance in Targretin, bexarotene, belongs to a group of medicines known as retinoids, 
which are related to vitamin A. 

Targretin capsules are used by patients with advanced stage cutaneous T-cell lymphoma (CTCL) 
whose disease has not responded to other therapies. CTCL is a condition in which certain cells of the 
body’s lymph system called T-lymphocytes become cancerous and affect the skin.

2. What you need to know before you take Targretin

Do not take Targretin:

- if you are allergic to bexarotene or any of the other ingredients of this medicine (listed in section 
6).

- if you are pregnant or breast feeding or if you can become pregnant and are not using effective 
birth control measures.

- if you have a history of pancreatitis, have uncontrolled lipid (blood fats) elevations (high blood 
cholesterol or high blood triglycerides), have a condition known as hypervitaminosis A, have 
uncontrolled thyroid disease, have insufficient liver function or have an ongoing systemic 
infection.

Warnings and precautions
Talk to your doctor before taking Targretin
- if you have a known hypersensitivity to retinoids (related to vitamin A), suffer from liver 

disease, have high blood lipids or take medicines which may cause high blood lipids, have 
uncontrolled diabetes mellitus (sugar diabetes), have had gall bladder or biliary tract disease, or 
consume excessive amounts of alcohol.

- if you have ever had any mental health problems including depression, aggressive tendencies or 
mood changes. This is because taking Targretin may affect your mood.

Your fasting blood lipid determinations may have to be performed before therapy is initiated and at 
weekly intervals afterwards, and then monthly while taking this medicine.



21

Blood tests to evaluate the function of your liver and thyroid gland and to monitor your red blood cell 
and white blood cell counts will be obtained before therapy is started and will be monitored during 
therapy.

Periodic eye exams may be needed if you experience visual difficulties while taking this medicine.

Minimise exposure to sunlight as much as possible and avoid exposure to sun lamps. 

Do not take more than 15,000 International Units of vitamin A supplements per day during treatment.

Mental health problems
You may not notice some changes in your mood and behaviour and so it is very important that you tell 
your friends and family that this medicine could affect your mood and behaviour. They may notice 
these changes and help you identify any problems that you need to talk to your doctor about.

Children and adolescents
Targretin capsules should not be used in children or adolescents.

Other medicines and Targretin
Tell your doctor if you are taking, have recently taken or might take any other medicines, such as
 ketoconazole and itraconazole (used against fungal infections),
 erythromycin, clarithromycin and rifampicin (used against bacterial infections),
 phenytoin and phenobarbital (used against seizures),
 gemfibrozil (used to reduce high levels of fats in the blood such as triglycerides and 

cholesterol),
 vitamin A supplements, protease inhibitors (used against viral infections),
 tamoxifen (used against some forms of cancer),
 dexamethasone (used for inflammatory conditions),
 insulin, agents enhancing insulin secretion, or insulin-sensitisers (used against diabetes 

mellitus).

This is important as using more than one medicine at the same time can strengthen or weaken the 
effect of the medicines.

Targretin with food and drink
Targretin should be taken with food (see section 3). If you regularly consume grapefruit or grapefruit 
juice, please consult your doctor as these have the potential to alter your body’s response to Targretin 
therapy.

Pregnancy and breast-feeding
Targretin may be harmful to a developing foetus.  DO NOT use Targretin if you are pregnant or 
breast-feeding. If you are pregnant or breast-feeding, think you may be pregnant or are planning to 
have a baby, ask your doctor for advice before taking this medicine.

If you are capable of becoming pregnant, you must have a pregnancy test within one week before you 
start therapy, confirming you are not pregnant. You must use effective contraception (birth control) 
continuously starting one month before beginning therapy until one month after you stop taking 
Targretin. It is recommended that two reliable forms of contraception be used together. If you are 
taking a hormonal contraceptive (for example, birth control pills), you should discuss this with your 
doctor.

If you are male and your partner is pregnant or capable of becoming pregnant, you must use condoms 
during sexual intercourse while taking bexarotene and for at least one month after the last dose.



22

Driving and using machines
It is not known whether Targretin has an effect on your ability to drive a car or operate machinery. If 
you experience dizziness or problems with your vision during therapy, do not drive or operate 
machinery.

Targretin contains sorbitol and butylated hydroxyanisole
Targretin contains a small amount of sorbitol (a type of sugar). If you have an intolerance to some 
sugars, speak to your doctor before taking this medicinal product.
Butylated hydroxyanisole may cause irritation to the mucous membranes, therefore the capsules must 
be swallowed intact and not chewed.

3. How to take Targretin

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

The doctor will prescribe a suitable dose for you.
The recommended dose is generally 4 to 10 capsules to be taken once daily. Take your prescribed 
number of capsules at the same time each day with a meal. The capsules can be taken immediately 
before, during or immediately after the course of the meal, if preferred. The capsules should be 
swallowed whole and not chewed.

How long you should take Targretin
Although some patients have improvement within the first several weeks, most patients require several 
months or more of treatment to improve.

If you take more Targretin than you should
If you have taken more than the prescribed dose of Targretin, you must contact your doctor.

If you forget to take Targretin
If you forget to take one dose, take your daily dose with your next meal on the same day, then take 
your usual dose as normal, the following day. Do not take a double dose in one day to make up for a 
forgotten dose the previous day.

