DEPALEPT SYRUP

Israel - English - Ministry of Health

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Active ingredient:
VALPROIC ACID AS SODIUM
Available from:
CTS CHEMICAL INDUSTRIES LTD, ISRAEL
ATC code:
N03AG01
Pharmaceutical form:
SYRUP
Composition:
VALPROIC ACID AS SODIUM 200 MG / 5 ML
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
CTS CHEMICAL INDUSTRIES LTD, ISRAEL
Therapeutic group:
VALPROIC ACID
Therapeutic area:
VALPROIC ACID
Therapeutic indications:
Generalized or partial epilepsy secondary generalized epilepsy and mixed forms of epilepsy.
Authorization number:
033 72 22644 00
Authorization date:
2013-07-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

27-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

27-06-2019

Depalept – Patient safety

information card

The information in this patient safety information card is intended for women who have been prescribed

Depalept and can become pregnant )are of childbearing age(. Read this patient safety information card

along with the patient insert within the drug's package and if you have any questions, consult a doctor or a

pharmacist.

Keep the patient information safety card. You may have to read it again.

Risks to the fetus

When taken by a pregnant woman Depalept may harm the fetus.

If you are a woman of childbearing age, the doctor shall prescribe Depalept for you only if no other drug can

benefit you.

Before you receive a prescription for this drug, the doctor will explain to you what might happen to your baby if

you become pregnant while taking Depalept.

If at a later stage you decide that you would like to become pregnant, do not stop taking your drug until you

have discussed it with your doctor and have together decided on a plan to replace this drug with a different

one, if possible.

It seems that when taken during pregnancy Depalept poses a higher risk compared to other anti-epileptic

drugs, whether as monotherapy or with another anti-epileptic. The higher the dosage, the higher the risks, but

there is a risk with any dosage.

The drug may cause severe congenital malformations and can interfere with the child's developmental process

when he grows up.

Congenital malformations include spina bifida )when the bones in the spine do not develop correctly(; face and

skull abnormalities, heart, kidneys, urinary tract and genitalia abnormalities; limbs malformations.

If you take Depalept during pregnancy, you will be at a higher risk compared to other women for giving birth

to a child with congenital malformations which require medical attention. Since Depalept has been used

for many years, it is known that 11 out of 100 babies of women taking Depalept will suffer from congenital

malformations, compared to 2-3 babies out of each 100 born among the rest of the population.

It is estimated that 30-40% of preschool-age children whose mothers took Depalept during pregnancy may

suffer from developmental problems at the tender age. These children may suffer from a delay in starting to

walk and talk, from lower intelligence and from difficulties in language and memory.

Autistic Spectrum Disorders and Childhood Autism are more often diagnosed in children exposed to Depalept,

and there is some evidence that the children might be at an increased risk to develop symptoms of Attention

Deficit Hyperactivity Disorder )ADHD(.

Before and during treatment with Depalept

You should ensure that you are using an effective contraceptive.

Tell the doctor immediately if you are pregnant or think that you might be pregnant.

Your doctor will explain to you the risks to the fetus, in case you become pregnant.

If you considering trying to become pregnant, do not stop taking Depalept or stop using a contraceptive until

you have consulted with the doctor that prescribed the drugs for you. You should consult with your doctor as

much in advance as possible before you become pregnant, so that you will be able to take several measures

for your pregnancy to go as smoothly as possible and the risks to you and your fetus are reduced as much as

possible.

The doctor may have to adjust Depalept's dosage or to substitute the therapy with another drug before you

begin trying to become pregnant. If you become pregnant, you will be monitored very closely for treatment of

your epilepsy/bipolar disorder as well as for following the development of your fetus.

Ask your doctor regarding taking folic acid while trying to become pregnant. Folic acid may reduce the risk for

early termination which exists in any pregnancy and the risk for spina bifida.

However, it is unlikely that it will reduce the risk of congenital malformations associated with Depalept use.

Информационный листок по безопасности для пациентки- Депалепт

Информация, содержащаяся в данном листке по безопасности, предназначена для женщин

детородного возраста, получивших рецепт на Депалепт. Прочтите данный листок по безопасности

вместе с инструкцией по применению, которая прилагается к лекарству. Если у Вас имеются какие-либо

вопросы, проконсультируйтесь с врачом или фармацевтом.

Храните данный листок по безопасности. Возможно, Вам понадобится прочитать его снова.

Риски для плода

При приеме во время беременности Депалепт может нанести вред плоду.

Если Вы – женщина детородного возраста, врач может прописать Вам Депалепт только при отсутствии

другого подходящего для Вас препарата.

Прежде чем Вы получите рецепт на данный препарат, Ваш врач объяснит вам, что может произойти с

Вашим младенцем, если Вы забеременеете во время приёма Депалепта.

Если Вы решите забеременеть после начала приёма Депалепта, не переставайте принимать его,

предварительно не обсудив этого со своим лечащим врачом и не спланировав переход на прием

другого препарата, если такая возможность существует.

По-видимому, прием Депалепта во время беременности сопряжен с более высоким риском по

сравнению с другими лекарствами от эпилепсии, как в случае приема в качестве монотерапии, так и

в качестве дополнения к другому лекарству от эпилепсии. Риск присутствует при любой дозировке и

увеличивается при повышении дозировки.

Препарат может вызвать тяжелые врожденные дефекты и повредить развитию ребенка в процессе его

роста.

Врожденные дефекты включают расщепление позвоночника spina bifida )абнормальное развитие

костей позвоночника(; деформации лица и черепа; порок сердца, почек, пороки развития мочевых

путей и половых органов; дефекты конечностей.

Если Вы будете принимать Депалепт во время беременности, у Вас повышается риск )по сравнению

с другими женщинами( рождения ребенка с врожденными дефектами, требующими лечения. Так как

Депалепт находится в употреблении в течение многих лет, известно, что у женщин, принимающих

Депалепт, 11 из 100 младенцев страдают врожденными дефектами, по сравнению с 2-3 из 100

младенцев, у остальной части населения.

Считается, что от 30% до 40% детей дошкольного возраста, чьи матери принимали Депалепт во время

беременности, могут страдать от проблем развития в раннем возрасте. Эти дети могут страдать от

задержки начала ходьбы и развития речи, умственной отсталости и затруднениями в развитии языка и

памяти.

Детский аутизм и нарушения в рамках аутистического спектра диагностируются чаще у детей, которые

подверглись воздействию Депалепта. Существуют некоторые свидетельства того, что эти дети

находятся в группе повышенного риска развития симптомов дефицита внимания и гиперреактивности

)ADHD(.

До и во время лечения Депалептом

Убедитесь, что Вы используете эффективный контрацептив

Немедленно сообщите врачу, если Вы беременны или думаете, что можете быть беременны.

В случае беременности, Ваш врач объяснит Вам риски для плода.

Если Вы собираетесь забеременеть, не прекращайте приём Депалепта и не прекращайте

использование контрацептивов, не обратившись, предварительно, к врачу, который выписал Вам

это лекарство. Kак можно более заблаговременно проконсультируйтесь с врачом прежде чем

забеременеть, дабы принять ряд мер для того, чтобы Ваша беременность прошла как можно

спокойнее, и понизить риски для Вас и Вашего плода.

Возможно, прежде чем Вы попытаетесь зачать ребенка, врачу потребуется изменить дозу Депалепта

или перевести Вас на лечение другим препаратом. Если Вы забеременеете, Вы будете находиться под

очень тщательным наблюдением, как в целях лечения эпилепсии/биполярного расстройства, так и для

контроля за развитием Вашего плода.

Проконсультируйтесь с Вашим врачом о приеме фолиевой кислоты во время попыток зачатия.

