TOCTINO 30 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
ALITRETINOIN
Available from:
NEOPHARM SCIENTIFIC LTD
ATC code:
D11AX19
Pharmaceutical form:
CAPSULES SOFT
Composition:
ALITRETINOIN 30 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
SWISS CAPS GMBH, GERMANY
Therapeutic group:
ALITRETINOIN
Therapeutic area:
ALITRETINOIN
Therapeutic indications:
For use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids .Patients in whom the eczema has predominantly hyperkeratotic features are more likely to respond to treatment than in those in whom the eczema predominantly presents as pompholyx .
Authorization number:
146 64 33164 00
Authorization date:
2016-12-14

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

28-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

28-02-2019

Pregnancy Prevention Program

Patient Information Brochure

This information brochure contains important information about the treatment with

Toctino and the risk of birth defects when taking this medicine.

This information brochure is part of the pregnancy prevention program for Toctino. Before

taking Toctino you are advised to read the entire information brochure carefully. This

information brochure supplements the guidelines you will receive from your doctor or

pharmacist, but does not replace them. Read the patient information leaflet before you use

this medicine because it also contains important information about how to take this

medicine, information about side effects, and special warnings. If you have any questions or

concerns about taking Toctino, consult your doctor or pharmacist.

Information about birth defects

The active ingredient in Toctino is alitretinoin, which belongs to the retinoid group. Medicines in

this group, including Toctino, are highly likely to harm unborn babies and cause severe birth

defects even if only taken for a short period during pregnancy. Furthermore, Toctino increases

the chance of miscarriage, so you must follow all the instructions in the Toctino pregnancy

prevention program that are listed below.

Important information for female patients

Do not use Toctino if you are pregnant.

You must not get pregnant during the course of treatment with Toctino and for one month

after completing treatment with Toctino.

If you think you might be pregnant despite using contraception, stop taking Toctino

immediately and consult your doctor.

This medicine has been prescribed specifically for you. Do not share this medicine with

another person, particularly with another woman, even if he or she has the same medical

problem that you have. Please return any unused medicines to the pharmacy.

Do not donate blood during the course of treatment and for one month after ending your

treatment, because the woman who gets this blood may be pregnant and her unborn baby

may be exposed to the risk.

You will be given your first prescription after you have a negative pregnancy test, conducted

before starting treatment, or if your doctor can positively rule out the possibility of pregnancy

(for example due to sterilization).

If you are of child-bearing age and there is a chance that you will become pregnant, you will

have to show a negative pregnancy test every month. After receiving a definite negative

pregnancy test, you will be given a Toctino prescription for the following month.

You will have a final pregnancy test one month after completing the treatment with Toctino.

Talk to your doctor or gynecologist about effective contraception.

You must use at least one very effective contraception method (such as an intrauterine

device or implant) or correctly use two effective contraception methods that work differently

(such as oral contraceptives together with a condom) before starting this treatment, during

the course of this treatment, and for a month after stopping the treatment.

Because any contraceptive method, including oral hormonal contraceptives (the Pill), may fail

and allow you to get pregnant, it is preferable to use two different contraception methods.

One main method (such as the Pill or some other hormonal contraceptive or an intrauterine

device) together with a barrier method such as condoms, a diaphragm with spermicide, etc.

You must not take Toctino if you are breastfeeding because Toctino may pass into your

breast milk.

Talk to your doctor if you are planning to take other medicines or herbal remedies, particularly

if you are taking contraceptive pills or some other hormonal contraceptive.

When your treatment is completed, return any unused medicines to your doctor or

pharmacist.

Important information for male patients

Do not donate blood during the course of treatment and for one month after ending your

treatment. If a woman who receives your blood gets pregnant, her unborn baby is at high risk

of developing birth defects. When your treatment is completed, return any unused medicines

to your doctor or pharmacist.

Do not share Toctino with another person, even if he or she has the same medical problem

that you have.

Studies have shown that a small amount of Toctino was present in sperm. These levels are

considered too low to have an effect on your partner’s unborn baby.

Based on pre-clinical studies (animal studies), male fertility may be compromised by

treatment with Toctino. However, in these studies no impact was observed on reproductive

parameters even when using a high dose that resulted in blood concentrations of the

medicine that are similar to those in humans.

Patient Card

Patient Reminder Card

Doctor name:

Phone number:

Do not use Toctino when pregnant

If a pregnant woman takes Toctino it can be very harmful to her unborn baby.

If you are pregnant or think you might be pregnant, stop taking Toctino immediately and

consult your doctor.

Read the package leaflet carefully before you start using this medicine.

If you have any questions or concerns about taking Toctino, consult your doctor or

pharmacist.

What you need to do if you can possibly get pregnant:

- You must use at least one very effective contraception method (such as an intrauterine

device or implant) or correctly use two effective contraception methods that work differently

(such as oral contraceptives together with a condom) before starting this treatment, during

the course of this treatment, and for a month after stopping the treatment.

- You must not get pregnant during the course of treatment with Toctino and for one month

after stopping treatment with Toctino.

- You must go for routine follow-up tests and have regular pregnancy tests:

- Before you start treatment, you will have to have a pregnancy test and it must be

negative.

- In order to make sure that you are not pregnant while taking this treatment, you will

have to have regular pregnancy tests, ideally every month. In addition, you will have to

have a final pregnancy test one month after stopping treatment.

Reminder to female and male patients:

This medicine has been prescribed specifically for you. Do not share this medicine with another

person. Please return any unused medicines to the pharmacy.

