TARGRETIN 75mg capsule me medication leaflet

Targretin 75 mg soft capsules

Each capsule contains 75 mg of bexarotene.

Excipient(s) with known effect: sorbitol

For the full list of excipients, see section 6.1.

Soft capsule.

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

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

Bexarotene therapy should only be initiated and maintained by physicians experienced in the treatmentof patients with CTCL.

The recommended initial dose is 300 mg/m2/day. Initial dose calculations according to body surfacearea are as follows:

Table 1 Recommended initial dose

Initial dose level (300 mg/m2/day) Number of 75 mg Targretin

Body Surface Area (m2) Total daily dose (mg/day) capsules0.88 - 1.12 300 41.13 - 1.37 375 51.38 - 1.62 450 61.63 - 1.87 525 71.88 - 2.12 600 82.13 - 2.37 675 92.38 - 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, ortemporarily suspended, if necessitated by toxicity. When toxicity is controlled, doses may be carefullyreadjusted upward. With appropriate clinical monitoring, individual patients may benefit from dosesabove 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.

The safety and efficacy of bexarotene in children (aged below 18 years) have not been established. Nodata are available.

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 orolder and younger patients, but greater sensitivity of some older individuals to bexarotene cannot beruled out. The standard dose should be used in the elderly.

No formal studies have been conducted in patients with renal insufficiency. Clinical pharmacokineticdata indicate that urinary elimination of bexarotene and its metabolites is a minor excretory pathwayfor bexarotene. In all evaluated patients, the estimated renal clearance of bexarotene was less than1 ml/minute. In view of the limited data, patients with renal insufficiency should be monitoredcarefully while on bexarotene therapy.

For oral use.

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

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.

Ongoing systemic infection.

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 notdonate blood for transfusion. Butylated hydroxyanisole, an ingredient in Targretin, may causeirritation to the mucous membranes, therefore the capsules must be swallowed intact and not chewed.

Hyperlipidaemia has been identified as an effect associated with the use of bexarotene in clinicalstudies. Fasting blood lipid determinations (triglycerides and cholesterol) should be performed beforebexarotene therapy is initiated and at weekly intervals until the lipid response to bexarotene isestablished, which usually occurs within two to four weeks, and then at intervals no less than monthlythereafter. Fasting triglycerides should be normal or normalised with appropriate intervention prior tobexarotene therapy. Every attempt should be made to maintain triglyceride levels below 4.52 mmol/lin order to reduce the risk of clinical sequelae. If fasting triglycerides are elevated or become elevatedduring treatment, institution of antilipaemic therapy is recommended, and if necessary, dosereductions (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 werenot affected by concomitant administration of atorvastatin. However, concomitant administration ofgemfibrozil 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.

Acute pancreatitis associated with elevations of fasting serum triglycerides has been reported inclinical studies. Patients with CTCL having risk factors for pancreatitis (e.g., prior episodes ofpancreatitis, uncontrolled hyperlipidaemia, excessive alcohol consumption, uncontrolled diabetesmellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associatedwith pancreatic toxicity) should not be treated with bexarotene, unless the potential benefit outweighsthe risk.

Liver Function Test (LFT) abnormalities

LFT elevations associated with the use of bexarotene have been reported. Based on data from ongoingclinical trials, elevation of LFTs resolved within one month in 80% of patients following a decrease indose or discontinuation of therapy. Baseline LFTs should be obtained, and LFTs should be carefullymonitored weekly during the first month and then monthly thereafter. Consideration should be givento a suspension or discontinuation of bexarotene if test results reach greater than three times the upperlimit 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 oftennoted as a reversible reduction in thyroid hormone (total thyroxine [total T4]) and thyroid-stimulatinghormone (TSH) levels. Baseline thyroid function tests should be obtained and then monitored at leastmonthly during treatment and as indicated by the emergence of symptoms consistent withhypothyroidism. Patients with symptomatic hypothyroidism on bexarotene therapy have been treatedwith thyroid hormone supplements with resolution of symptoms.