Фолиевая кислота может понизить риск раннего выкидыша )присутствующий при каждой беременности(

и риск расщепления позвоночника )spina bifida(.

Вместе с тем, маловероятно, что приём фолиевой кислоты позволит понизить риск врожденных

дефектов, связанных с использованием Депалепта.

"ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ"

PRESCRIBING INFORMATION

1.

NAME OF THE MEDICINAL PRODUCT

Depalept 200 enteric coated tablets

Depalept 500 enteric coated tablets

Depalept Syrup

Depalept oral Solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Depalept 200 enteric coated tablets:

Sodium valproate

200 mg/tab

Depalept 500 enteric coated tablets:

Sodium valproate

500 mg/tab

Depalept Syrup:

Each teaspoon (5 ml) contains:

Sodium Valproate

200 mg/5 ml

Depalept oral Solution:

Each ml contains:

Sodium Valproate

200 mg/1ml

3. PHARMACEUTICAL FORM

Depalept 200 enteric coated tablets

Depalept 500 enteric coated tablets

Depalept Syrup

Depalept oral Solution

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Depalept is indicated for the treatment of generalized or partial epilepsy secondary generalized epilepsy

and mixed forms of epilepsy.

4.2 Posology and method of administration:

In female children, female adolescents, women of childbearing potential and pregnant women

Depalept should be initiated and supervised by a specialist experienced in the management of epilepsy.

Treatment should only be initiated if other treatments are ineffective or not tolerated (see Section 4.4 and

Section 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably

Depalept should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged

release formulation. The daily dose should be divided into at least two single doses.

In view of the dosage strength this medicinal product is for use in adults and children weighing over than 17 kg

only.

Depalept 500 mg and Depalept 200 mg gastro-resistant tablets are not suitable for children under the

age of 6 years (risk of choking).

Dosage

The mean dosage is 20 -30 mg/kg per day. However, if seizures are not brought under control at this dosage

it may be increased and patients must be closely monitored.

− In children, the usual dosage is about 30 mg/kg per day in divided doses.

− In adults and adolscents, the usual dosage is 20 to 30 mg/kg per day in divided dose.

− In elderly patients, the dosage should be determined based on the control of seizures.

The daily dosage should determined based on age and body weight, however, the significant variations in inter-

individual sensitivity to valproate must be taken into account.

No clear correlation between the daily dose, serum levels and the therapeutic effect has been established: the

dosage should be determined on the basis of the clinical response.

Determination of valproic acid plasma levels should be considered along with clinical monitoring when control of

seizures is not achieved or when adverse effects are suspected. The effective therapeutic range is usually

between 40 and 100 mg/L (300 to 700 μmol/L).

Method of administration.

Oral use.

Administer only the oral solution with the syringe for oral administration supplied in the box and the syrup with

the measuring cup supplied in the box..

The daily dose is to be administrered as 2 or 3 divided doses, preferably during meals:

as 2 divided doses in patients under 1 year of age,

as 3 divided doses in patients over 1 year of age.

The solution is to be ingested after diluting in a small quantity of non-fizzy drink.

Initiation of Depalept therapy (oral administration):

If the patient is already being treated and is taking other antiepileptics, begin administering sodium

valproate gradually, to reach the optimal dose in approximately two weeks, then reduce the

concomitant treatments if necessary on the basis of treatment efficacy.

If the patient is not taking any other antiepileptics, the dosage should preferably be increased step-

wise every 2 or 3 days, in order to reach the optimal dose in approximately one week.

If necessary, combination treatment with other antiepileptics should be instituted gradually (see 4.5

Interaction with other medicinal products and other forms of interaction).

Liver function tests should be performed before starting treatment (see Section 4.3) and then

periodically for the first 6 months, particularly in patients at risk (see Section 4.4).

Blood tests (complete blood count including platelets, bleeding time and coagulation parameters) are

recommended prior to treatment, then after 15 days and at the end of treatment, and also before any

surgery, and in the event of hematomas or spontaneous bleeding (see Section 4.8).

In patients with renal insufficiency, elevated circulating valproic acid concentrations in the blood

should be taken into account and the dosage should be reduced accordingly.

4.3 Contraindications

History of hypersensitivity to valproate , divalproate, valpromide or to one of the ingredients of the

medicinal product.

Acute hepatitis.

Chronic hepatitis.

Hepatic porphyria

Personal or familial history of severe hepatitis, in particular drug related.

Combination use with mefloquine and St.-John`s-wort

(see Section 4.5).

Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding

mitochondrial enzyme polymerase γ (POLG, e.g. Alpers-Huttenlocher Syndrome) and in children

under two years of age who are suspected of having a POLG-related disorder (see Section 4.4)

Patients with known urea cycle disorders (see Section 4.4)

4.4 Special warnings and special precautions for use

Special Warnings

Patient Card:

This product is marketed with patient safety information card (patient card). Please explain to the

patient the implications of this treatment.

Female children/Female adolescents/Woman of childbearing potential/Pregnancy

Depalept should not be used in female children, in female adolescents, in women of child-bearing

potential and in pregnant women unless alternative treatments are ineffective or not

tolerated,because of its high teratogenic potential and risk of neuro-developmental disorders in

infants exposed in- utero to valproate.

The benefit and risk should be carefully reconsidered at regular treatment reviews at puberty and

urgently when a woman of child bearing potential treated with Depalept plans a pregnancy, or if she

becomes pregnant.

Women of child-bearing potential must use effective contraception during treatment and be

completely informed of the risks associated with the use of Depalept during pregnancy (see section

4.6).

The prescriber must ensure that the patient is provided with comprehensive information on the risks

alongside relevant materials, such as a patient information leaflet, to support her understanding of the

risks.

In particular the prescriber must ensure the patient understands:

The nature and the magnitude of the risks of exposure during pregnancy, in particular the

teratogenic risks and the risks of neuro-developmental disorders.

The need to use effective contraception.

The need for regular review of treatment.

The need to rapidly consult her physician if she is thinking of becoming pregnant or there is a

possibility of pregnancy.

In women planning to become pregnant all efforts should be made to switch to appropriate alternative

treatment prior to conception, if possible (see Section 4.6).

Valproate therapy should only be continued after a reassessment of the benefits and risks of the

treatment with valproate for the patient by a physician experienced in the management of epilepsy or

bipolar disorder.

The introduction of an antiepileptic may, in rare cases, be followed by an increase in seizures or the onset of a

new type of seizure in the patient, independently of the spontaneous fluctuations observed in some types of

epilepsy. In the case of valproate, this mainly involves a change in concomitant antiepileptic treatment or a

pharmacokinetic interaction (see Section 4.5), toxicity (liver disease or encephalopathy) (see Sections 4.4 and

4.8) or overdose.

Since this medicinal product is transformed into valproic acid in the body, it should not be combined with other

medicinal products undergoing the same transformation to avoid an overdose of valproic acid (e.g. divalproate,

valpromide).

Liver diseases:

Conditions of onset:

Exceptional cases of liver damage with a severe or sometimes fatal outcome have been reported.

Infants and young children under the age of 3, especially in cases of multiple anticonvulsant therapy, presenting

with severe epilepsy and, in particular, epilepsy associated with brain damage, mental retardation and/or a

genetic metabolic or degenerative disease are the most at risk. Over the age of 3, the incidence of onset is

significantly reduced and gradually decreases with age.

In the great majority of cases, such liver damage has been observed within the first 6 months of treatment,

usually between the 2nd and 12th week and generally during multiple-agent antiepileptic treatment.

Warning signs:

Early diagnosis is primarily based on the clinical picture. In particular, two types of signs that can precede

jaundice should be taken into account, particularly in patients at risk (see Conditions of onset):

firstly, non-specific systemic signs, generally of sudden onset, such as asthenia, anorexia, lethargy,

drowsiness, sometimes accompanied by repeated vomiting and abdominal pain.

secondly, a recurrence of epileptic seizures despite proper treatment compliance.

It is recommended that patients, or their families in the case of children, be informed that they should immediately

consult a doctor if this type of clinical picture occurs. In addition to a physical examination, liver function tests

should immediately be performed.

Confirmation of abnormally low PT values, especially if there are also other abnormal laboratory findings

(significant reduction in fibrinogen and coagulation factors, elevated bilirubin, elevated transaminase levels -

see section 4.4), requires discontinuation of treatment (and, as a precaution, salicylate derivatives if they are

concomitantly prescribed, since they use the same metabolic pathway).

Bleeding and other hematopoietic disorders

Valproate is associated with dose-related thrombocytopenia. Valproate use has also been associated with

decreases in other cell lines and myelodysplasia. Because of reports of cytopenias, inhibition of the secondary

phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor

deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts, count including

platelets, bleeding time and coagulation tests are recommended before initiating therapy and at periodic intervals

and also before any surgery, and in the event of hematomas or spontaneous bleeding

(see Section 4.8).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan

Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with

other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or

myositis sometimes resembling an acute viral infection. Eosinophilia is often present.

Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is

important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present

even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated

immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or

symptoms cannot be established.

Pancreatitis:

Pancreatitis with a sometimes fatal outcome has been reported in exceptional cases. This can be observed

irrespective of age and treatment duration, with young children appearing to be particularly at risk.

Pancreatitis with an unfavorable outcome is generally observed in young children or in patients with severe

epilepsy, brain damage or those taking multiple-agent antiepileptic treatments.

If pancreatitis is associated with hepatic insufficiency, the risk of a fatal outcome is increased.

In the event of acute abdominal pain or gastrointestinal signs such as nausea, vomiting and/or anorexia, a

diagnosis of pancreatitis must be considered and, in patients with elevated pancreatic enzymes, treatment

should be discontinued, and the necessary alternative therapeutic measures implemented.

Risk of suicide:

Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several

indications. A meta-analysis of randomized, placebo controlled trials of anti-epileptic drugs has also shown a

small increased risk of suicidal ideation and behavior. The causes of this risk are unknown and the available data

do not make it possible to rule out an increased risk with valproate.

Consequently, patients should be monitored for signs of suicidal ideation and behavior, and appropriate

treatment should be considered. Patients (and their care providers) should be advised to seek medical advice

immediately should signs of suicidal ideation or behavior emerge.

Interaction with other medicinal products:

Depalept 200 and Depalpet 500 contain, respectively, 28 mg and 70 mg of sodium per tablet.

Depalept Syrup contains 29 mg of sodium per 5 ml and Depalept oral solution contains 28 mg of sodium per 1 ml.

This must be taken into account in patients following a strict low-sodium diet.

Co-administration of this medicinal product with lamotrigine or with penems is not recommended (see

Section 4.5).

Patients with known or suspected mitochondrial disease

Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of

mitochondrial DNA as well as the nuclear- encoded POLG gene. In particular, acute liver failure and liver-related

deaths have been associated with valproate treatment at a higher rate in patients with hereditary neurometabolic

syndromes caused by mutations in the gene for mitochondrial enzyme polymerase γ (POLG; e.g. Alpers-

Huttenlocher Syndrome). POLG-related disorders should be suspected in patients with a family history or

suggestive symptoms of a POLG-related disorder, including but not limited to un-explained encephalopathy,

refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor

regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated

migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical

practice for the diagnostic evaluation of such disorders (see Section 4.3).

Precautions for use

It should be emphasized that, as with most anti-epileptics, an isolated and transient, moderate elevation in

transaminase levels may be observed, without any clinical signs, particularly at the start of treatment.

Should this occur, it is recommended that a more complete laboratory workup be performed (in particular,

prothrombin time), that the dosage be re-evaluated if necessary, and that the tests be repeated based on

changes in the parameters.

In children under the age of 3, it is recommended that sodium valproate only be used as single-agent treatment,

after having weighed the therapeutic value against the risk of liver disease and pancreatitis in patients in this age

group (see Section 4.4).

In children, avoid the simultaneous prescription of salicylate derivatives, due to the risk of hepatotoxicity (see

section 4.4) and the risk of bleeding.

This medicinal product is not recommended in patients with urea cycle enzyme deficiencies. A few cases of

hyperammonemia associated with stupor or coma have been described in these patients.

In children with a history of unexplained hepatic and gastrointestinal disturbances (anorexia, vomiting, cytolytic

episodes), episodes of lethargy or coma, mental retardation or with a family history of neonatal or infant death,

metabolic tests and, in particular, fasting and post-prandial ammonemia tests must be performed prior to any

valproate treatment.

Although it is recognized that this medicinal product only causes immunological disturbances in exceptional

cases, the benefit/risk ratio should be carefully weighed for use in patients with systemic lupus erythematosus.

In the event of acute abdominal pain or gastrointestinal signs such as nausea, vomiting and/or

anorexia, a diagnosis of pancreatitis must be considered and, in patients with elevated pancreatic

enzymes, treatment should be discontinued, and the necessary alternative therapeutic measures

implemented

When initiating treatment, the patient should be informed of the risk of weight gain and of the appropriate

measures which are mainly dietary to be taken to minimize this effect.

As valproate is excreted primarily in the urine, partly in the forms of ketone bodies, ketone body excretion test for

ketonuria may yield false positive results in patients with diabetes.

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the

greater risk of rhabdomyolysis when taking sodium valproate.

Alcohol intake is not recommended during treatment with sodium valproate.

4.5 Interactions with other medicinal products and other forms of interaction

The concomitant use of proconvulsant medicines or those that lower the epileptogenic threshold should be taken

into account or may even be advised against or contraindicated depending on the severity of the risk

encountered. These medicines notably include most antidepressants (imipramine antidepressants, selective

serotonin reuptake inhibitors) and Benzodiazepines, neuroleptics (phenothiazine and butyrophenones),

mefloquine (see below), Bupropion, tramadol.

Contraindicated combination (see Section 4.3 contraindications):

Mefloquine

In epileptic patients, risk of onset of epileptic seizures due to the increased metabolism of valproic acid and the

seizure-inducing effect of mefloquine.

St.-John`s-Wort

Risk of reduced plasma concentrations and reduced efficacy of the anticonvulsant.

Inadvisable combination (see 4.4 Special warnings):

Salicylic derivatives

In children, avoid prescription of salicylic derivatives at the same time due to the risks of hepatotoxicity (see

Special warnings) and the risk of bleeding.

As a precautionary measure if concomitantly prescribed, salicylate compounds should also be discontinued, since

they use the same metabolic pathway.

Lamotrigine

Higher risk of increased lamotrigine toxicity, particularly serious skin reactions (toxic epidermal necrolysis)

Furthermore, an increase in lamotrigine plasma concentrations may occur (decreased hepatic metabolism by

valproate sodium), and increase the lamotrigine mean half life by nearly two-fold.

If coadministration proves necessary, close clinical monitoring is required.

Penems

Risk of seizures due to a rapid decrease in valproic acid plasma concentrations, which may become

undetectable.

Decrease in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents

resulting in a 60-100% decrease in valproic acid levels within two days, sometimes associated with convulsions.

Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients

stabilized on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, close

monitoring of valproic acid blood level should be performed.

Combination requiring special precautions for use:

Aztreonam

Risk of seizures due to reduced valproic acid plasma concentrations. Clinical monitoring, plasma assays and

possibly dose adjustment of the anticonvulsant during treatment with the anti-infective agent and after its

discontinuation.