Visits table

Use this table to record the dates of your visits to the doctor:

Doctor name:

Phone number:

Doctor signature

Pregnancy test

result

Contraceptives in

use

Visit date

Positive

Negative

Date:

Positive

Negative

Date:

Positive

Negative

Date:

Positive

Negative

Date:

Positive

Negative

Date:

Positive

Negative

Date:

Positive

Negative

Date:

Reporting side effects

You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of

Medication’ on the Ministry of Health home page (www.health.gov.il) which links to an online form for

reporting side effects. You can also use this link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.

gov.il

You can also report directly to the Patient Safety Unit at Neophram:

drugsafety@neophamgroup.com tel. 03-9373796 or 1-800-250-255

The format and content of this card were reviewed and approved by the Ministry of Health in October

2018.

Pregnancy Prevention Program Patient Information Brochure

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Toctino 10 mg

capsules, soft

Toctino 30 mg

capsules, soft

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule, soft contains 10 mg or 30 mg of alitretinoin

Excipients with known effect

Soya-bean oil.

Each 10 mg capsule contains 176.50 mg soya-bean oil.Each 30 mg capsule contains 282.40 mg soya-

bean oil.

Sorbitol. Each 10 mg capsule contains 20.08 mg sorbitol.

Each 30 mg capsule contains 25.66 mg sorbitol.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule, soft

The Toctino 10 mg capsule is a brown oval capsule approximately 11 mm in length and 7 mm in width

marked with “A1”.

The Toctino 30 mg capsule is a red-brown oval capsule approximately 13 mm in length and 8 mm in

width marked with “A3”.

Patient safety information Card

The marketing of Toctino is subject to a risk management plan (RMP) including a ‘Patient safety

information card’. The ‘Patient safety information card’, emphasizes important safety information that

the patient should be aware of before and during treatment.

Please explain to the patient the need to review the card before starting treatment.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Toctino is indicated for use in adults who have severe chronic hand eczema that is unresponsive to

treatment with potent topical corticosteroids.

Patients in whom the eczema has predominantly hyperkeratotic features are more likely to respond to

treatment than in those in whom the eczema predominantly presents as pompholyx (see section 5.1).

4.2

Posology and method of administration

Toctino should only be prescribed by dermatologists, or physicians with experience in the use of

systemic retinoids who have full understanding of the risks of systemic retinoid therapy and monitoring

requirements. Prescriptions of Toctino for women of childbearing potential should be limited to 30 days

of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing,

issuing a prescription and dispensing of Toctino should occur on the same day.

The recommended dose for Toctino is 10 mg or 30 mg once daily.

The recommended starting dose for Toctino is 30 mg once daily. A dose reduction to 10 mg once daily

may be considered in patients with unacceptable adverse reactions to the 30 mg dose. In studies

investigating 10 mg and 30 mg daily doses, both doses resulted in clearing of the disease. The 30 mg

dose provided a more rapid response and a higher response rate. The 10 mg daily dose was associated

with fewer adverse events (see section 5.1).

Duration of treatment

A treatment course of Toctino may be given for 12 to 24 weeks depending on response. Discontinuation

of therapy is recommended in patients who have achieved clear or almost clear hands earlier than 24

weeks (see section 5.1). Discontinuation of therapy should also be considered for patients who still have

severe disease after the initial 12 weeks of continuous treatment.

Retreatment

In the event of relapse, patients may benefit from further treatment courses of Toctino (see section 5.1).

Method of administration

The capsules should be taken with a main meal once daily, preferably at the same time each day (see

section 5.2).

Toctino should not be prescribed if the patient’s eczema can be adequately controlled by standard

measures, including skin protection, avoidance of allergens and irritants, and treatment with potent

topical corticosteroids.

Paediatric population

Toctino is not recommended for use in patients under 18 years of age.

Renal impairment

Toctino is contraindicated in patients with severe or end stage renal impairment (see section 4.3).

Toctino is not recommended for use in patients with moderate renal impairment as there is insufficient

data (see section 5.2).

No alteration of dosage or dosing frequency is required in patients with mild renal impairment (see

section 5.2).

Hepatic impairment

Toctino is contraindicated in patients with hepatic impairment (see section 4.3).

Elderly

No alteration of dosage and dosing frequency is required in patients over 65 years (see section 5.2).

4.3

Contraindications

Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.6).

Toctino is contraindicated in woman of childbearing potential unless all of the conditions of the

Pregnancy Prevention Programme are met (see section 4.4).

Toctino contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare hereditary

fructose intolerance should not take this medicine.

Toctino is contraindicated in nursing mothers.

Toctino is also contraindicated in patients

With hepatic insufficiency

With severe renal insufficiency

With uncontrolled hypercholesterolemia

With uncontrolled hypertriglyceridemia

With uncontrolled hypothyroidism

With hypervitaminosis A

With hypersensitivity either to alitretinoin, to other retinoids or to any of the excipients listed in

section 6.1, in particular in case of allergies to peanut or soya

Receiving concomitant treatment with tetracyclines (see section 4.5).

4.4

Special warnings and precautions for use

Teratogenic effects

Toctino is a powerful human teratogen inducing a high frequency of severe and life threatening birth

defects.

Toctino is strictly contraindicated in:

- Pregnant women

- Women of childbearing potential unless all of the conditions of the Pregnancy Prevention

Programme

are met

Pregnancy Prevention Programme

This medicinal product is

TERATOGENIC.

Alitretinoin is contraindicated in women of childbearing potential unless all of the following conditions

of the Pregnancy Prevention Programme are met:

Toctino is indicated for use in adults who have severe chronic hand eczema that is unresponsive

to treatment with potent topical corticosteroids (see section 4.1 “Therapeutic indications”).

The potential for pregnancy must be assed for all female patients.

She understands the teratogenic risk.

She understands the need for rigorous follow-up, on a monthly basis.

She understands and accepts the need for effective contraception, without interruption, 1 month

before starting treatment, throughout the entire duration of treatment and for 1 month after the

end of treatment. At least one highly effective method of contraception (i.e. a user-independent

form) or two complementary user-dependent forms of contraception should be used.

Individual circumstances should be evaluated in each case, when choosing the contraception

method, involving the patient in the discussion, to guarantee her engagement and compliance with

the chosen measures.

Even if she has amenorrhoea she must follow all of the advice on effective contraception.

She is informed and understands the potential consequences of pregnancy and the need to rapidly

consult if there is a risk of pregnancy or if she might be pregnant.

She understands the need and accepts to undergo regular pregnancy testing before, ideally

monthly during treatment and 1 month after stopping treatment.

She has acknowledged that she has understood the hazards and necessary precautions associated

with the use of alitretinoin.

These conditions also concern women who are not currently sexually active unless the prescriber

considers that there are compelling reasons to indicate that there is no risk of pregnancy.

The prescriber must ensure that:

The patient complies with the conditions for pregnancy prevention as listed above, including

confirmation that she has an adequate level of understanding.

The patient has acknowledged the aforementioned conditions.

The patient understands that she must consistently and correctly use one highly effective method

of contraception (i.e. a user-independent form) or two complementary user-dependent forms of

contraception, for at least 1 month prior to starting treatment and is continuing to use effective

contraception throughout the treatment period and for at least 1 month after cessation of treatment.

Negative pregnancy test results have been obtained before, during and 1 month after the end of

treatment. The dates and results of pregnancy tests should be documented.

If pregnancy occurs in a woman treated with Toctino, treatment must be stopped and the patient should

be referred to a physician specialised or experienced in teratology for evaluation and advice.

If pregnancy occurs after stopping treatment there remains a risk of severe and serious malformation of

the foetus. The risk persists until the product has been completely eliminated, which is within one month

following the end of treatment.

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention and should

be referred for contraceptive advice if they are not using effective contraception. If the prescribing

physician is not in a position to provide such information the patient should be referred to the relevant

healthcare professional.

As a minimum requirement, female patients of childbearing potential must use at least one highly

effective method of contraception (i.e. a user-independent form), or two complementary user-dependent

forms of contraception.

Contraception should be used for at least 1 month prior to starting treatment,

throughout treatment and continue for at least 1 month after stopping treatment with Toctino, even in

patients with amenorrhoea.

Individual circumstances should be evaluated in each case when choosing the contraception method,

involving the patient in the discussion to guarantee her engagement and compliance with the chosen

measures.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of

25 mIU/mL are recommended to be performed, as follows:

Prior to starting therapy

At least one month after the patient has started using contraception, and shortly (preferably a few days)

prior to the first prescription, the patient should undergo a medically supervised pregnancy test. This

test should ensure the patient is not pregnant when she starts treatment with alitretinoin.

Follow-up visits

Follow-up visits should be arranged at regular intervals, ideally monthly. The need for repeated

medically supervised pregnancy tests every month should be determined according to local practice

including consideration of the patient’s sexual activity, recent menstrual history (abnormal menses,

missed periods or amenorrhoea) and method of contraception. Where indicated, follow-up pregnancy

tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the

prescriber.

End of treatment

1 month after stopping treatment, women should undergo a final pregnancy test.

Prescribing and dispensing restrictions

For women of childbearing potential, the prescription duration of alitretinoin should ideally be limited

to 30 days in order to support regular follow up, including pregnancy testing and monitoring. Ideally,

pregnancy testing, issuing a prescription and dispensing of alitretinoin should occur on the same day.

This monthly follow-up will allow ensuring that regular pregnancy testing and monitoring is performed

and that the patient is not pregnant before receiving the next cycle of medication.

Male patients

The available data suggests that the level of maternal exposure from the semen of patients receiving

Toctino, is not of a sufficient magnitude to be associated with teratogenic effects of Toctino. Based on

non-clinical findings, the male fertility may be compromised by treatment with Toctino (see section

5.3).

Male patients should be reminded that they must not share their medication with anyone, particularly

not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return any

unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 1 month following discontinuation of alitretinoin

because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to alitretinoin the

Marketing Authorisation Holder will provide educational material to reinforce the warnings about the

teratogenicity of alitretinoin, to provide advice on contraception before therapy is started and to provide

guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the

strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be

given by the physician to all patients, both male and female.

Psychiatric disorders

Depression,

depression

aggravated,

anxiety,

aggressive

tendencies,

mood

alterations,

psychotic

symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients

treated with systemic retinoids, including alitretinoin (see section 4.8). Particular care needs to be taken

in patients with a history of depression and all patients should be monitored for signs of depression and

referred for appropriate treatment if necessary. Prior to initiation of Toctino and at each visit during

therapy, patients should be asked about any psychiatric disorder, depression, or mood disturbance.

Patients should stop Toctino if they develop depression, mood disturbance, psychosis, or aggression.

However, discontinuation of Toctino may be insufficient to alleviate symptoms and therefore further

psychiatric or psychological evaluation may be necessary. Awareness by family or friends may be useful

to detect mental health deterioration.

UV light

The effects of UV light are enhanced by retinoid therapy. Therefore patients should avoid excessive

exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sun-protection product

with a high protection factor of at least SPF 15 should be used.

Skin and subcutaneous tissues disorders

Patients who experience dryness of the skin and lips should be advised to use a skin moisturizing

ointment or cream and a lip balm.

Musculo-skeletal and connective tissue disorders

Treatment with other systemic retinoids has been associated with bone changes including premature

epiphyseal closure, hyperostosis, and calcification of tendons and ligaments.

Myalgia, arthralgia and increased serum creatinine phosphokinase values have been observed in patients

treated with alitretinoin.

Eye disorders

Treatment with alitretinoin has been associated with dry eyes. The symptoms usually resolve after

discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or

by the application of tear replacement therapy. Intolerance to contact lenses may occur which may

necessitate the patient to wear glasses during treatment.

Treatment with systemic retinoids has been associated with corneal opacities and keratitis. Decreased

night vision has been observed in patients treated with alitretinoin. These effects usually resolve after

discontinuation of therapy.

Patients experiencing visual difficulties should be referred to an ophthalmologist. Withdrawal of

alitretinoin may be necessary.

Benign intracranial hypertension

Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of

benign intracranial hypertension, some of which involved concomitant use of tetracyclines (see section

4.3 and section 4.5). Signs and symptoms of benign intracranial hypertension include headache, nausea

and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial

hypertension should discontinue alitretinoin immediately.

Lipid Metabolism

Alitretinoin has been associated with an increase in plasma cholesterol and triglyceride levels. Serum

cholesterol and triglycerides (fasting values) should be monitored. Alitretinoin should be discontinued

if hypertriglyceridaemia cannot be controlled at an acceptable level.

Pancreatitis

Toctino should be discontinued if symptoms of pancreatitis occur (see section 4.8).

Triglyceride levels in excess of 800 mg/dL (9 mmol/L) are sometimes associated with acute pancreatitis,

which may be fatal.

Thyroid function

Changes in thyroid function tests have been observed in patients receiving alitretinoin, most often noted

as a reversible reduction in thyroid stimulating hormone (TSH) levels and T4 [free thyroxine].

Hepatobiliary disorders

Treatment with other systemic retinoids has been associated with transient and reversible increases in

liver transaminases. In the event of persistent clinically relevant elevation of transaminase levels,

reduction of the dose or discontinuation of treatment should be considered.

Gastrointestinal disorders

Systemic retinoids, including alitretinoin, have been associated with inflammatory bowel disease

(including regional ileitis) in patients without a history of intestinal disorders. If severe diarrhoea is

observed diagnosis of IBD should be considered and alitretinoin should be discontinued immediately.

Allergic reactions

Anaphylactic reactions have been rarely reported in systemic retinoids, in some cases after previous

topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of

allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous

involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful

monitoring.

High risk patients

In patients with diabetes, obesity, cardiovascular risk factors or a lipid metabolism disorder undergoing

treatment with alitretinoin, more frequent checks of serum values for lipids and/or blood glucose may

be necessary.

Sorbitol

Toctino capsules contain sorbitol. 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

Pharmacokinetic interaction

Alitretinoin is metabolized by cytochrome P450 (CYP) 2C9, CYP2C8, CYP3A4 and undergoes

isomerisation.

Concomitant medications that may affect the pharmacokinetics of alitretinoin

Co-administration with CYP3A4 inhibitors such as ketoconazole increases the plasma level of

alitretinoin and therefore dose reduction to 10 mg should be considered. The effects of other inhibitors

of CYP3A4 have not been studied.

A reduction in dose to 10 mg should be considered when alitretinoin is co-administered with potent

CYP2C9 inhibitors (e.g. fluconazole, miconazole, oxandrolone) or potent CYP2C8 inhibitors (e.g.

gemfibrozil).

Simvastatin did not affect the pharmacokinetics of alitretinoin.

No pharmacokinetic interactions were observed when alitretinoin was co-administered with ciclosporin.

Effect of alitretinoin on the pharmacokinetics of concomitant medications

Alitretinoin may increase the exposure of CYP2C8 substrates; therefore co-administration with

amiodarone

CYP2C8

substrate

with

long

half-life

narrow

therapeutic

index)

recommended. Caution should be used if alitretinoin is co-administered with other medications that are

substrates for CYP2C8 (e.g. paclitaxel, rosiglitazone, repaglinide).

Decreases of <25 % in simvastatin and simvastatin acid plasma levels was observed when co-

administered with alitretinoin. The effects on other similar medicinal products have not been studied.

Alitretinoin did not affect the pharmacokinetics of ketoconazole or ciclosporin.

Pharmacodynamic interactions

Patients should not take vitamin A or other retinoids as concurrent medication due to the risk of

hypervitaminosis A.

Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant

use of retinoids and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided

(see sections 4.3 and section 4.4).

4.6

Fertility, pregnancy and lactation

Pregnancy

Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.3). If pregnancy

does occur in spite of the pregnancy prevention precautions during treatment with Toctino or in

the month following discontinuation of therapy, there is a great risk of very severe and serious

malformation of the foetus.

Alitretinoin is a retinoid and therefore is a potent teratogen. The foetal malformations associated with

exposure

retinoids

include

central

nervous

system

abnormalities

(hydrocephalus,

cerebellar

malformation/abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities

(absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia),

cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of

great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is

also an increased incidence of spontaneous abortion

(see sections 4.3, 4.4)

Breast-feeding

Alitretinoin is highly lipophilic, therefore the passage of alitretinoin into human milk is very likely. Due

to the potential risk for the exposed child, the use of alitretinoin is contraindicated in nursing mothers.

Fertility

Small amounts of alitretinoin (above endogenous levels) have been detected in the semen of some

healthy volunteers receiving 40 mg of alitretinoin and drug accumulation in semen is not expected.

Assuming

complete

vaginal

absorption,

these

amounts,

would

have

negligible

effect

endogenous plasma levels of the female partner or a foetus and therefore do not appear to pose a risk to

the foetus if the partner is pregnant. Based on non-clinical findings, male fertility may be compromised

by treatment with Toctino (see section 5.3).

4.7

Effects on ability to drive and use machines

Decreased night vision has been reported in patients treated with alitretinoin and other retinoids. Patients

should be advised of this potential problem and warned to be cautious when driving or operating

machines.

4.8

Undesirable effects

The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) unresponsive to

treatment with potent topical corticosteroids has been evaluated in two randomised, double blind,

placebo-controlled clinical studies (see section 5.1).

The most frequent adverse drug reactions (ADRs) observed under alitretinoin therapy are headache

(30 mg: 23.9%; 10 mg: 10.8%), erythema (30 mg: 5.5%; 10 mg: 1.7%), nausea (30 mg: 5.1%; 10 mg:

2.4%), flushing (30 mg: 5.9%, 10 mg: 1.6%), and laboratory changes consisting of increased levels of

triglycerides (30 mg: 35.4%; 10 mg: 17.0%), increased cholesterol (30 mg: 27.8%; 10 mg: 16.7%),

decreased levels of thyroid stimulating hormone (TSH, 30 mg: 8.4%, 10 mg: 6.0%) and decreased levels

of free T4 (30 mg: 10.5%; 10 mg: 2.9%). These reversible ADRs are dose dependent and may therefore

be alleviated by dose reduction.

Very

common

(≥ 1/10)

Common

(≥

1/100

<

1/10)

Uncommo

n

(≥

1/1000,

< 1/100)

Rare

(≥ 1/10,000 <

1/1000)

Very Rare

(<1/10000)

Unknown

Blood and

lymphatic

system

disorders

Anaemia,

increased

iron binding

capacity,

monocytes

decreased;

thrombocyte

s increased

Immune

system

disorders

Anaphylactic

reactions,

hypersensitiv

Endocrine

Disorders

decreased,

free

decreased

Psychiatri

c

disorders

Depression,

depression

aggravated,

aggressive

tendencies,

Suicide, suicide

attempt, suicidal

ideation,

psychotic

disorder,

Very

common

(≥ 1/10)

Common

(≥

1/100

<

1/10)

Uncommo

n

(≥

1/1000,

< 1/100)

Rare

(≥ 1/10,000 <

1/1000)

Very Rare

(<1/10000)

Unknown

anxiety,

mood

alterations

abnormal

behaviour

Nervous

system

disorders

Headache

Dizziness

Benign

intracranial

hypertension

Eye

disorders

Conjunctivit

eye,

eye irritation

Blurred

vision,

cataract

Decreased

night vision

Ear

and

labyrinth

disorders

Tinnitus

Vascular

disorders

Flushing,

hypertensio

Vasculitis

Respirato

ry,

thoracic

and

mediastin

al

disorders

Epistaxis

Gastroint

estinal

disorders

Nausea,

mouth,

vomiting

Dyspepsia

Inflammatory

bowel

disease

Hepatobili

ary

disorders

Transaminas

e increased

Skin

and

subcutane

ous tissues

disorders

skin,

lips,

cheileitis,

eczema

dermatitis

erythema,

alopecia

Pruritus,

rash, skin

exfoliation

, asteatotic

eczema

Nail

disorders,

photosensitiv

ity reaction,

hair texture

changes

Musculo-

skeletal

and

connective

tissue

disorders

Arthralgia

myalgia

Exostosis,

(hyperosto

sis),

ankylosing

spondylitis

General

disorders

and

administr

ation

site

conditions

Fatigue

Peripheral

oedema

Investigati

ons

Hypertrigl

yceridemia

high

density

lipoprotein

Blood

creatinine

phosphokina

se increased

Very

common

(≥ 1/10)

Common

(≥

1/100

<

1/10)

Uncommo

n

(≥

1/1000,

< 1/100)

Rare

(≥ 1/10,000 <

1/1000)

Very Rare

(<1/10000)

Unknown

decreased,

hyperchole

sterolemia

The overall incidence of adverse events was not higher than those observed in the corresponding

placebo group.

The following adverse events have not been observed in clinical trials with alitretinoin, but have been

observed with other retinoids: diabetes mellitus, colour blindness (colour vision deficiencies), and

contact lens intolerance (see section 4.4).

Changes in bone mineralization and extra-osseous calcifications have been associated with systemic

retinoid

treatment.

clinical

studies

with

alitretinoin,

degenerative

changes

spine

ligamentous calcifications were frequent findings in patients with chronic hand eczema before treatment

(baseline), with minor progression in a small number of patients during treatment. These observations

were consistent with age dependent degenerative changes. Assessments of bone density (DXA) did not

indicate a dose dependent effect on bone mineralization.

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation

using

online

form

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.g

ov.il

and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

4.9

Overdose

Alitretinoin is a derivative of vitamin A. Alitretinoin has been administered in oncological clinical

studies at dosages of more than 10-times of the therapeutic dosage given for chronic hand eczema. The

adverse effects observed were consistent with retinoid toxicity, and included severe headache, diarrhoea,

facial flushing, hypertriglyceridemia. These effects were reversible.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: other dermatologicals

ATC code: D11AH04

Mechanism of action

The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell

differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation. Unlike

other retinoids, which are specific agonists of either RAR or RXR receptors, alitretinoin binds to

members of both receptor families. The mechanism of action of alitretinoin in chronic hand eczema is

unknown. Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are

relevant to skin inflammation. Alitretinoin suppresses the production of chemokines that are involved

in recruitment of leukocytes to sites of skin inflammation, reduces expansion of T lymphocytes and

antigen-presenting cells, and inhibits effect on cell differentiation. CXCR3 ligands and CCL20

chemokines, expressed in eczematous skin lesions, are down-regulated by alitretinoin in cytokine-

stimulated keratinocytes and dermal endothelial cells. In addition, alitretinoin suppresses the expansion

of cytokine activated leucocytes subsets and antigen presenting cells.

It has been observed that in humans alitretinoin only minimally affects sebum secretion.

Clinical efficacy

The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) unresponsive to

treatment with potent topical corticosteroids has been evaluated in two randomised, double blind,

placebo-controlled Phase 3 studies.

The primary endpoint in these studies was the proportion of patients achieving Physicians Global

Assessment (PGA) ratings of clear or almost clear hands at the end of therapy (see Table 1). The

treatment duration was 12 to 24 weeks.

The BAP00089 study (BACH) was conducted in Europe and Canada, and included 1032 severe CHE

patients who had no response or a transient response (initial improvement and worsening of disease

despite continued treatment) to potent topical corticosteroids or were intolerant of potent topical

corticosteroids.

phenotypes

were

included;

approximately

patients

hyperkeratotic only CHE, however the majority of patients had multiple phenotypes. Essentially all

patients had signs of skin inflammation, comprising of erythema and/or vesicles. Treatment with

alitretinoin led to a significantly higher proportion of patients with clear/almost clear hands, compared

to placebo. The response was dose dependent (see Table 1).

Secondary endpoints included the proportion of partial responders (patients achieving at least mild

disease), time to response (achieving clear to almost clear hands), reduction in modified total lesion

symptom score (mTLSS), patient global assessment (PaGA) of disease severity, and reduction in extent

of disease (see Table 1).

The second study, BAP001346 (HANDEL) was conducted in the US and included 596 with severe CHE

who had no response or a transient response (initial improvement and worsening of disease despite

continued

treatment) to

potent

topical

corticosteroids

were intolerant

potent

topical

corticosteroids. Subjects were considered unresponsive if they had severe CHE after at least 2 weeks of

treatment with a very potent topical corticosteroid during a 16-week run-in period. All phenotypes of

CHE were included.

Secondary endpoints included estimated median time to response (time from the start of randomised

study treatment to first PGA assessment of clear or almost clear), reduction in modified total lesion

symptom score (mTLSS), patient global assessment (PaGA) of disease severity, and reduction in extent

of disease at end of therapy (see Table 1).

Table 1 Results: Primary and Key Secondary Endpoints

BAP00089 (BACH)

BAP01346 (HANDEL)

Primary Endpoint

10 mg

30 mg

Placebo

30 mg

Placebo

ITT Population

N = 418

N = 409

N = 205

N = 298

N = 298

PGA at end of treatment n (%)

Total Response

115 (27.5%)

195 (47.7%)

34 (16.6%)

118 (39.6%)

44 (14.8%)

Clear

39 (9.3%)

90 (22.0%)

6 (2.9%)

58 (19.5%)

14 (4.7%)

Almost Clear

76 (18.2%)

105 (25.7%)

28 (13.7%)

60 (20.1%)

30 (10.1%)

Comparison

Placebo

P = 0.004

P <0.001

P <0.001

Secondary Endpoints

PaGA at the end of treatment n (%)

Clear

Almost

Clear

101 (24.2%)

163 (39.9%)

31 (15.1%)

117 (39.3%)

41 (13.8%)

Comparison

Placebo

P = 0.013

P <0.001

P <0.001

Percent Change from Baseline mTLSS at the end of treatment

Mean (STD)

-50.79 (36.13)

-60.80 (38.58)

-37.30

(37.65)

-53.99

(40.16)

-29.86 (37.83)

Median

-56.25

-75.0

-38.68

-67.70

-24.40

Min – Max

-100 – 66.7

-100 – 175

-100 – 72.7

-100 – 60

-100 – 63.6

Comparison

Placebo

P <0.001

P <0.001

P <0.001

Percent Change from Baseline in Extent of Disease at the end of treatment

Mean (STD)

-40.01 (49.57)

-54.15 (46.89)

-31.93

(45.56)

-46.56

(53.75)

-24.20 (48.21)

Median

-50.0

-75.0

-33.33

-62.50

-18.20

Min – Max

-100 – 200

-100 – 140

-100 – 130

-100 – 166.7

-100 – 140

Comparison

Placebo

P = 0.016

P <0.001

P <0.001

Median Time to Response for Responders at the end of treatment

Median (Days)

115.0

85.0

65.0

117.0

Comparison

Placebo

P = 0.01

P <0.001

P <0.001

Partial Response Rate (clear, almost clear, or mild disease)

N (%)

207 (49.5%)

254 (62.1%)

74 (36.1%)

a: From pairwise continuity corrected chi-square tests versus placebo based on proportion of responders.

b: From non-parametric Kruskal Wallis test versus placebo based on mean change from baseline.

c: From Log Rank Test versus placebo based on median time to response.

Duration of treatment

A longitudinal dose response analysis of Phase 3 studies (BAP00089, BAP001346, & BAP00091 –

Cohort A) showed that once subjects had clear or almost clear hands, there was no relationship between

the duration of treatment and the likelihood of relapse. Therefore, discontinuation of therapy is

recommended in patients who have achieved clear or almost clear hands earlier than 24 weeks (see

section 4.2). In the pivotal clinical studies 67% of subjects who responded to alitretinoin treatment did

not return to severe disease 24 weeks after stopping treatment and therefore would not be candidates for

retreatment within that time period.

Retreatment

A retreatment study (BAP00091 – Cohort A) investigated the efficacy and safety of a second course of

treatment in patients who previously responded to treatment in the BAP00089 study, but who relapsed.

Patients were randomised to the same dose they received in their initial treatment (10 or 30 mg) or to

placebo in a 2:1 ratio. (N=70 alitretinoin, N=47 placebo). Results suggest that patients who previously

responded to alitretinoin treatment may benefit from retreatment.

5.2

Pharmacokinetic properties

Absorption

Alitretinoin is a low solubility, low permeability compound with a low and variable bioavailability.

Alitretinoin is not consistently absorbed from the gastrointestinal tract in fasted state. The systemic

exposure is substantially (>2-fold) enhanced when taken with a high-fat meal.

In vitro

data from a gastrointestinal system suggest the amount of alitretinoin available for absorption

differs with fat intake (when given with an approximately 25% fat meal, the amount available for

absorption is less than when given with ~40% or ~60% fat meal). Therefore, alitretinoin should be

administered with a main meal once daily, preferably at the same time of day to maximise exposure.

After administration of alitretinoin 30 mg once daily with a meal containing approximately 40% fat, the

median T

is 4 hours, the average C

is 177 ng/mL, and the average AUC

is 405 ng*hr/mL.

Peak plasma concentrations (C

) and exposure (AUC) of alitretinoin increase with increasing single

doses over the range of 5 to 150 mg. AUC values of alitretinoin increases proportionally with dose for

once daily doses of 10 mg to 30 mg. The C

of alitretinoin may increase less than proportionally with

increasing dose.

Distribution

Alitretinoin is 99.1% bound to plasma proteins. The volume of distribution of alitretinoin is estimated

to be greater than the extracellular volume (>14L), but less than total body water.

Metabolism

Alitretinoin is metabolized by CYP2C9, CYP2C8, and CYP3A4

isoenzymes to form 4-oxo-alitretinoin.

Both compounds undergo isomerisation into tretinoin (or isotretinoin) and their 4-oxo metabolites. After

oral administration of alitretinoin 4-oxo-alitretinoin is the main observed active circulating metabolite

with an AUC which accounts for >70% of the AUC of the parent drug. The isomers of alitretinoin

(tretinoin,

isotretinoin)

4-oxo-alitretinoin

(4-oxo-tretinoin

4-oxo-isotretinoin)

minor

accounting for <12% of exposure of parent drug

. 4-oxo-alitretinoin is further glucuronidated and

eliminated in urine.

There

consistent

time-dependent

changes

(neither

induction

accumulation)

pharmacokinetics of alitretinoin or its measured metabolites

Elimination

Alitretinoin is an endogenous retinoid. Alitretinoin concentrations return to endogenous levels within 2

to 3 days after treatment cessation.

Excretion of a radio-labelled dose of alitretinoin was complete, with approximately 94% of the dose

recovered within 14 days. Radio-labelled material was eliminated mainly in urine as metabolites (63%,

with <1% as unchanged parent drug) with a smaller fraction (approx. 30% with 1% as unchanged parent

drug) in faeces. The most abundant excretion compound is the glucuronide of 4-oxo-alitretinoin

amounting to 6.5% of the dose in urine.

The elimination half-life averaged 9 hours for alitretinoin and 10 hours for 4-oxo-alitretinoin.

Pharmacokinetic in special populations

The pharmacokinetics of alitretinoin and its measured metabolites in special populations (obesity,

gender, age, and renal impairment) were evaluated in a study in 32 subjects with moderate to severe

CHE receiving alitretinoin for 12 to 24 weeks. These analyses showed:

Obesity

Increased body weight or body mass index (BMI) does not result in clinically significant changes in

alitretinoin or 4-oxo-alitretinoin exposure.

Gender

There are no clinically significant gender-related differences in alitretinoin or 4-oxo-alitretinoin AUC

and Cmax.

Elderly

While the pharmacokinetic data in elderly subjects is limited (n=6 over 60 years of age and n=3 over 65

years of age), there does not appear to be a relationship between increasing age and the dose-normalized

AUC or Cmax of alitretinoin or 4 oxo-alitretinoin.

A longitudinal dose-response model from clinical efficacy studies shows that elderly subjects (n=126)

have an earlier and more pronounced response to treatment and are less likely to relapse, but are more

likely to experience elevated triglyceride levels after 12 to 16 weeks of treatment.

Renal Impairment

While

pharmacokinetic

data

subjects

with

moderate

renal

impairment

available,

pharmacokinetics of alitretinoin are not affected by mild renal impairment, with an average AUC of 342

(range: 237-450) and 312 (195-576) ng

h/mL in those with an estimated creatinine clearance 60-90

mL/min (n=8) or > 90 mL/min (n=23), respectively normalised to an alitretinoin 30 mg dose

. The C

and AUC

(0-tau)

of 4-oxo-alitretinoin may be slightly higher in subjects with mild renal impairment,

although the effect is small (< 20%).

No data are available in subjects with severe renal impairment (CrCl <30 mL/min) or end stage renal

disease.

Hepatic Impairment

A pharmacokinetic study conducted in 8 subjects with liver cirrhosis and Child-Pugh Class A (mild,

n=6) or B (moderate, n=2) and in 8 gender, age, height and weight-matched healthy subjects shows that

there are no clinically relevant differences between patients with hepatic impairment and healthy

subjects in the C

(mean± standard deviation [SD]: 101 ± 40 ng/mL vs 144±40 ng/mL, respectively)

or AUC (mean±SD: 248 ± 116 ng/mL vs 314 ± 86 ng/mL, respectively) of alitretinoin. The C

(mean±

SD: 30± 20 ng/mL vs 56 ± 25ng/mL, respectively) and AUC (mean±SD: 162± 82 ng/mL vs 219±49

ng/mL, respectively) of 4-oxo-alitretinoin are lower in patients with hepatic impairment.

There are no data available in subjects with severe hepatic impairment and limited data in patients with

moderate hepatic impairment.

Alitretinoin kinetics has not been studied in patients below 18 years.

