ENTUMIN

Israel - English - Ministry of Health

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Active ingredient:
CLOTIAPINE
Available from:
TARO INTERNATIONAL LTD, ISRAEL
ATC code:
N05AX09
Pharmaceutical form:
TABLETS
Composition:
CLOTIAPINE 40 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
DELPHARM L’AIGLE, FRANCE
Therapeutic group:
CLOTIAPINE
Therapeutic area:
CLOTIAPINE
Therapeutic indications:
For the treatment of severe mental and emotional disorders (Neuroleptic).
Authorization number:
023 40 21411 00
Authorization date:
2017-07-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

15-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

15-06-2020

Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

ENTUMIN

®

40 mg

Tablets

Active ingredient and its quantity:

Each tablet contains:

Clotiapine 40 mg

For the list of inactive ingredients see section 2 "Important information about some of this

medicine's ingredients" and section 6 "Additional information".

Read the entire leaflet carefully before you start using this medicine. This leaflet contains

concise information about this medicine. If you have any further questions, consult your doctor

or pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to others. It may harm

them even if it seems to you that their illness is similar to yours.

1. What is this medicine intended for?

For the treatment of severe mental and emotional disorders (neuroleptic).

Therapeutic group:

Antipsychotic

2. Before using this medicine

X

Do not use this medicine:

If you are sensitive (allergic) to the active ingredient (clotiapine) or to any of the other

ingredients in this medicine (see section 6).

In states of unconsciousness or severe CNS depression.

If you have a predisposition to seizures.

If you have increased intraocular pressure (narrow angle glaucoma).

If you are breastfeeding.

In children below the age of 16 years.

Special warnings about using this medicine

! Before using Entumin, tell your doctor if:

You suffer from any of the following problems: prostate disease, intestinal, renal, cardiac

(including a disorder known as QT interval prolongation) or hepatic disorder, Parkinson's

disease, low blood pressure (hypotension), dementia.

Any of your family members has a history of blood clots, since blood clot formation has been

already associated with such medicines.

Additional warnings:

Immediately contact a doctor if you develop fever.

Entumin-Eng-final-05.2020

The treatment must be stopped gradually.

Children and adolescents:

Entumin should not be administered to children below the age of 16 years.

Tests and follow up:

During the treatment period with this medicine, blood pressure monitoring should be

conducted in elderly patients.

In patients with history of low white blood cell levels or drug induced leukopenia/neutropenia,

the doctor will conduct frequent complete blood count monitoring in the first treatment

months.

In patients with neutropenia, the doctor will closely monitor fever or other infection

symptoms.

!Drug interactions

If you are taking or have recently taken other medicines, including nonprescription

medications and dietary supplements, tell your doctor or pharmacist. Particularly if you are

taking:

Substances affecting the CNS such as: alcohol, sedatives, analgesics, hypnotics, MAO

inhibitors and antihistamines.

Antihypertensive medicines.

Lithium.

Medicines prolonging the QT interval or causing electrolyte imbalance.

!Using this medicine and alcohol consumption

Avoid drinking alcohol.

!Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think that you may be pregnant or are planning to become

pregnant, consult your doctor or pharmacist before taking this medicine.

Pregnancy

Immediately notify your doctor upon confirmation of pregnancy. The doctor is the most

appropriate person to decide whether to prescribe Entumin during pregnancy.

The following symptoms may occur in neonates born to mothers who have taken Entumin

during the last trimester (last 3 months of their pregnancy): tremor, muscle stiffness and/or

muscle weakness, somnolence, agitation, respiratory distress and feeding difficulties. If your

baby demonstrates any of the above symptoms, contact a doctor.

Breastfeeding

Do not use Entumin during breastfeeding. The metabolites of Entumin are excreted in breast

milk.

!Driving and using machines

Avoid driving or operating machines, especially at the beginning of treatment, since Entumin

may cause somnolence and reduce your reaction capacity.

!Important information about some of this medicine’s ingredients

Entumin-Eng-final-05.2020

The tablets contain lactose. If you have been told in the past by a doctor that you have an

intolerance to certain sugars, consult your doctor before starting treatment with this medicine.

3. How to use this medicine?

Always use this medicine according to your doctor's instructions. Check with your doctor or

pharmacist if you are not sure about your dose or about how to take this medicine.

Only your doctor will determine your dose and how you should take this medicine.

Do not exceed the maximal daily dosage of 360 mg in divided doses.

In underweight patients, patients with liver or kidney disease and in the elderly, treatment

should be started at lower doses, and the dosage should be gradually increased.

Do not exceed the recommended dose.

Do not chew!

Swallow the medicine with some water.

The tablet can be split at the score line and crushed.

If you have accidentally taken a higher dose, you may experience: somnolence or significant

agitation, a comatose state, seizures, difficulties breathing, blood pressure drop, very rapid or

irregular heart rate, tremor, muscle stiffness. If you have taken an overdose, or if a child has

accidentally swallowed some medicine, immediately see a doctor or go to a hospital emergency

room and bring the medicine package with you.

If you forgot to take Entumin

Do not take a double dose to compensate for the forgotten dose.

If you stop taking Entumin

The treatment must be stopped gradually. Even if your health improves, do not stop taking this

medicine without consulting your doctor.

Adhere to the treatment as recommended by your doctor.

Do not take medicines in the dark! Check the label and dose every time you take a

medicine. Wear glasses if you need them.

If you have any further questions about using this medicine, consult your doctor or

pharmacist.

4. Side effects:

Like with all medicines, using Entumin may cause side effects in some users. Do not be

alarmed by this list of side effects; you may not experience any of them.

Consult your doctor immediately if you notice any of the following symptoms:

- Venous

blood clots, especially in the legs (the symptoms observed include swelling, pain and

redness in the leg), which may move along the blood vessels to the lungs, causing chest pain

and difficulties breathing.

- If fever develops.

Entumin-Eng-final-05.2020

The most common side effects, especially at the beginning of treatment, are dizziness (and

sometimes incidents of loss of consciousness) with a sudden change in the body state,

sensation of dry mouth, visual disturbances and constipation.

In rare cases (≥ 1/10,000; < 1/1,000) the following effects may occur: somnolence or agitation

and confusion, tremor, muscle stiffness, restlessness, extremely rapid heart rate.

If you experience any side

effect, if any side effect gets worse, or if you experience a side

effect not mentioned in this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by clicking on the link “Reporting side

effects following drug treatment” found on the Ministry of Health homepage (www.health.gov.il

that directs you to the online form for reporting side effects, or by entering the link:

https://sideeffects.health.gov.il/

5. How to store the medicine?

Avoid poisoning! This medicine, and any other medicine, should be kept in a closed

place out of the reach and sight of children and/or infants in order to avoid poisoning.

Do not induce vomiting unless explicitly instructed to do so by the doctor!

Do not use the medicine after the expiry date (exp. date) that appears on the package.

The expiry date refers to the last day of that month.

Storage conditions

Do not store above 25°C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist

how to discard medicines you no longer use. These measures will help protect the

environment.

6. Additional information

In addition to the active ingredient, this medicine also contains:

Lactose, maize starch, cellulose microcrystalline, gelatin, colloidal anhydrous silica,

paraffin liquid, talc, magnesium stearate.

What the medicine looks like and contents of the pack:

Round and flat white to yellowish tablets, with a slanted edge and a score line on one side,

packed in a blister (tray) package.

Each pack contains 30 or 500 tablets.

Not all pack sizes may be marketed.

Registration holder’s name and address:

Taro International Ltd., 14 Hakitor St., Haifa Bay 2624761

Manufacturer's name and address:

DELPHARM L’AIGLE,

Zone Industrielle 1, Route De Crulai 61300 L'aigle, France

Entumin is a registered trademark of Juvise Pharmaceuticals.

Entumin-Eng-final-05.2020

This format was determined by the Ministry of Health and its content was reviewed and

approved by the Ministry of Health in June 2015 and updated according to the guidelines of the

Ministry of Health in March 2020.

Registration number of the medicine in the National Drug Registry of the Ministry of

Health:

023.40.21411.00

Entumin-Eng-final-05.2020

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Entumin

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Clotiapine 40 mg

Excipient with known effect:

Entumin 40 mg tablets contain lactose.

This medicinal product is contraindicated in patients with rare hereditary problems of

galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablets.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the treatment of severe mental and emotional disorders (neuroleptic)

4.2

Posology and method of administration

Posology

Initial treatment

3 to 5 tablets daily in 2 or 3 divided doses may prove sufficient.

The daily oral dose may be increased to a maximum of 360 mg in divided doses,

especially in cases of agitation/excitation.

The initial dosage may be given for periods of weeks or even months.

Maintenance and long-term treatment:

20 to 160 mg daily per os in 2 to 3 divided

doses.

Specific populations

In underweight patients, patients with liver or kidney disease and in elderly patients,

lower initial doses and a gradual dosage increase are indicated.

Paediatric population

The safety and efficacy of Entumin in children aged less than 16 years have not yet

been established.

Method of administration

Entumin 40 mg tablets are for oral use. Entumin 40 mg tablets should not be chewed,

should be administered with a small amount of water.

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4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in

section 6.1.

Comatose states, severe CNS depression and post-encephalitic syndrome.

Marked predisposition to convulsions: especially epilepsy.

Children under 16 years of age.

Contraindications due to the anticholinergic action:

absolute: angle-closure glaucoma.

4.4

Special warnings and precautions for use

Caution should be exercised:

in elderly patients, due to their high sensitivity (sedation and hypotension);

in severe cardiovascular disorders, due to haemodynamic changes, especially

hypotension;

in patients with renal and/or hepatic impairment, due to the risk of overdose;

in patients with prostatic hypertrophy, marked intestinal atony;

in patients with Parkinson’s disease.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic

medications.

Since patients treated with antipsychotic agents often have acquired risk factors for

VTE, all possible risk factors for VTE must be identified before and during Entumin

treatment and preventive measures must be taken.

During all antipsychotic treatments, intense initial sedation and several days of

immobilisation may promote thrombus formation in predisposed patients.

In the event of hyperthermia, treatment must be suspended, since such hyperthermia

may be one of the constituents of the malignant syndrome (pallor, hyperthermia,

autonomic disorders) described with neuroleptics.

Discontinuation of treatment must be gradual; any concomitant antiparkinson

medications must be administered for longer, in view of their generally shorter

plasma half-life.

As with other neuroleptic agents, hyperprolactinaemia such as that induced by taking

Entumin may worsen the prognosis of breast cancer, although no formal link has been

established. Entumin should be administered with caution in such situations.

Class effects

An increased risk of adverse cerebrovascular reactions has been observed in patients

with dementia treated with some atypical antipsychotic agents. The mechanism for

this increased risk is not known. An increased risk cannot be excluded for other

antipsychotics or other patient populations. Caution is recommended when using

Entumin in the treatment of patients with risk factors for stroke.

In elderly patients with dementia-related psychosis, the efficacy and safety of

Entumin have not been studied. Observational studies suggest that elderly patients

with dementia-related psychosis treated with antipsychotics are at increased risk of

mortality. In the literature, risks predisposing this patient population to an increased

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risk of mortality when treated with antipsychotics are: anaesthesia, the presence of

cardiac disorders (e.g. cardiac arrhythmia) or lung disorders (e.g. pneumonia, with or

without aspiration). Caution is recommended when using Entumin in the treatment of

dementia.

As with other antipsychotics, caution is recommended in patients with known

cardiovascular disease or a family history of QT interval prolongation and caution is

recommended when Entumin is prescribed at the same time as medicinal products

known to prolong the QTc interval.

In clinical trials and/or in post-marketing experience, events of

leukopenia/neutropenia have been reported temporarily associated with antipsychotic

agents. Cases of agranulocytosis have also been reported. Risk factors for

leukopenia/neutropenia include a pre-existing low white blood cell count and a

history of drug-induced leukopenia/neutropenia. In patients with a history of a low

and clinically significant white blood cell count or drug-induced

leukopenia/neutropenia, a full blood count should be performed frequently during the

first few months of therapy and discontinuation of Entumin treatment should be

envisaged at the first sign of any clinically significant decrease in the number of white

blood cells in the absence of any other causative factors. Patients with clinically

significant neutropenia should be carefully monitored for fever and other symptoms

or signs of infection and treated rapidly if such symptoms or signs occur. Treatment

with Entumin must be discontinued in patients with severe neutropenia (absolute

neutrophil count <1,000/mm

) and their white blood cell count must be monitored

until it returns to normal.

4.5

Interaction with other medicinal products and other forms of interaction

Entumin can potentiate the:

CNS effects of alcohol, tranquillisers, anaesthetics, hypnotics, analgesics,

MAOIs and antihistamines;

hypotensive effect of antihypertensive agents;

toxicity of lithium.

with

other

antipsychotic

agents,

caution

recommended

when

Entumin

prescribed at the same time as medicinal products known to prolong the QTc interval

or lead to an electrolyte imbalance.

4.6

Fertility, pregnancy and lactation

Pregnancy

Neonates exposed to antipsychotics (including Entumin) during the third trimester of

pregnancy are at risk of adverse reactions, including extrapyramidal symptoms and/or

withdrawal symptoms, which may vary in terms of severity and duration

post partum

The following reactions have been reported: agitation, hypertonia, hypotonia, tremor,

somnolence, respiratory distress, feeding problems. As a result, neonates must be

closely monitored.

Breastfeeding

The metabolites of Entumin are excreted in human milk. A decision must be made

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Entumin-SPC-final 04.2020

whether to discontinue breastfeeding or to discontinue/abstain from Entumin therapy,

taking into account the benefit of breastfeeding for the child and the benefit of therapy

for the woman. In the event of prolonged administration in the mother, neuroleptics

can induce extrapyramidal disorders and hyperreflexia in the neonate.

4.7

Effects on ability to drive and use machines

Entumin can cause somnolence, especially at the start of treatment, and thus diminish

the patient’s ability to react. Sedation is greatly increased upon concomitant use of

alcohol or other agents with a depressant effect on the CNS (hypnotics, tranquillisers,

analgesics, antihistamines).

4.8

Undesirable effects

Autonomic:

Particularly during the first few days of treatment,

Orthostatic hypotension which may cause syncope in elderly individuals.

Atropine-like effects: dry mouth, constipation, accommodation disturbances.

Neurological:

Effects on the CNS, comprising sedation, agitation and states of confusion, are rare.

Extrapyramidal disorders, such as dystonia, akathisia (fear of sitting down) and

pseudoparkinsonism are usually mild and can easily be controlled by antiparkinson

agents.

Rare but sometimes irreversible tardive dyskinesias may be observed during

prolonged courses of treatment.

Neuroleptic malignant syndrome (catatonia, obnubilation; akinesia, rigidity,

opisthotonus, dysregulation of the autonomic nervous system, hyperpyrexia) may

occur in the first few days of treatment when treatment is combined with another

medicinal product or when the dosage is increased.

Eye:

Blurred vision (uncommon).

Miscellaneous:

Cases of venous thromboembolism, including cases of pulmonary embolism and

cases of deep vein thrombosis, have been reported with antipsychotic medications –

Frequency not known.

Very rare cases of QT interval prolongation, which might be associated with torsades

de pointes, have been observed, although a causal link with the use of Entumin cannot

be conclusively demonstrated. Cases of leukopenia/neutropenia have been reported in

temporal relationship with antipsychotics. Cases of agranulocytosis have also been

reported.

Hyperkinesia, EEG changes, oedema, rash, hyperpyrexia, sweating, acute

pancreatitis, thrombocytopenia, gastroenteritis, paralytic ileus: isolated cases, with a

possible relationship with Entumin, have been observed.

Pregnancy, puerperium and perinatal conditions:

Frequency not known: neonatal drug withdrawal syndrome.

Reporting of suspected adverse reactions

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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 by using an online form

https://sideeffects.health.gov.il

4.9

Overdose

The danger of overdose is increased with concomitant use of CNS depressants.

Symptoms:

somnolence, unconsciousness, coma, agitation, convulsions,

thermolability, respiratory depression, hypotension, collapse, tachycardia,

arrhythmias, Parkinson’s syndrome.

Treatment:

there is no specific antidote. Treatment is symptomatic and is performed

in a specialised environment:

Gastric lavage followed by administration of adsorbent charcoal (peritoneal

dialysis and haemodialysis are not very effective).

Monitoring of cardiac and respiratory functions: in the event of hypotension:

plasma substitutes; if necessary, administration of a vasopressor (do not use

adrenaline, as it has an inverse effect).

In the event of convulsions: benzodiazepines.

Correction of disturbances in electrolyte and acid-base metabolism.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics, antipsychotics.

ATC code: N05AH06.

Entumin is a neuroleptic of the dibenzothiazepine group which acts by inhibiting the

central dopaminergic receptors.

Its action manifests in three phases:

A rapid symptomatic effect which may appear from the very first day and

concerns anxiety.

A predominant, progressive sedative action on psychomotor activity and

vigilance.

An antipsychotic action that sets in more slowly, in stages; improvements do not

involve any secondary depressive reactions, even after long-term treatment.

5.2

Pharmacokinetic properties

Due to method-related difficulties, the pharmacokinetics and metabolism are not yet

fully understood.

In animals, absorption of radioactively (tritium) labelled clotiapine is good and rapid,

with elimination occurring within 24 to 140 hours, depending on the species, at a rate

of 65 - 80% via the urine and faeces.

In humans, absorption of clotiapine after oral administration is good and its

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biotransformation is almost complete. The metabolites are, for the vast majority,

glucuronides highly soluble in water which are eliminated via the urine. The main

metabolite is N-dimethyl sulphoxide; 25 - 40% of the administered dose is recovered

in the urine as unchanged substance (approx. 10%) or known metabolites.

5.3

Preclinical safety data

No data supplied.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose, maize starch, microcrystalline cellulose, gelatin, colloidal anhydrous silica,

liquid paraffin, talc, magnesium stearate.

6.2

Incompatibilities

Not applicable

6.3

Shelf life

The expiry date of the product is indicated on the packaging material

6.4

Special precautions for storage

Do not store above 25°C.

6.5

Nature and contents of container

Pack of 30 or 500 scored tablets packed in blisters, PVC/PVDC with Alu heat seal

lacquer.

Not all pack sized may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements.

MANUFACTURER

Delpharm L’aigle, Zone Industrielle 1, Route De Crulai, 61300 L'aigle, France

For:

Juvisé Pharmaceuticals SAS

149 boulevard Stalingrad

69100 Villeurbanne

France

8.

MARKETING AUTHORISATION HOLDER

Taro International Ltd., 14 Hakitor St., Haifa Bay 2624761

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9.

MARKETING AUTHORISATION NUMBERS

023.40.21411.00

This leaflet format was set by the MOH and its content has been reviewed and

approved in June 2014 and updated according to the guidelines of the Ministry of

Health in March 2020.

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