Carbamazepine

Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition,

reduced valproic acid plasma concentrations due to increased hepatic metabolism by carbamazepine. Clinical

monitoring, plasma assays and dose adjustment of both anticonvulsants.

Felbamate

Increased valproic acid serum concentrations due to a 22% to 50% decrease in valproic acid clearance, with

a risk of overdose.

Clinical and laboratory monitoring and possible valproate dose adjustment during treatment with

felbamate and after its discontinuation. In addition, valproic acid can reduce mean felbamate clearance by up to

16%.

Phenobarbital (and by extrapolation, primidone)

Increased plasma concentrations of phenobarbital with signs of overdose, due to inhibition of hepatic metabolism,

occurring most often in children. In addition, reduced valproic acid plasma concentrations due to an increase in its

hepatic metabolism by phenobarbital.

Clinical monitoring for the first 15 days of combined administration and immediate reduction of phenobarbital

doses if any signs of sedation occur; in particular, plasma concentrations of the two anticonvulsants should be

monitored.

Valproic acid metabolites levels may be increased in case of concomitant use with phenytoin or phenobarbital.

Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of

hyperammonemia.

Phenytoin (and by extrapolation fosphenytoin)

Variations in phenytoin plasma concentrations. In addition, risk of reduced valproic acid plasma concentrations

due to increase of its hepatic metabolism by phenytoin.

Clinical monitoring, plasma assays and possible dose adjustment of both anticonvulsants.

Rifampicin

Risk of seizures due to increase hepatic metabolism of valproate by rifampicin.

Clinical monitoring and monitoring of laboratory parameters and possible dose adjustment of the anticonvulsant

during treatment with rifampicin and after its discontinuation.

Topiramate and acetazolamide

Risk of the onset of hyperammonemia or encephalopathy, generally attributed to valproate when administered

concomitantly with topiramate.

Increased clinical and laboratory monitoring at the beginning of treatment and in the event of symptoms

suggesting this effect.

Zidovudine

Risk of increased adverse effects of Zidovudine, particularly hematological effects, due to decreased metabolism

by valproic acid.

Regular clinical and laboratory monitoring. A blood count should be performed to test for anemia during the first

two months of the combination.

Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

Rufinamide

Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration

of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.

Cimetidine, Erythromycin

Valproate serum levels may be increased in case of concomitant use, as a result of reduced hepatic metabolism.

Vitamin K dependent factor anticoagulant

Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K dependent

factor anticoagulant.

Aspirin

In case of concomitant use of valproate and highly protein bound agents, valporic acid free serum levels may be

increased.

Combination to be taken into account:

Nimodipine (oral route and by extrapolation, injectable route)

Risk of enhanced hypotensive effect of nimodipine due to an increase in its plasma concentrations (decreased

metabolism by valproic acid).

Other forms of interaction:

Quetiapine

Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.

Oral contraceptives

As valproate has no enzyme-inducing activity, it does not reduce the efficacy of estrogen-progestogen in women

using hormonal contraception.

Lithium:

Depalept has no effect on serum lithium levels.

Protease inhibitors

Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma level when co-administered.

Cholestyramine

Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.

4.6 Pregnancy and lactation

Pregnancy

Depalept should not be used in female children, in female adolescents, in women of childbearing potential and in

pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to

use effective contraception during treatment.

In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment

prior to conception, if possible.

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes.

Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of

congenital malformations than valproate monotherapy.

Congenital malformations

Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of

epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95%

CI: 8.16 -13.29). This is a greater risk of major malformations than for the general population, for whom the risk is

about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.

Available data show an increased incidence of minor and major malformations. The most common types of

malformations include neural tube closure defects (approximately 2 to 3%), facial dysmorphism, cleft lip and

palate, craniostenosis, cardiac, renal and urogenital defects (in particular, hypospadias), limb defects (including

bilateral aplasia of the radius), and multiple anomalies involving various body systems.

Neuro- disorders

Studies have shown that exposure to valproate in utero increases the risk of neuro-developmental disorders of

the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists,

cannot be established based on available data. The period of risk could involve the entire pregnancy.

Studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their

early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking

and understanding) and memory problems.

Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero

was on average 7-10 points lower than those children exposed to other antiepileptics. Although the role of

confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of

intellectual impairment may be independent from maternal IQ.

There are limited data on the long term outcomes.

Available data show that children exposed to valproate in utero are at increased risk of pervasive developmental

disorders (autism spectrum disorders) (approximately three-fold) and childhood autism (approximately five-fold)

compared with the general study population.

Limited data to date suggests that children exposed to valproate in utero may be more likely to develop symptoms

of attention deficit/hyperactivity disorder (ADHD).

Female children, female adolescents and women of childbearing potential (see above and Section 4.4)

Depalept should not be used in female children, in female adolescents, in women of childbearing potential and

pregnant women unless alternative treatments are ineffective or not tolerated. Women of childbearing potential

must use effective contraception during treatment.

If a woman wants to plan a pregnancy or if she is pregnant:

a pre-conception consultation is recommended

valproate therapy should be reassessed,

all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

-Valproate therapy should not be discontinued without reassessment of the benefits and risks of the treatment

with valproate for the patient by a physician experienced in the management of epilepsy. During pregnancy,

maternal tonic-clonic seizures and status epilepticus with hypoxia may have serious consequences and even be

fatal for the mother and the unborn child.

If based on a careful evaluation of the risks and benefits, valporate treatment is continued during the pregnancy

(no alternative), it is recommended to:

Use the lowest effective dose and divide the daily dose valproate into several small doses to be taken

throughout the day. The use of a prolonged-release formulation may be preferable to other treatment

formulations in order to avoid high peak plasma concentrations.

Provide folate supplementation before the pregnancy, which may decrease the risk of neural tube closure

defects common to all pregnancies. However the available evidence does not suggest it prevents the

malformations due to valproate exposure.

Institute specialized prenatal monitoring in order to detect the possible occurrence of neural tube defects

or other malformations.

Before delivery:

Coagulation tests should be performed, including in particular a platelet count, fibrinogen levels and coagulation

time (activated partial thromboplastin time: aPTT) in the mother before delivery.

- Risk in the neonate

Exceptional cases of hemorrhagic syndrome have been reported in neonates whose mothers have taken

sodium

valproate

during

pregnancy.

This

hemorrhagic

syndrome

related

thrombocytopenia,

hypofibrinogenemia and/or to decrease in other coagulation factors; afibrinogenemia has also been reported

and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors

induced by phenobarbital and enzymatic inducers. Normal hemostasis test results in the mother do not make it

possible to rule out hemostasis abnormalities in the neonate.

Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be

investigated in neonates.

Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during

the third trimester of the pregnancy.

Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during

pregnancy.

Withdrawal

syndrome

(such

particular,

agitation,

irritability,

heper-excitability,

jitterness,

hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates

whose mothers have taken valproate during the last trimester of pregnancy.

Breast-feeding:

Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels.

Hematological disorders have been shown in breast-fed newborns/infants of treated women (see Section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depalept

therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman

Fertility

Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using

valproate (see Section 4.8). Valproate administration may also impair fertility in men (in particular, decreased

sperm motility) (see Section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment

discontinuation.

4.7 Effects on ability to drive and use machines

The attention of patients, particularly those who drive or use machines, must be drawn to the risk of drowsiness,

especially in the event of multiple-agent anticonvulsant therapy or concomitant administration with other medicinal

products that may increase drowsiness

4.8 Undesirable effects

Classification of expected incidence rates:

Very common (≥ 10 %) Common (≥1 and <10%); Uncommon (≥ 0.1 and <1%)

Rare (≥ 0.01 and <0.1%); Very rare (<0.01%), Unknown (cannot be estimated from available data).

Congenital, familial and genetic disorders

Congenital malformations and neuro-developmental disorders (see Sections 4.4 and 4.6).

Blood and lymphatic system disorders

Common: anemia, thrombocytopenia

Cases of dose-dependent thrombocytopenia have been reported, generally discovered systematically

and without any clinical repercussions.

In patients with asymptomatic thrombocytopenia, if possible, given the platelet level and control of the

disease,

simply

reducing

dosage

this

medicinal

product

usually

leads

resolution

thrombocytopenia.

Uncommon: pancytopenia, leucopenia

Rare:

bone

marrow

aplasia

pure

cell

aplasia,

Agranulocytosis,

macrocytic

anaemia,

macrocytosis.

Investigations

Common: weight gain*

Rare coagulation factors decreased (at least one), abnormal coagulation tests (such as increased

prothrombin time, increased activated partial thromboplastin time, increased thrombin time, increased

INR)

(see

section

4.6),

Vitamin

(biotin)

deficiency/biotinidase deficiency.

as weight gain is a risk factor for polycystic ovary syndrome, patient weight must be carefully monitored (see Section 4.4).

Nervous system disorders

Very common: tremor.

Common:

extrapyramidal

disorder,

stupor*,

sedation

seizures*,

memory

disorders,

headache,

nystagmus, dizziness

Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia.

Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder.

Cases of

stupor and lethargy sometimes leading to transient coma (encephalopathy)

have been observed with valproate; regressing on treatment

discontinuation or dose reduction. These states most often occur during multiple-agent therapy (particularly phenobarbital or topiramate) or following a

sudden increase in valproate doses.

Ear and labyrinth disorders

Common: deafness

Respiratory, thoracic and mediastinal disorders

Uncommon: pleural effusion.

Gastrointestinal disorders

Very common: Nausea.

Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, abdominal pain upper,

diarrhea frequently occur at the start of treatment, but they usually disappear after a few days without

discontinuing the treatment.

Uncommon: pancreatitis, with possibly fatal outcome requiring early treatment discontinuation (See

section 4.)

Renal and urinary disorders

Uncommon: renal failure

Rare: enuresis, tubulointerstitial nephritis,

urinary incontinence, reversible Fanconi syndrome but the

mode of action is as yet unclear.

Skin and subcutaneous tissue disorders

Common: hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders

Uncommon: angioedema, rash, hair disorder (such as hair texture abnormal, hair colour changes, hair

growth abnormal)

Rare: toxic epidermal necrolysis, Stevens-Jonson syndrome, erythema multiforme, Drug Rash with

Eosinophilia and Systemic Symptoms (DRESS) syndrome (see section 4.4).

Musculoskeletal and connective tissue disorders:

Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on

long-term therapy with sodium valproate. The mechanism by which sodium valproate affect bone

metabolism has not been identified.

Rare: systemic lupus erythematosus (see section 4.4), rhabdomyolysis (See section 4.4).

Endocrine disorders

Uncommon: syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism,

virilism, acnea, androgenic alopecia, and/or increase in androgen hormone levels)

Rare: hypothyroidism (see section 4.6)

Metabolism and nutrition disorders

Common: hyponatraemia,

Rare: hyperammonaemia* (see section 4.4), obesity

*Isolated and moderate hyperammonemia with no changes in liver parameters can be observed, especially during multiple-agent therapy, and does not

warrant treatment discontinuation.

However, cases of hyperammoneamia with neurological symptoms (which may progress to coma) have also been reported, and require additional tests (see

Section 4.4).

Neoplasm benign, malignant and unspecified (incl. cysts and polyps)

Rare: myelodysplastic syndrome.

Vascular disorders

Common: bleeding (see section 4.4 and 4.8)

Uncommon: vasculitis.

General disorders and administration site conditions

Uncommon: hypothermia, non-severe oedema peripheral

Hepatobiliary disorders

Common: liver disease (See section 4.4).

Reproductive system and breast disorders

Common: menstrual irregularities

Uncommon: amenorrhea,

Rare: impact on spermatogenesis (in particular, decreased sperm motility), polycystic ovaries.

Psychiatric disorders

Common: confusional state, hallucinations, aggression*, agitation*, attention deficit disorders*.

Rare: behavioral disturbances*, psychomotor hyperactivity*, learning disabilities *

* These ADRs are principally observed in the pediatrics population.

Reporting of suspected adverse reactions

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

Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.he

alth.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

4.9 Overdose

The clinical signs of massive acute poisoning usually include a calm coma, which may be more or less deep,

with muscule hypotonia, hyporeflexia, miosis, reduced respiratory autonomy and metabolic acidosis,

hypotension and collapse/ cardiovascular shock.

A few cases of intracranial hypertension related to cerebral edema have been described.

Patient management in a hospital setting includes: gastric lavage if indicated, maintenance of effective

diuresis, cardiorespiratory monitoring. In very serious cases, extra-renal purification may be performed if

necessary.

Naloxone has been successfully used in a few isolated cases. In case of massive overdose, hemodialysis and

hemoperfusion have been used successfully.

The prognosis of such poisoning is generally favorable. However a few deaths have been reported.

In the event of overdose, the sodium content in formulations containing valproate can lead to hypernatremia.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ANTI-EPILEPTIC

ATC Code: N03AG01

Valproate produces its pharmacological effects mainly on the central nervous system.

These anti-convulsant properties are produced against very different types of convulsive seizures in animals and

epilepsies in humans.

Experimental and clinical studies on valproate suggest two types of anti-convulsant action.

The first is a direct pharmacological effect related to plasma concentrations of valproate and concentrations in the

brain.

The second is apparently an indirect effect probably related to metabolites of valproate which persist in the brain

or with changes in neurotransmitters or with direct membrane effects.

The hypothesis most generally recognized is that of gamma-aminobutyric acid (GABA) whose concentrations

increase after administration of valproate.

Valproate decreases the duration of the intermediate phases of sleep with a concomitant increase in slowwave

sleep.

5.2 Pharmacokinetic properties

The various pharmacokinetic studies conducted on valproate have shown that:

The bioavailability in the blood following oral administration is close to 100%.

Most of the substance is distributed in the blood and the rapid exchange extra-cellular fluids.

It is also distributed in the CSF and the brain.

The half-life is 15 to 17 hours.

A therapeutic efficacy usually requires minimum serum concentrations of 40-50 mg/l, with a

wide range between 40 and 100 mg/l. If higher plasma levels prove necessary, the expected

benefits must be weighed against the risk of occurrence of unwanted effects, particularly dose-

dependent effects. However, levels remainig above 150 mg/l require a reduction in the dose.

Plasma concentration at the steady state is reached within 3 to 4 days.

Binding of valproate to plasma proteins is very high. It is dose-dependent and saturable

Valproate is excreted mainly in the urine following metabolization by glucuronic conjugation and beta-

oxidation.

- Valproate is dialyzable, but hemodialysis affects only the unbound fraction of plasma valproate (about 10%).

Valproate does not an inducer of enzymes involved in the cytochrome P 450 metabolic system,

contrary to most other anti-epileptic agents, as a result, it does not accelerate its own degredation,

nor that of other substances, such as estrogen -progestogens and oral anticoagulants.

6. PHARMACEUTICAL PARTICULARS

6.1 Excipients

Depalept 200 enteric coated tablets:

Purified talc, povidone (K25), maize starch, cellulose acetate phtalate, calcium silicate, polyethylene glycol

400, diethyl phthalate, povidone (K90), titanium dioxide micronized ,magnesium stearate.

Depalept 500 enteric coated tablets:

Purified talc, povidone (K25), cellulose acetate phthalate, maize starch, calcium silicate, povidone (K90),

polyethylene glycol 400, diethyl phthalate, titanium dioxide micronized, magnesium stearate, Iron yellow oxide

E172.

Depalept Syrup:

Sucrose, sorbitol solution 70%, sodium methyl hydroxybenzoate, saccharin sodium, ponceau 4R, cherry

flavour, sodium propyl hydroxybenzoate, purified water.

Depalept oral Solution:

Urea, diluted hydrochloric acid or sodium hydroxide, purified water.

6.2 Special precautions for storage

Depalept tablets must be kept in a cool, dry, dark place, at room temperature (below 25

C). Can be used up to

2 months from opening.

depalept syrup should be stored at 25ºC . Can be used up to 2 months from opening.

Depalept oral solution should be stored at 25ºC. Can be used up to 2 months from opening.

7. PRESENTATION

Depalept Enteric-Coated tablets 200 mg: 40 tablets

Depalept Enteric-Coated tablets 500 mg: 40 tablets

Depalept Solution: Bottles of 50 ml

Depalept Syrup: Bottles of 110 ml

8. MANUFACTURER:

CTS Chemical Industries Ltd., Kiryat Malachi

THE FORMAT OF THIS LEAFLET WAS DETERMINED BY THE MINISTRY OF HEALTH AND ITS CONTENT

WAS CHECKED AND APPROVED IN 11/2015

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.202.20

.202.20

.202.20

_____________ ךיראת

1109/01/92

__________

םושירה רפסמו תילגנאב רישכת םש

:

Depalept 200- 0483023229

Depalpet 500- 0337122348

Depalpet Oral Solution- 1166823129

Depalept Syrup- 0337222644

ש

םושירה לעב ם

________

טצכ

תוימיכ תוישעת

מ"עב

__________________

ה טורפל דעוימ הז ספוט דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Posology and

administration

route

Dosage should be

established according to age

and body weight.

A good correlation has not

been established between

daily dose, serum

concentration and therapeutic

effect and optimum dosage

should be determined

essentially according to the

clinical response; the

determination of valproic acid

plasma levels may be

considered in addition to

clinical monitoring when

adequate seizure control is

not achieved or when adverse

effects are suspected. The

reported effective range is

usually between 40-100

mg/litre (300-700 umol/litre).

Depalept 500 mg and

Depalept 200 mg

gastro-resistant

tablets are not

suitable for children

under the age of 6

years (risk of

choking).

Posology

Average daily dosage:

Infants

children:

per kg (the syrup

In female children, female adolescents,

women of childbearing potential and

pregnant women

Depalept should be initiated and

supervised by a specialist experienced in

the management of epilepsy or bipolar

disorder. Treatment should only be

initiated if other treatments are ineffective

or not tolerated (see Section 4.4 and

Section 4.6) and the benefit and risk

should be carefully reconsidered at regular

treatment reviews. Preferably Depalept

should be prescribed as monotherapy and

at the lowest effective dose, if possible as

a prolonged release formulation. The daily

dose should be divided into at least two

single doses.

In view of the dosage strength this

medicinal product is for use in adults and

children weighing over than 17 kg only.

Depalept 500 mg and Depalept

200 mg gastro-resistant tablets are

not suitable for children under the

age of 6 years (risk of choking).

Dosage

The Initial daily dosage is usually 10-15

mg/kg, after which doses are increased up

to the optimum dose (see

Initiation of treatment)

The mean dosage is 20 -30 mg/kg per

day. However, if seizures are not brought

under control at this dosage

it may be increased and patients must be

closely monitored.

− In children, the usual dosage is about 30

mg/kg per day.

− In adults, the usual dosage is 20 to 30

oral

solution

forms

should

preferably

used)

divided

doses.

Adolscents

adults:

(the

tablet

chrono

tablet

forms

should

preferably

be used) in divided

doses.

mg/kg per day.

− In elderly patients, the dosage should be

determined based on the control of

seizures.

The daily dosage should determined

based on age and body weight, however,

the significant variations in inter-individual

sensitivity to valproate must be taken into

account.

No clear correlation between the daily

dose, serum levels and the therapeutic

effect has been established: the dosage

should be determined on the basis of the

clinical response.

Determination of valproic acid plasma

levels should be considered along with

clinical monitoring when control of seizures

is not achieved or when adverse effects

are suspected. The effective therapeutic

range is usually between 40 and 100 mg/L

(300 to 700 μmol/L).

Contraindication

History

hypersensitivity

valproate

divalproate,

valpromide

ingredients

medicinal product.

Acute hepatitis.

Chronic hepatitis.

Personal

familial

history

severe hepatitis, in

particular

drug

related.

Hepatic porphyria

Combination

with

mefloquine

St.-John`s-

wort

(see Section

4.5 Interaction with

other

medicinal

products and other

forms

interaction).

History of hypersensitivity to

valproate , divalproate,

valpromide or to one of the

ingredients of the medicinal

product.

Acute hepatitis.

Chronic hepatitis.

Hepatic porphyria

Personal or familial history of

severe hepatitis, in particular

drug related.

Combination use with

mefloquine and St.-John`s-wort

(see Section 4.5).

Patients known to have

mitochondrial disorders caused

by mutations in the nuclear

gene encoding

mitochondrial enzyme

polymerase γ (POLG, e.g.

Alpers-Huttenlocher Syndrome)

and in children

under two years of age who are

suspected of having a POLG-

related disorder (see Section

4.4)

Patients with known urea cycle

disorders (see Section 4.4)

Special warnings

and special

precautions for

use

The introduction of an

antiepileptic may, in rare

cases, be followed by an

increase in seizures or the

onset of a new type of seizure

in the patient, independently of

the spontaneous fluctuations

observed in some types of

epilepsy. In the case of

valproate, this mainly involves

a change in concomitant

Patient Card:

This product is marketed with

patient safety information card

(patient card). Please explain to

the patient the implications of

this treatment.

Female children/Female

adolescents/Woman of

childbearing

potential/Pregnancy

antiepileptic treatment or a

pharmacokinetic interaction

(see Section 4.5 Interaction

with other medicinal products

and other forms of interaction),

toxicity (liver disease or

encephalopathy) (see Sections

4.4 Special warnings and

special precautions for use

and 4.8 Undesirable effects) or

overdose.

Since this medicinal product is

metabolized into valproic acid,

it should not be combined with

other medicinal products

undergoing the same

transformation to avoid an

overdose of valproic acid (e.g.

divalproate, valpromide).

It is recommended that

patients, or their families in the

case of children, be informed

that they should immediately

consult a doctor if this type of

clinical picture occurs. In

addition to a physical

examination, liver function

tests should immediately be

performed.

Detection:

Liver function tests should be

performed before therapy and

then periodically during the

first 6 months of therapy.

Tests reflecting protein

synthesis and, in particular, PR

(prothrombin rate) are the

most pertinent of the

conventional tests.

Confirmation of an abnormally

low prothrombin rate,

especially if accompanied by

other abnormal laboratory

findings (significant reduction

in fibrinogen and coagulation

factors, elevated bilirubin,

elevated transaminase levels -

see Section 4.4 Special

warnings and special

precautions for use), requires

discontinuation of sodium

valproate treatment (and, as a

precautionary measure,

salicylate derivatives if they

are concomitantly prescribed,

since they use the same

metabolic pathway).

Depalept should not be used in

female children, in female

adolescents, in women of child-

bearing

potential and in pregnant

women unless alternative

treatments are ineffective or not

tolerated,because of its high

teratogenic potential and risk of

neuro-developmental disorders

in infants exposed in- utero to

valproate.

The benefit and risk should be

carefully reconsidered at

regular treatment reviews at

puberty and urgently when a

woman of child bearing

potential treated with Depalept

plans a pregnancy, or if she

becomes pregnant.

Women of child-bearing

potential must use effective

contraception during treatment

and be completely informed of

the risks associated with the

use of Depalept during

pregnancy (see section 4.6).

The prescriber must ensure

that the patient is provided with

comprehensive information on

the risks

alongside relevant materials,

such as a patient information

leaflet, to support her

understanding of the risks.

In particular the prescriber must

ensure the patient understands:

nature

magnitude of the risks of

exposure

during

pregnancy, in particular the

teratogenic

risks

risks

neuro-

developmental disorders.

The need to use effective

contraception.

The need for regular review

of treatment.

The need to rapidly consult

physician

thinking

becoming

pregnant or there is a

possibility of pregnancy.

In women planning to become

pregnant all efforts should be

made to switch to appropriate

alternative

treatment prior to conception, if

possible (see Section 4.6).

Valproate therapy should only

be continued after a

reassessment of the benefits

Pancreatitis:

Pancreatitis with a sometimes

fatal outcome has been

reported in exceptional cases.

Young children are at

particular risk but this risk

decreases with increasing age.

Severe seizures, neurological

impairment or anticonvulsant

therapy may be at risk factors.

If pancreatitis is associated

with hepatic insufficiency, the

risk of a fatal outcome is

increased.

Patients experiencing acute

abdominal pain should have a

prompt medical evaluation. In

case of pancreatitis, Sodium

Valporate should be

discontinued.

Woman of childbearing

potential:

A decision to use Sodium

Valporate in woman of

childbearing potential should

be taken after very careful

evaluation, if the benefits of its

use outweigh the risks of

congenital anomalies to the

unborn child (i.e. in situations

where other treatments are

ineffective or not tolerated).

This decision is to be taken;

before Sodium Valporate is

prescribed for the first time as

well as before a woman

already treated with sodium

valproate is planning a

pregnancy. Women of child-

bearing potential must use

effective contraception during

treatment.

Suicidal ideation and

behavior:

Suicidal ideation and behavior

have been reported in patients

treated with antiepileptic

agents in several indications. A

meta-analysis of randomized,

placebo controlled trials of

anti-epileptic drugs has also

shown a small increased risk

of suicidal ideation and

behavior. The mechanism of

this effect is not known.

Therefore, patients should be

monitored for signs of suicidal

ideation and behavior, and

appropriate treatment should

be considered. Patients (and

caregivers of patients) should

be advised to seek medical

and risks of the treatment with

valproate for the patient by a

physician experienced in the

management of epilepsy or

bipolar disorder.

The introduction of an antiepileptic may, in

rare cases, be followed by an increase in

seizures or the onset of a new type of

seizure in the patient, independently of the

spontaneous fluctuations observed in some

types of epilepsy. In the case of valproate,

this mainly involves a change in

concomitant antiepileptic treatment or a

pharmacokinetic interaction (see Section

4.5), toxicity (liver disease or

encephalopathy) (see Sections 4.4 and 4.8)

or overdose.

Since this medicinal product is transformed

into valproic acid in the body, it should not

be combined with other medicinal products

undergoing the same transformation to

avoid an overdose of valproic acid (e.g.

divalproate, valpromide).

Liver diseases:

Conditions of onset:

Exceptional cases of liver damage with a

severe or sometimes fatal outcome have

been reported.

Infants and young children under the age of

3, especially in cases of multiple

anticonvulsant therapy, presenting with

severe epilepsy and, in particular, epilepsy

associated with brain damage, mental

retardation and/or a genetic metabolic or

degenerative disease are the most at risk.

Over the age of 3, the incidence of onset is

significantly reduced and gradually

decreases with age.

In the great majority of cases, such liver

damage has been observed within the first

6 months of treatment, usually between the

2nd and 12th week and generally during

multiple-agent antiepileptic treatment.

Warning signs:

Early diagnosis is primarily based on the

clinical picture. In particular, two types of

signs that can precede jaundice should be

taken into account, particularly in patients at

risk (see Conditions of onset):

firstly, non-specific systemic signs,

generally of sudden onset, such as

asthenia, anorexia, lethargy,

drowsiness, sometimes accompanied

advice immediately should

signs of suicidal ideation or

behavior emerge.

Interaction with other medicinal

products:

Coadministration of this

medicinal product with

Carbapenems agents is not

recommended (see Section

4.5 Interaction with other

medicinal products and other

forms of interaction).

Decrease in blood levels of

valporic acid have been

reported when it is co-

administered with carbapenem

agents resulting in a 60-100%

decrease in valporic acid

levels within two days,

sometimes associated with

convulsions. Due to the rapid

onset and the extent of the

decrease, co-administration of

carbapenem agents in patients

stabilized on valporic acid

should be avoided. If treatment

with these antibiotics cannot

be avoided, close monitoring

of valporic acid blood level

should be performed.

by repeated vomiting and abdominal

pain.

secondly, a recurrence of epileptic

seizures despite proper treatment

compliance.

It is recommended that patients, or their

families in the case of children, be informed

that they should immediately consult a

doctor if this type of clinical picture occurs.

In addition to a physical examination, liver

function tests should immediately be

performed.

Confirmation of abnormally low PT values,

especially if there are also other abnormal

laboratory findings

(significant reduction in fibrinogen and

coagulation factors, elevated bilirubin,

elevated transaminase levels -

see section 4.4), requires discontinuation of

treatment (and, as a precaution, salicylate

derivatives if they are

concomitantly prescribed, since they use

the same metabolic pathway).

Bleeding and other hematopoietic

disorders

Valproate is associated with dose-related

thrombocytopenia. Valproate use has also

been associated with decreases in other

cell lines and myelodysplasia. Because of

reports of cytopenias, inhibition of the

secondary phase of platelet aggregation,

and abnormal coagulation parameters,

(e.g., low fibrinogen, coagulation factor

deficiencies, acquired von Willebrand’s

disease), measurements of complete blood

counts, count including platelets, bleeding

time and and coagulation tests are

recommended before initiating therapy and

at periodic intervals and also before any

surgery, and in the event of hematomas or

spontaneous bleeding

(see Section 4.8).

The introduction of an antiepileptic may, in

rare cases, be followed by an increase in

seizures or the onset of a new type of

seizure in the patient, independently of the

spontaneous fluctuations observed in some

types of epilepsy. In the case of valproate,

this mainly involves a change in

concomitant antiepileptic treatment or a

pharmacokinetic interaction (see Section

4.5), toxicity (liver disease or

encephalopathy) (see Sections 4.4 and 4.8)

or overdose.

Drug Reaction with Eosinophilia and

Systemic Symptoms

(DRESS)/Multiorgan hypersensitivity

reaction

Drug Reaction with Eosinophilia and

Systemic Symptoms (DRESS), also known

as Multiorgan

Hypersensitivity, has been reported in

patients taking valproate. DRESS may be

fatal or life-threatening.

DRESS typically, although not exclusively,

presents with fever, rash, and/or

lymphadenopathy, in association with other

organ system involvement, such as

hepatitis, nephritis, hematological

abnormalities, myocarditis, or myositis

sometimes resembling an acute viral

infection. Eosinophilia is often present.

Because this disorder is variable in its

expression, other organ systems not noted

here may be involved. It is important to note

that early manifestations of hypersensitivity,

such as fever or lymphadenopathy, may be

present even though rash is not evident. If

such signs or symptoms are present, the

patient should be evaluated immediately.