Leucopenia

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

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

Depression, depression aggravated, anxiety, and mood alterations have been reported in patientstreated with systemic retinoids, including bexarotene. Particular care should be taken in patients with ahistory of depression. Patients should be monitored for signs of depression and referred for appropriatetreatment if necessary. Awareness by family or friends may be useful to detect mental healthdeterioration.

Lens opacities

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

Vitamin A supplementation

Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin Asupplements 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, agentsenhancing insulin secretion (e.g. sulfonylureas), or insulin-sensitisers (e.g. thiazolidinediones). Basedon 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 asmonotherapy have been reported.

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

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

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

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

Effects of other substances on bexarotene

No formal studies to evaluate interactions with bexarotene have been conducted. On the basis of theoxidative metabolism of bexarotene by cytochrome P450 3A4 (CYP3A4), coadministration with other

CYP3A4 substrates such as ketoconazole, itraconazole, protease inhibitors, clarithromycin anderythromycin may theoretically lead to an increase in plasma bexarotene concentrations. Furthermore,co-administration with CYP3A4 inducers such as rifampicin, phenytoin, dexamethasone orphenobarbital may theoretically cause a reduction in plasma bexarotene concentrations.

Caution is advised in case of combination with CYP3A4 substrates having a narrow therapeuticmargin 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 thatconcomitant administration of gemfibrozil resulted in substantial increases in plasma concentrations ofbexarotene. The mechanism of this interaction is unknown. Under similar conditions, bexaroteneconcentrations 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 ofbexarotene may result in an auto-induction of its own metabolism and, particularly at dose levelsgreater than 300 mg/m2/day, may increase the rate of metabolism and reduce plasma concentrations ofother substances metabolised by cytochrome P450 3A4, such as tamoxifen. For example bexarotenemay reduce the efficacy of oral contraceptives (see sections 4.4 and 4.6).

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 section4.4).

Laboratory test interactions

CA125 assay values in patients with ovarian cancer may be accentuated with bexarotene therapy.

In all clinical trials, patients were instructed to take Targretin capsules with or immediately followinga meal. In one clinical study, plasma bexarotene AUC and Cmax values were substantially higherfollowing the administration of a fat-containing meal versus those following the administration of aglucose solution. Because safety and efficacy data from clinical trials are based upon administrationwith 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 maytheoretically lead to an increase in plasma bexarotene concentrations.

There are no adequate data from the use of bexarotene in pregnant women. Studies in animals haveshown 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 iscontraindicated in pregnancy (see section 4.3).

If this medicinal product is used inadvertently during pregnancy, or if the patient becomes pregnantwhile taking this medicinal product, the patient should be informed of the potential hazard to thefoetus.

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 usedfrom the time of the negative pregnancy test through the initiation of therapy, during therapy and for atleast one month following discontinuation of therapy. Whenever contraception is required, it isrecommended that two reliable forms of contraception be used simultaneously. Bexarotene canpotentially induce metabolic enzymes and thereby theoretically reduce the efficacy ofoestroprogestative contraceptives (see section 4.5). Thus, if treatment with bexarotene is intended in awoman with childbearing potential, a reliable, non-hormonal contraceptive method is alsorecommended. Male patients with sexual partners who are pregnant, possibly pregnant, or maypotentially become pregnant must use condoms during sexual intercourse while taking bexarotene andfor at least one month after the last dose.

It is unknown whether bexarotene is excreted in human milk. Bexarotene should not be used inbreast-feeding mothers.

There are no human data on the effect of bexarotene on fertility. In male dogs, some effects have beendocumented (see section 5.3). Effects on fertility cannot be excluded.

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 whoexperience dizziness or visual difficulties during therapy must not drive or operate machinery.