If you stop taking Targretin
Your doctor should determine how long you should take Targretin, and when treatment may be 
stopped. Do not stop taking your medication until your doctor advises you to do so.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

Tell your doctor as soon as possible if you feel any deterioration in your condition while you are 
taking Targretin. Sometimes it is necessary to adjust the dose or interrupt treatment. Your doctor will 
advise you on what to do.

The following side effects were reported in patients with CTCL who were treated with the 
recommended initial dose of capsules.



23

Very common (can occur in more than 1 in 10 patients treated):
Low white blood cell count.
Lowering of thyroid hormones level.
Elevation of blood fats (triglycerides and cholesterol).
Skin reactions (Itching, redness, irritation, peeling).
Headache, fatigue, pain.

Common (can occur in up to 1 in 10 patients treated):
Low red blood cell count, enlarged lymph nodes, worsening of lymphoma.
Thyroid disorder.
Elevation of liver enzymes, impaired kidney function, low protein in blood, weight gain.
Insomnia, dizziness, reduced skin sensation.
Dry eyes, deafness, abnormal sensations of the eye including irritation and heaviness.
Swelling of legs and arms.
Nausea, diarrhoea, dry mouth, dry lips, loss of appetite, constipation, excess gas, abnormal liver 
function tests, vomiting.
Dry skin, skin disorder, loss of hair, skin ulcer, acne, skin thickening, skin nodule, increased sweating.
Joint aches, bone pain, muscle aches.
Chills, abdominal pain, allergic reaction, infection.

Uncommon (can occur in up to 1 in 100 patients treated):
Blood disorders, eosinophilia, leukocytosis, lymphocytosis, purpura, elevated and decreased numbers 
of blood platelets.
Overactive thyroid.
Elevated bilirubin in the blood, impaired kidney function, gout, decreased HDL cholesterol.
Agitation, difficulties with balance, depression, increased skin sensation on touching, abnormal nerve 
sensations, vertigo.
Abnormal vision, blurred vision, inflammation of the eye lids, cataract, inflammation of the white part 
of the eye, lesion of the cornea of the eye, ear disorder, defect in field of vision.
Swelling, bleeding, high blood pressure, fast heart rate, visible vein enlargement, dilation of blood 
vessels.
Gastrointestinal disorder, liver failure, inflammation of the pancreas.
Changes in hair, herpes simplex, nail disorder, pustular rash, serous drainage, skin discoloration.
Muscle weakness.
Proteins in urine, abnormal kidney function.
Back pain, skin infection, fever, parasitic infection, abnormal laboratory test, disorder of mucous 
membrane, tumour.

Rare fatal side effects are acute inflammation of the pancreas, bleeding in the head, and liver failure. 

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Targretin

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the 
last day of that month.

Do not store above 30C. Keep the bottle tightly closed.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


24

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Targretin contains

Each Targretin capsule contains 75 mg of the active substance bexarotene. 

The capsules also contain the other ingredients macrogol, polysorbate, povidone and butylated 
hydroxyanisole.

The capsule shell consists of gelatin, sorbitol special-glycerine blend (glycerin, sorbitol, sorbitol 
anhydrides (1,4-sorbitan), mannitol and water), titanium dioxide (E171) and printing ink (SDA 35A 
alcohol (ethanol & ethyl acetate), propylene glycol (E1520), iron oxide black (E172), polyvinyl 
acetate phthalate, purified water, isopropyl alcohol, macrogol 400, ammonium hydroxide 28%).

What Targretin looks like and contents of the pack

Targretin is available as soft capsules for oral use in a white plastic bottle containing 100 capsules.

Marketing Authorisation Holder
Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany
e-mail: medinfo_de@eisai.net 

Manufacturer
Eisai Manufacturing Limited
Mosquito Way
Hatfield 
Hertfordshire
AL10 9SN
United Kingdom

Or

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Eisai SA/NV
Tél/Tel: +32 (0)800 158 58

Lietuva
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vokietija)

България
Eisai GmbH
Teл.: + 49 (0) 69 66 58 50
(Германия)

Luxembourg/Luxemburg
Eisai SA/NV
Tél/Tel: +32 (0)800 158 58
(Belgique/Belgien)



25

Česká republika
Eisai GesmbH organizačni složka
Tel: + 420 242 485 839

Magyarország
Ewopharma Hungary Ltd.
Tel: +36 1 200 46 50

Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Malta
Associated Drug Co. Ltd
Tel: + 356 2277 8000

Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50

Nederland
Eisai B.V.
Tel: + 31 (0) 900 575 3340

Eesti
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Saksamaa)

Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Ελλάδα
Arriani Pharmaceutical S.A.
Τηλ: + 30 210 668 3000

Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0

España
Eisai Farmacéutica, S.A.
Tel: + (34) 91 455 94 55

Polska
Ewopharma AG Sp. z o.o.
Tel: +48 (22) 620 11 71

France
Eisai SAS
Tél: + (33) 1 47 67 00 05

Portugal
Eisai Farmacêtica, Unipessoal Lda
Tel: + 351 214 875 540

Hrvatska
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Njemačka)

România
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germania)

Ireland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germany)

Slovenija
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Nemčija)

Ísland
Eisai AB
Sími: + 46 (0)8 501 01 600
(Svíþjóð)

Slovenská republika
Eisai GesmbH organizačni složka
Tel.: + 420 242 485 839
(Česká republika)

Italia
Eisai S.r.l.
Tel: + 39 02 5181401

Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi)

Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
(Ελλάδα)

Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600



26

Latvija
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vācija)

United Kingdom
Eisai Europe Ltd.
Tel: +44 (0)208 600 1400

This leaflet was last revised in 

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET