Panretin - patient leaflet, side effects, dosage

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• 4.4 Special warnings and precautions for use

Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin gel in the clinical studies. However, patients must be cautioned to minimise exposure of treated areas to sunlight or other ultraviolet (UV) light. (see section 5.3).

It is recommended that daily dietary intake of vitamin A should not exceed the Recommended Dietary Intake value.

Alitretinoin may cause harm to the foetus. Women of c form of contraception during treatment with Panretin g after cessation of treatment.

• 4.5 Interaction with other medicinal products and other forms of interaction

The use of other topical products on Panretin treated KS lesions should be avoided. Mineral oil may be used between Panretin applications in order to help prevent excessive dryness or itching.

However, mineral oil should not be applied for at least two hours before or after the application of

Panretin. .nr

It is not recommended for patients to apply Panretin gel concurrently with products that contain N,N -diethyl-m -toluamide (DEET ), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

The range and frequency of detection of quantifiable plasma 9-cis -retinoic acid concentrations in patients with KS applying the medicinal product to up to 64 lesions were comparable to respective values in untreated patients. Therefore, there is a low potential for interactions with

ic medicinal products.

There was no clinical evidence in the vehicle-controlled studies of interactions with systemic antiretroviral agents, including protease inhibitors; macrolide antibiotics and azole antifungals. While no data are available, it is possible that co-administration of medicinal products which induce CYP isozymes may reduce circulating levels of alitretinoin, with a possible negative effect on the efficacy of Panretin gel.

• 4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during, and up to one month after cessation of treatment.

Men using Panretin should take precautions to ensure that their female partners do not become pregnant.

Pregnancy

Orally administered retinoids have been associated with congenital abnormalities. When used in accordance with the prescribing information topically administered retinoids are generally assumed to result in low systemic exposure due to minimal dermal absorption. However there could be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure.

In rabbits, alitretinoin was shown to be teratogenic at a dose which resulted in plasma concentrations about 60 times the highest observed plasma concentration in male patients with KS following topical application of the gel. However, it is not currently certain to what extent topical treatme Panretin gel would increase 9-cis -retinoic acid plasma concentrations, in women with naturally occurring levels; therefore, Panretin is contraindicated ( see section 4.3) i women planning a pregnancy. If the product is used during pregnancy, or if th pregnant while taking this drug, treatment should be discontinued.

Breast-feeding

It is not known whether this medicinal product is excreted in uman milk. Based on the plasma concentrations observed in patients, milk concentrations of low risk for the infant. However, because of the potential

gel in infants being breast-fed, mothers must disc medicinal product and not initiate breast-feeding

Care should be taken not to bring the neonate into skin contact with areas to which Panretin has been recently applied. It is recommended that fected mothers do not breast-feed their children to

exclude the risk of transmission o

Fertility

No specific studies on fertility have been conducted in men or women. However, alitretinoin is teratogenic so both men and women should take adequate precautions to avoid female partners becoming pregnant.

• 4.7 Effects on ability to drive and use machines r cutaneous use and is unlikely to have an effect on the ability to drive and use

  Panretin machine

  
  

desirable effects

Adverse events associated with the use of Panretin gel in AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity typically begins as erythema; with continued application of Panretin gel erythema may increase and oedema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, oedema, and vesiculation. When applying Panretin gel, 69.1% of patients experienced adverse drug reactions at the application site.

Table 3 shows the following application-site drug-related adverse reactions were reported during clinical studies in patients with KS. The frequency of adverse events are classified as very common (>1/10), common (>1/100 to <1/10), and uncommon (>1/1,000 to <1/100). Adverse events include verbatim terms in parentheses.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3 ________ Adverse reactions reported in patients in clinical trials

System Organ Class (MedDRA terminology)	Very common	Common	Uncommon
Blood and lymphatic system disorders			Lymphadenopathy
Nervous system disorders		Paraesthesia (stinging, tingling)
Vascular disorders		Haemorrhage (bleeding at or around lesions), Oedema (oedema, swelling, inflammation), Peripheral oedema	Phlebitis, Vascular disorder
Skin and subcutaneous tissue disorder	Skin disorder (cracking, scab, crusting, excoriation, drainage, oozing), Rash (erythema, redness, scaling, irritation, dermatitis), Pruritus (itching, pruritus)	Skin ulcer, Serous drainage, Exfoliative dermatitis (flaking, peeling, desquamation, exfoliation), Skin discoloration (browmZ discoloration,/ surrounding hyperpigmentation, paler), Dry skin	Cellulitis, Vesiculobullous rash, Maculopapular rash, Allergic reaction r
General disorders and administration site conditions	Pain (burning, pain, soreness)		Infection, including bacterial infection

The safety of Panretin gel has been assessed in clinical studies of more than 469 patients with AIDS-related KS, 439 of whom were treated with an alitretinoin concentration of 0.1%.