5.3

Preclinical safety data

Acute toxicity

As with other retinoids, the acute toxicity of alitretinoin was low in mice and rats. The LD

after

intraperitoneal administration was >4000 mg/kg after 24 hours and 1400 mg/kg after 10 days. The

approximate LD

after oral administration in rats was 3000 mg/kg.

Chronic toxicity

Alitretinoin was tested in long-term studies up to 9 months in dogs and 6 months in rats. Signs of toxicity

were dose-related and occurred at exposures similar to the human therapeutic exposure based on AUC.

Effects were characteristic for retinoids (consistent with hypervitaminosis A), and were generally

spontaneously reversible.

Teratogenicity

Like other retinoids, alitretinoin has been shown to be teratogenic

in vitro

in vivo

Due to the teratogenic potential of alitretinoin, women of childbearing potential must adhere to strict

pregnancy prevention measures during and 1 month following alitretinoin therapy (see section 4.3,

section 4.4 and section 4.6).

Fertility

Alitretinoin was tested in a study of fertility and early embryonic development in rats. No effects on

male or female reproductive parameters were observed at the highest dose tested which reached similar

plasma concentrations as those observed in humans.

As with other retinoids reversible effects on male reproductive organs were observed in experimental

animals in the form of disturbed spermatogenesis and associated degenerative lesions of the testes. The

safety margin in dogs with regard to the no-effect level of toxicity to male reproductive organs was 1-6

for a human dose of 30 mg.

Mutagenicity

in vitro

in vivo

tests, alitretinoin has been shown not to be mutagenic.

Carcinogenicity

Alitretinoin was tested in 2-year carcinogenicity studies in rats and mice. Dose-related retinoid-specific

toxicity was seen at higher doses, but no carcinogenic potential was noted.

Phototoxicity

Alitretinoin was found to be phototoxic

in vitro

in vivo.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content:

Soya-bean oil, refined

Partially hydrogenated soya-bean oil

Triglycerides, medium chain

Beeswax, yellow

All-rac-α-tocopherol

Capsule shell:

Gelatin

Sorbitol, liquid (non-crystallising)

Water purified

Glycerol

Iron oxide, red (E172)

10 mg capsules- Iron oxide, black (E172)

30 mg capsules- Iron oxide, yellow (E172)

6.2

Incompatibilities

Not applicable

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Toctino 10 mg –

Do not store above 30

C. Store in the original package. Keep the blister in the outer carton in order to

protect from light.

Toctino 30 mg –

Do not store above 25

C. Store in the original package. Keep the blister in the outer carton in order to

protect from light.

6.5

Nature and contents of container

PVC/PE/PVDC/Aluminum blisters. Pack sizes of 30 capsules, soft.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed in accordance with local

requirements.

7

MANUFACTURER

SwissCaps GmbH

Grassingerstrasse 9, D-83043 Bad Aibling, Germany

8.

REGISTRATION NUMBERS

Toctino 10 MG:

145-92-33163

Toctino

30

MG:

146-64-33164

9.

REGISTRATION HOLDER

Neopharm Scientific Ltd., Hashiloach 6, P.O.Box 7063 Petach- Tikva 49170.

The content of this leaflet was approved by the Ministry of Health in December 2016 and updated

according to the guidelines of the Ministry of Health in January 2019.

.201

Toctino 30 mg,

capsules soft

Toctino 10 mg,

capsules soft

וניטקוט

10

ג"מ

,

תוכר תולוספק

וניטקוט

30

ג"מ

,

תוכר תולוספק

,ה/דבכנ ת/חקור ,ה/אפור

םינולעה

אפורל

ב ונכדוע ןכרצלו ראוני

2019

.הרמחה םיווהמה םייונישה םיניוצמ וז העדוהב

.יתחת וקב ןמוסמ ףסוותהש טסקט

:ליעפה רמוחה

Alitretinoin 10 mg, 30 mg

ןלהל

חסונ

היוותהה

מה רשוא

רישכתל

:

For use in adults who have severe chronic hand eczema that is unresponsive to treatment with

potent topical corticosteroids.

Patients in whom the eczema has predominantly hyperkeratotic features are more likely to

respond to treatment than in those in whom the eczema predominantly presents as pompholyx.

ל ןולעב םיירקיעה םינוכדעה :םיאבה םיפיעסב ושענ אפור

4.8

Undesirable effects

Common

(≥ 1/100 < 1/10)

Uncommon

(≥ 1/1000, < 1/100)

Rare

(≥ 1/10,000 < 1/1000)

Skin and

subcutan

eous

tissues

disorders

Dry skin, dry lips, cheileitis,

eczema

, dermatitis

erythema, alopecia

Pruritus, rash, skin

exfoliation, asteatotic eczema

Nail disorders,

photosensitivity

reaction,

hair texture

changes

:םיאבה םיפיעסב ושענ ןכרצל ןולעב םיירקיעה םינוכדעה

4

.

תועפות

יאוול

...

תועפות

יאוול

תורידנ

תועפות)

תועיפומש

1-10

םישמתשמ

ךותמ

(10,000

:

ילכב תקלד

םד

תויעב

םיינרופיצב

תושיגר

רתי

לש

רועה

רואל

שמשה

יוניש םי

רעישה םקרמב

...

ולעה

אפורל

ןכרצלו

םימסרופמ

.תואירבה דרשמ רתאבש תופורתה רגאמב

ןתינ

לבקל

ולע הלא םינ

ספדומ םי

לע

די

ינפ

הרישי :םושירה לעבל

מ"עב קיפיטנייס םרפואינ 'חר , חולישה

.ד.ת

7063

הווקת חתפ

4917001

לט , ןופ

03-9373753

,הכרבב

לוסב ןאיכ

חקור

הנוממ

מ"עב קיפיטנייס םרפואינ

Similar products

Search alerts related to this product

View documents history

Share this information