The safety of bexarotene has been examined in clinical studies of 193 patients with CTCL whoreceived 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 mostcommonly reported adverse reactions to Targretin were hyperlipaemia ((primarily elevatedtriglycerides) 74%), hypothyroidism (29%), hypercholesterolaemia (28%), headache (27%),leucopenia (20%), pruritus (20%), asthenia (19%), rash (16%), exfoliative dermatitis (15%), and pain(12%).

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 adversereactions 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(MedDRAterminology*)

Blood Dyscrasia

Purpura

Coagulation Disorder

Blood and Coagulation Time Increased2,3

Lymphoma Like Reactionlymphatic Anaemia1

Leucopenia Lymphadenopathysystem 1,2,3 Thrombocytopenia3

Hypochromic Anaemiadisorders Thrombocythemia

Eosinophilia1

Leukocytosis2

Lymphocytosis

Endocrine

Hypothyroidism Thyroid Disorder Hyperthyroidismdisorders

Weight Gain

Gout

SGOT Increased

Metabolism Bilirubinemia1,3

Hyperlipaemia SGPT Increasedand nutrition BUN Increased1

Hypercholesterolaemia Lactic Dehydrogenase Increaseddisorders High Density Lipoprotein

Creatinine Increased

Decreased

Ataxia

Neuropathy

Dizziness

Nervous system Vertigo

Hypesthesiadisorders Hyperaesthesia

Insomnia

Depression1,2,3

Agitation

Cataract Specified1,2,3

Amblyopia3

Visual Field Defect

Dry Eyes

Eye disorders Corneal Lesion

Eye Disorder

Abnormal Vision1,2,3

Blepharitis

Conjunctivitis3

System Organ

Class

Very Common Common Uncommon(MedDRAterminology*)

Ear andlabyrinth

Deafness Ear disorderdisorders

Cardiac

Tachycardiadisorders

Vascular

Peripheral Oedema Oedema3disorders

Vasodilatation1,2,3

Varicose Vein

Diarrhoea1,3

Nausea3

Anorexia1 Pancreatitis1,3

Gastrointestinal

Liver Function Tests Abnormal Hepatic Failuredisorders

Cheilitis2 Gastrointestinal Disorder1

Dry Mouth2,3

Flatulence

Skin Ulcer

Alopecia1 Serous Drainage1

Skin Hypertrophy Herpes Simplex

Skin and Exfoliative Dermatitis

Skin Nodule Pustular Rashsubcutaneous Pruritus

Acne Skin Discoloration3tissue disorders Rash

Sweating Hair Disorder1

Dry Skin2,3 Nail Disorder1,3

Skin Disorder

Musculoskeletal Bone Painand connective Arthralgia Myasthaenia1tissue disorders Myalgia

Renal and

Albuminuria1,3urinary

Kidney Function Abnormaldisorders

Neoplasm

Allergic Reaction Fever1,2,3

Pain Infection Cellulitisdisorders and

Headache Chills1 Infection Parasiticadministration

Asthaenia Abdominal Pain Mucous Membrane Disorder3site conditions

Hormone Level Altered1 Back Pain1,2,3

Lab Test Abnormal1: 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 300mg/m2/day in non-CTCL cancer patients.3: adverse reactions noted with increased frequency when bexarotene was administered at a dose of >300mg/m2/day (compared to administration to CTCL patients at 300 mg/m2/day) in non-CTCL cancerpatients.

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

Newly observed adverse reactions

Ecchymosis, petechia, abnormal white blood cells, thromboplastin decreased, abnormal erythrocytes,dehydration, increased gonadotrophic luteinizing hormone, weight loss, increased alkalinephosphatase, 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, tasteperversion, 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, legcramps, haematuria, flu syndrome, pelvic pain, and body odour.