The incidence of drug-related skin disorder, skin ulcer, pain and rash appeared to be greater in patients applying Panretin gel four times daily than in those applying it less frequently.

However, the incidence of other equally common drug-related adverse events such as pruritus, oedema, exfoliative dermatitis and dry skin did not appear to increase as a function of the frequency of application.

The incidence of mild/moderate rash (all events regardless of causality) was less in patients treated for less than 16 weeks than in those treated for 16 weeks or more (mild, 33% v 63%; moderate, 29% v 43%). The incidence of severe skin rash was independent of the duration of treatment (10% in both cases).

Local dermal toxicity associated with Panretin gel therapy generally resolved with treatment adjustment or discontinuation (see section 4.2).

Only two serious adverse reactions were reported (sepsis and cellulitis in the same patient).

The adverse events seen with Panretin gel are similar to those seen with other topical retinoids. It is unlikely that the undesirable systemic side effects associated with oral retinoids will be observed with the use of Panretin gel because the range and frequency of quantifiable 9-cis -retinoic acid plasma levels concentrations after application of the medicinal product were comparable to the range and frequency of quantifiable plasma concentrations of circulating, naturally occurring 9-cis -retinoic acid in untreated individuals.

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.

4.9 Overdose

No case of overdose has been reported.

Systemic toxicity following acute overdose with topical application of Panretin gel is unlikely.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacody­namic properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: LO1XX22

Although the molecular action of alitretinoin is thought to be mediated through interaction with the retinoid receptors, the exact mechanism of action of this medicinal product in the topical treatment of cutaneous lesions of AIDS-related KS is unknown. Alitretinoin (9-cis -retinoic acid), a naturally-occurring endogenous hormone related to vitamin A, binds to and activates all known intracellular retinoid receptor subtypes (RARa, RARp, RARy, RXRa, RXRp, RXRy). Once activated, these receptors function as ligand dependent ription factors that regulate

the expression of specific genes. The regulation of gene e by alitretinoin controls the

process of cellular differentiation and proliferation in bo and neoplastic cells. The

efficacy of Panretin gel in treating KS lesions may b alitretinoin to inhibit the in vitro growth of KS cells.

2. Protocol-specified dose regimen was application twice a day (BD) only, with downward adjustments for toxicity.

In the open label phase of Study 1 (N = 184), the overall response rate increased to 66.7%. In Study 2a (N = 99), the overall response rate increased to 56.1%.

In study 1, of 110 responding patients, 36 (33%) relapsed, while all but four still being on active treatment.

Response rates were analysed both by the patient as the unit of analysis and by the lesion. Table 5 provides the individual lesion response rates for patients being treated with Panretin in the Phase III studies.

Table 5 Index/indicator lesion1 responses within patients durin

on study in initial blinded phase

	Patients with given number of index/indicator lesion responlesJCCR or PR)
	Study 1		Study 2
Number of Responding	Panretin (N=134)	Vehicle (N=134)	Panretin (N=62)y	Vehicle (N=72)
Lesions2,3	N %4	N %4	N %4	N %4
At Least One	73 (54.5%)	42 (31.3%)	¿3X3.2%)	21 (29.2%)
At Least Four	27 (20.1%)	8 (6.0%)	<<¿12.9%)	2 (2.8%)

1.

2.

3.

Study 1, 6 index lesions; Study 2, up to 8 index lesions

Each index lesion assessed individually for response.

Lesions responding during the first 12 weeks on study, initial blinded phase, confirmed over at least four study weeks (confirmation of response may have occurred after 12 weeks for some lesions in Study 1).

Percentages calculated as number of patients with responding lesions divided by total number of patients in the initial blinded phase.

hed a partial response (PR) but had not attained clinical complete response (CCR) within the first 12 weeks of treatment developed a CCR during continuing treatment be weeks. The projected time for lesions that were in partial

response (PR) to later attain clical complete response (CCR) was 168 days. It is recommended that Panretin gel should be applied for an initial treatment period of up to 12 weeks. In lesions that have responded to treatment during this time, application may be continued provided that the response improves or is maintained and the product continues to be tolerated. If a complete response of a lesion occurs, no further application of Panretin gel should be made to the responding lesion.

There are no data regarding the efficacy of Panretin gel when applied to complicated lesions ymphoedema is present).

Plasma concentrations of 9-cis -retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of Panretin gel for up to 60 weeks. A subset of these patients were followed during treatment of up to 64 lesions (range 4–64, median 11.5 lesions) for up to 44 weeks (range 2–44, median

15 weeks). In this latter group, the range and frequency of detection of quantifiable 9-cis -retinoic acid plasma concentrations in patients with KS after application of the medicinal product were comparable to the range and frequency of detection of quantifiable plasma concentrations of circulating, naturally-occurring 9-cis -retinoic acid in untreated individuals.

5.3 Preclinical safety data

Toxicology

Three doses of alitretinoin (0.01%, 0.05%, or 0.5%) in a topical gel formulation were given to rats in a 28-day dermal toxicology study. Observed effects at the application site included erythema, epidermal thickening, scaling and loosening of the stratum corneum. Clinical pathology evaluations revealed significant increases in absolute polymorphonuclear leukocyte counts, monocyte counts, percentage of monocytes and decreases in percentage of lymphocyte differential white blood cell counts on day 29 of rats treated with alitretinoin 0.5% gel. Clinical chemistry evaluations revealed biologically relevant significant increases in the mean BUN and alkaline phosphatase values in females after the 28-day treatment. Serum LDL was increased in both male and female groups at Day 29. There were no biologically relevant haematology differences or serum chemistry differences after the 14-day period. Observed increases in me

heart-to-final body weight differences were attributed principally to the difference in the terminal body weights. Following treatment with alitretinoin 0.5% gel, mean plasma concentrations in the female rats were generally below the lower limit of quantitation and mean plasma concentrations in the male rats were about 200 nMol. In contrast to

findings in rats, plasma concentrations of 9-cis -retinoic acid in patients wit Panretin gel never exceeded 0.638 ng/ml (2.13 nMol). This level is about 1 concentration measured in male rats.

Genotoxicity

Alitretinoin was studied for genotoxic potential using the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in h mutation test. The medicinal product was not genotoxic.

Carcinogenesis, mutagenesis, impairment of fertilit

Studies have not been performed to determine the carcinogenic potential of alitretinoin.

However, the mutagenic potential has been evaluated, and alitretinoin has tested negative in the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO ceon test.

Teratogenicity

n rabbits, alitretinoin induced gross malformations at a dose e. This dose in rabbits resulted in plasma concentrations more

observed plasma concentration in patients with KS following topical gel. No gross malformations were observed following oral administration

2 times the human topical dose (which resulted in plasma concentrations ighest observed plasma concentration in patients with KS following topical the gel). However, an increased rate of fused sternebrae was observed.

The phototoxicity potential of alitretinoin was assessed based on its chemical properties and data from a battery of in vitro tests. The results suggest that alitretinoin absorbs light in the UV range and is subject to photodegradation to other isomers (predominantly all-trans -retinoic acid). Alitretinoin was shown to have a weak potential to be a photo-irritant based on histidine and photoprotein binding. In cell-based in vitro assays, alitretinoin showed weak phototoxic potential.

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Ethanol

Macrogol 400

Hydroxypropyl­cellulose

Butylhydroxytoluene

• 6.2 Incompati­bilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. The use of other topical products on treated KS lesions should be avoided.

Panretin gel should not be used concurrently with products containing DEET.

• 6.3 Shelf life

Unopened: 3 years.

In-use: Any remaining tube should be discarded 90 days after first opening.

• 6.4 Special precautions for storage

Do not store above 25°C.

Store in the original container in order to protect from light.

Keep the container tightly closed.

After opening the tube for application, the tube cap must be provide an airtight seal. Opened tubes of Panretin gel must be protected from exposure to strong light and heat (e.g., direct sunlight).

• 6.5 Nature and contents of container

Panretin gel is supplied in a multi-use 60 Each carton contains one tube of gel.

• 6.6 Special precautions for di

  Any unused product or wa requirements.

  
  

  rial should be disposed of in accordance with local

  
  

  Panretin gel contai

  
  

  hol, keep away from naked flame.

  
  

  7.

  Germany

  
  

  ING AUTHORISATION HOLDER

  
  

  traße 36

  ankfurt am Main

  
  

  E-mail:

  
  

• 8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/1/00/149/001

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorization: 11 October 2000

Date of latest renewal: 27 September 2010

• 10. DATE OF REVISION OF THE TEXT

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

A MANUFACTURING AUTHORISATION HOLDER 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

Lyoner Straße 36

60528 Frankfurt am Main

Germany

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

B CONDITIONS OF THE MARKETING A

CONDITIONS OR RESTRICTIONS ON THE MARKETING AUTHORIS

ARDING SUPPLY AND USE IMPOSED N HOLDER

Medicinal product subject to restricted Characteristics, section 4.2)

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

ECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER

Not applicable.

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING

OUTER CARTON TEXT AND TUBE LABEL TEXT

• 1. NAME OF THE MEDICINAL PRODUCT

Panretin 0.1 % gel alitretinoin

• 2. STATEMENT OF ACTIVE SUBSTANCE 1 g of gel contains 1 mg alitretinoin (0.1%).

  3. LIST OF EXCIPIENTS

  
  

Also contains ethanol, macrogol 400, hydroxypropyl­cellulose, b

• 4. PHARMACEUTICAL FORM AND CONTE

  Gel, 60 g

  
  

• 5. METHOD AND ROUTE OF ADMINISTRATION

  For cutaneous use.

  Read the package leaflet before

  
  

  6. SPECIAL W

  OUT OF TH

  
  

THAT THE MEDICINAL PRODUCT MUST BE STORED AND REACH OF CHILDREN

R SPECIAL WARNING(S), IF NECESSARY

Not for application to the eyes or mucous membranes. Contains alcohol, keep away from naked flame.

• 8. EXPIRY DATE

EXP

• 9. SPECIAL STORAGE CONDITIONS

Do not store above 25°C.

Store in the original container in order to protect from light.

Keep the container tightly closed.

• 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

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

Package leaflet: Iinformation for the user

Panretin 0.1% gel Alitretinoin

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. 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 :

What Panretin is and what it is used for

What you need to know before you use Panretin

How to use Panretin

Possible side effects

How to store Panretin

Contents of the pack and other information

What Panretin is and what it is used for

Panretin belongs to a group of medicines that are related to vitamin A and known as retinoids.

Panretin is used in patients with AIDS-related Kaposi’s sarcoma (KS) and is for the treatment of the KS lesions:

where the surrounding skin is not swollen

if your doctor thinks that other treatments are not suitable for you.

need to know before you use Panretin

t use Panretin:

if you are allergic to alitretinoin or to similar medicines containing retinoids

if you are allergic to any of the other ingredients of this medicine (listed in section 6) if you are pregnant

if you are planning a pregnancy

if you are breast-feeding

on KS lesions close to any other skin complaint

Take special care with Panretin

• – Panretin is not approved for use in children and adolescents under 18 years of age.

• – Do not apply the gel on or near sensitive parts of your body such as eyes, nostrils, mouth,

lips, vagina, tip of the penis, rectum, or anus.

• – Do not apply the gel to healthy skin around a KS lesion. Panretin may cause unwanted

irritation or redness on healthy skin.

Do not use insect repellents containing DEET (N,N -diethyl-m -toluamide) or other products containing DEET while using Panretin.

Avoid prolonged exposure of the treated area to sunlight or other ultraviolet (UV) light (such as tanning lamps).

Mineral oil may be used between Panretin applications in order to help prevent excessive dryness or itching. However, mineral oil must not be applied for at least two hours before or after the application of Panretin.

Women of child-bearing age must use an effective method of birth control while using Panretin, and for one month after finishing treatment.

Other medicines and Panretin

Avoid the use of other products on your treated KS lesions such as insect repellents that y on your skin.

Tell your doctor or pharmacist if you are taking or have recently taken any o including medicines obtained without a prescription.

Panretin with food and drink

It is recommended that you should not eat more vitamin A in your die suggested by your doctor.

Pregnancy

DO NOT use Panretin if you are pregnant or thinking of be give you more information.

Breast-feeding

Do not breast-feed your baby while you are using Panretin. Care should be taken not to bring your baby into contact with areas of your skin treated recently with Panretin.

Driving and using machines

3.    How to use Panretin

drive or use machines.

Panretin is unlikely to affect your

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

time, use the pointed portion of the cap to puncture the metal safety seal.

anretin: For cutaneous use (on the skin) only retin twice a day to start with, once in the morning and once in the evening. After that, tor will decide how often you should apply the gel depending on the response of your d any side effects.

Apply Panretin to your KS lesions using a clean finger. Place a generous coating of gel over the whole surface of each lesion that you want to treat. You do not need to rub the gel into the lesion. You need to avoid applying the gel to the healthy skin around the lesion. Carefully applying the gel only to the area of the KS lesion will help to lessen any irritation or redness that may occur. Proper application will leave some gel visible on the surface of the lesion when you are finished.

Immediately after application, wipe the finger(s) you have used to apply the gel and any healthy skin touched by the gel with a disposable tissue. Wash your hands using soap and water and wipe the healthy skin touched by the gel.

Allow the gel to dry for three to five minutes before covering a treated area with loose clothing. Do not cover the treated lesions with any bandage or other material.

A mild soap is recommended when bathing or showering.

If you think that the effect of Panretin is too strong or too weak, talk to your doctor or pharmacist.

Avoid showering, bathing, or swimming for at least three hours after any application.

Avoid scratching the treated areas.

Panretin contains alcohol. Keep away from naked flame.

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

4.    Possible side effects

Like all medicines, Panretin can have side effects, although not everybody gets them. The side effects are most likely to appear at the site where Panretin was applied and typically begins as redness. With continued application of Panretin redness and irritation may increase and swelling at the site of the application may develop. If your side effects become too uncomfortable, with intense redness and irritation, rash, swelling, or pain, you should ask your doctor for advice on adjusting the dosage of your treatment. Most patients can continue to use Panretin by altering the number of times a day it is applied. Sometimes it is necessary to interrupt treatment, your doctor will inform you about this.

de effects have been noted on the skin where Panretin has been applied:

Very common (can occur in more than 1 in 10 patients treated):

Rash, scaling, irritation, redness

Cracking, scabbing, crusting, draining, oozing

Pain, burning, soreness

Itching

Common (can occur in less than 1 in 10 but in more than 1 in 100 patients treated):

Flaking, peeling, dry skin

Swelling, inflammation

Stinging, tingling

Bleeding

Skin discoloration

Skin ulcer

Uncommon (can occur in less than 1 in 100 but in more than 1 in 1000 patients treated):

Infection

Allergic reaction

Swollen lymph glands

Pale skin

If any of the side effects gets serious or if you notice any side effects not mentioned in this leaflet, please tell your doctor or pharmacist.

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. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Panretin

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

Do not use after the expiry date which is stated on the end of t he tube.

Do not store above 25°C.

Store in the original container in order to protect from light.

Keep the container tightly closed. Always use the cap to close the tube tightly after each use.

After opening, use within 90 days.

The opening of the Panretin tube is covered by a metal safety seal. If this seal has been punctured or is not visible when you first open the package, DO NOT USE and return the product to your pharmacy.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Contents of the pack and other informationWhat Panretin contains- The active substance is alitretinoin. 1 g of gel contains 1 mg of alitretinoin.

• – The other ingredients are ethanol, macrogol 400, hydroxypropyl­cellulose, and

What Panretin looks like and contents of the pack

Panretin is a clear yellow gel. It is supplied in a multi-use 60 g epoxy-lined aluminium tube.

Each carton contains one tube of gel.

Marketing Authorisation Holder

Eisai GmbH

Lyoner Straße 36

60528 Frankfurt am Main

Germany

E-mail:

Manufacturer

Eisai Manufacturing Limited

Mosquito Way

Hatfield

Hertfordshire

AL10 9SN

United Kingdom

Or

Eisai GmbH

Lyoner Straße 36

60528 Frankfurt am Main

Germany

For any information about this medicine please contact the local representative Authorisation Holder.

België/Belgiqu­e/Belgien

Eisai SA/NV

Tél/Tel: +32 (0)800 158 58

Efc^rapufl

Eisai GmbH

Ten.: + 49 (0) 69 66 58 50

(repMaHua)

Danmark

Eisai AB

Tlf: + 46 (0) 8 501 01 600

(Sverige)

Lietuva

Eisai GmbH

Tel: + 49 (Vokietij Luxe Eisa

GmbH

Tel.: + 49 (0) 69 66 58 50

(Németország)

Malta

Eisai GmbH

Tel.: + 49 (0) 69 66 58 50

(Il-Germanja)

Deutschland

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Tel: + 49

Eesti

Eisai

Tel: + 49 (0) 69 66 58 50

(Saksamaa)

Norge

Eisai AB

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(Sverige)

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Tql: +30 210 668 3000

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Eisai GesmbH

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