Single observations of the following were also reported: bone marrow depression, decreasedprothrombin, decreased gonadotrophic luteinizing hormone, increased amylase, hyponatraemia,hypokalaemia, hyperuricaemia, hypocholesterolaemia, hypolipaemia, hypomagnesaemia, abnormalgait, stupor, circumoral paraesthesia, abnormal thinking, eye pain, hypovolaemia, subduralhaematoma, 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, urineabnormality, breast enlargement, carcinoma, photosensitivity reaction, face oedema, malaise, viralinfection, enlarged abdomen.

The majority of adverse reactions were noted at a higher incidence at doses greater than300 mg/m2/day. Generally, these resolved without sequelae on dose reduction or withdrawal oftreatment. However, among a total of 810 patients, including those without malignancy, treated withbexarotene, there were three serious adverse reactions with fatal outcome (acute pancreatitis, subduralhaematoma and liver failure). Of these, liver failure, subsequently determined to be not related tobexarotene, was the only one to occur in a CTCL patient.

Hypothyroidism generally occurs 4-8 weeks after commencement of therapy. It may be asymptomaticand 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 tocause mucocutaneous, nail, and hair toxicities; arthralgia; and myalgia; which are frequently reportedwith retinoic acid receptor (RAR) -binding agents.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No clinical experience with an overdose of Targretin has been reported. Any overdose should betreated 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 acutetoxic effects. Single doses of 1500 mg/kg (9000 mg/m2) and 720 mg/kg (14,400 mg/m2) were toleratedwithout significant toxicity in rats and dogs, respectively.

Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XF03

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

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

Bexarotene capsules were evaluated in clinical trials of 193 patients with CTCL of whom 93 hadadvanced stage disease refractory to prior systemic therapy. Among the 61 patients treated at an initialdose 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 acomposite score of five clinical signs (surface area, erythema, plaque elevation, scaling andhypo/hyperpigmentation) which also considered all extracutaneous CTCL manifestations. The overallresponse rate according to this composite assessment was 31% (19/61) with a clinical completeresponse rate of 7% (4/61).

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

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

Metabolism: bexarotene metabolites in plasma include 6- and 7-hydroxy-bexarotene and 6- and7-oxo-bexarotene. In vitro studies suggest glucuronidation as a metabolic pathway, and thatcytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for formation of theoxidative metabolites. Based on the in vitro binding and the retinoid receptor activation profile of themetabolites, and on the relative amounts of individual metabolites in plasma, the metabolites havelittle impact on the pharmacological profile of retinoid receptor activation by bexarotene.

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 asignificant elimination pathway for bexarotene.

Pharmacokinetics in Special Populations

Age: Based on the population pharmacokinetic analysis of data for 232 patients aged ≥ 65 years and343 patients aged < 65 years, age has no statistically significant effect on bexarotenepharmacokinetics.

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

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

Bexarotene is not genotoxic. Carcinogenicity studies have not been conducted. Fertility studies havenot been conducted; however, in sexually immature male dogs, reversible aspermatogenesis (28-daystudy) and testicular degeneration (91-day study) were seen. When bexarotene was administered forsix months to sexually mature dogs, no testicular effects were seen. Effects on fertility cannot beexcluded. Bexarotene, in common with the majority of retinoids, was teratogenic and embryotoxic inan animal test species at systemic exposures that are achievable clinically in humans. Irreversiblecataracts involving the posterior area of the lens occurred in rats and dogs treated with bexarotene atsystemic 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 beenexcluded.

Capsule content:macrogolpolysorbatepovidonebutylated hydroxyanisole

Capsule shell:gelatinsorbitol special-glycerin blend (glycerin, sorbitol, sorbitol anhydrides (1,4-sorbitan), mannitol andwater)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, ammoniumhydroxide 28%)

Not applicable.

3 years

Do not store above 30oC.

Keep the bottle tightly closed.

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

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eisai GmbH

Edmund-Rumpler-Straße 360549 Frankfurt am Main

Germanye-mail: medinfo_de@eisai.net

EU/1/01/178/001

Date of first authorisation: 29 March 2001.

Date of latest renewal: 24 April 2006.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.