Valproate should be discontinued and not

be resumed if an alternative etiology for the

signs or symptoms cannot be established.

Pancreatitis:

Pancreatitis with a sometimes fatal

outcome has been reported in exceptional

cases. This can be observed irrespective of

age and treatment duration, with young

children appearing to be particularly at risk.

Pancreatitis with an unfavorable outcome is

generally observed in young children or in

patients with severe

epilepsy, brain damage or those taking

multiple-agent antiepileptic treatments.

If pancreatitis is associated with hepatic

insufficiency, the risk of a fatal outcome is

increased.

In the event of acute abdominal pain or

gastrointestinal signs such as nausea,

vomiting and/or anorexia, a

diagnosis of pancreatitis must be

considered and, in patients with elevated

pancreatic enzymes, treatment

should be discontinued, and the necessary

alternative therapeutic measures

implemented.

Risk of suicide:

Suicidal ideation and behavior have been

reported in patients treated with

antiepileptic agents in several indications. A

meta-analysis of randomized, placebo

controlled trials of anti-epileptic drugs has

also shown a small increased risk of

suicidal ideation and behavior. The causes

of this risk are unknown and the available

data do not make it possible to rule out an

increased risk with valproate.

Consequently, patients should be

monitored for signs of suicidal ideation and

behavior, and appropriate treatment should

be considered. Patients (and their care

providers) should be advised to seek

medical advice immediately should signs

of suicidal ideation or behavior emerge.

Patients with known or suspected

mitochondrial disease

Valproate may trigger or worsen clinical

signs of underlying mitochondrial diseases

caused by mutations of mitochondrial DNA

as well as the nuclear- encoded POLG

gene. In particular, acute liver failure and

liver-related deaths have been associated

with valproate treatment at a higher rate in

patients with hereditary neurometabolic

syndromes caused by mutations in the

gene for mitochondrial enzyme polymerase

γ (POLG; e.g. Alpers-Huttenlocher

Syndrome). POLG-related disorders

should be suspected in patients with a

family history or suggestive symptoms of a

POLG-related disorder, including but not

limited to un-explained encephalopathy,

refractory epilepsy (focal, myoclonic),

status epilepticus at presentation,

developmental delays, psychomotor

regression, axonal sensorimotor

neuropathy, myopathy cerebellar ataxia,

opthalmoplegia, or complicated migraine

with occipital aura. POLG mutation testing

should be performed in accordance with

current clinical practice for the diagnostic

evaluation of such disorders (see Section

4.3).

Precautions for use

It should be emphasized that, as with most

anti-epileptics, an isolated and transient,

moderate elevation in transaminase levels

may be observed, without any clinical

signs, particularly at the start of treatment.

Should this occur, it is recommended that

a more complete laboratory workup be

performed (in particular, prothrombin time),

that the dosage be re-evaluated if

necessary, and that the tests be repeated

based on changes in the parameters.

In children under the age of 3, it is

recommended that sodium valproate only

be used as single-agent treatment, after

having weighed the therapeutic value

against the risk of liver disease and

pancreatitis in patients in this age group

(see Section 4.4).

In children, avoid the simultaneous

prescription of salicylate derivatives, due to

the risk of hepatotoxicity (see section 4.4)

and the risk of bleeding.

This medicinal product is not

recommended in patients with urea cycle

enzyme deficiencies. A few cases of

hyperammonemia associated with stupor

or coma have been described in these

patients.

In children with a history of unexplained

hepatic and gastrointestinal disturbances

(anorexia, vomiting, cytolytic episodes),

episodes of lethargy or coma, mental

retardation or with a family history of

neonatal or infant death, metabolic tests

and, in particular, fasting and post-prandial

ammonemia tests must be performed prior

to any valproate treatment.

Although it is recognized that this

medicinal product only causes

immunological disturbances in exceptional

cases, the benefit/risk ratio should be

carefully weighed for use in patients with

systemic lupus erythematosus.

As valproate is excreted primarily in the

urine, partly in the forms of ketone bodies,

ketone body excretion test for ketonuria

may yield false positive results in patients

with diabetes.

Patients with an underlying carnitine

palmitoyltransferase (CPT) type II

deficiency should be warned of the greater

risk of rhabdomyolysis when taking sodium

valproate.

Interaction

Felbamate

Increased valproic acid serum

concentrations, with a risk of

overdose, by decrease

valporic acid clearance by 22%

to 50%, and decrease the

felbamate mean clearance by

up to 16%. Valproic acid

dosage should be monitored.

Clinical and laboratory

monitoring and possible

valproate dose adjustment

during treatment with

felbamate and after its

discontinuation.

Phenobarbital

Valproic acid increases

phenobarbital plasma

concentrations (due to

inhibition of hepatic

catabolism) and sedation may

occur, particulary in children.

Therefore, clinical monitoring

is recommended throughout

the first 15 days of combined

treatment with immediate

reduction of phenobarbital

doses if sedation occurs and

determination of phenobarbital

plasma levels when

appropriate.

Primidone:

Aztreonam

Risk of seizures due to reduced valproic

acid plasma concentrations. Clinical

monitoring, plasma assays and possibly

dose adjustment of the anticonvulsant

during treatment with the anti-infective

agent and after its discontinuation.

Felbamate

Increased valproic acid serum

concentrations, with a risk of overdose, by

decrease valporic acid clearance by 22% to

50%, and decrease the felbamate mean

clearance by up to 16%. Valproic acid

dosage should be monitored.

Clinical and laboratory monitoring and

possible valproate dose adjustment during

treatment with

felbamate and after its discontinuation.

Phenobarbital (and by extrapolation,

primidone)

Valproic acid increases phenobarbital

plasma concentrations (due to inhibition of

hepatic catabolism) and sedation may

occur, particulary in children. Therefore,

clinical monitoring is recommended

throughout the first 15 days of combined

treatment with immediate reduction of

phenobarbital doses if sedation occurs and

determination of phenobarbital plasma

levels when appropriate.

Valproic acid metabolites levels may be

increased in case of concomitant use with

Valproic acid increases

primidone plasma levels with

exacerbation of its adverse

effects (such as sedation),

these signs cease with long-

term treatment. Clinical

monitoring is recommended

especially at the beginning of a

combined therapy with dosage

adjustment when appropriate.

Phenytoin

Valporic acid decreases

phenytoin total plasma

concentration. Moreover,

Valporic acid increases the

phenytoin free form with

possible overdose symptoms

(Valporic acid displace

phenytoin from its plasma

protein binding sites and

reduces its hepatic

catabolism). Therefore, clinical

monitoring is recommended

when phenytoin plasma levels

are determined, the free form

should be evaluated.

Topiramate

Concomitant administration of

valproate and topiramate has

been associated with

encephalopathy and/or

hyperammonemia. Patients

treated with those two drugs

should be carefully monitored

for signs and symptoms of

hyperammonemic

encephalopathy.

Rifampicin

Rifampicin may decrease the

valproate blood levels resulting

in a lack of therapeutic effect.

Therefore, valproate dosage

adjustment may be necessary

when it is co-administered with

rifampicin.

Zidovudine

Valproic acid may raise

zidovudine plasma

concentration leading to

increased zidovudine toxicity.

Cimetidine, Erythromycin

Valproate serum levels may be

increased in case of

concomitant use, as a result of

reduced hepatic metabolism.

.

.

.

phenytoin or phenobarbital. Therefore

patients treated with those two drugs

should be carefully monitored for signs and

symptoms of hyperammonemia.

Phenytoin

Valporic acid decreases phenytoin total

plasma concentration. Moreover, Valporic

acid increases the phenytoin free form with

possible overdose symptoms (Valporic acid

displace phenytoin from its plasma protein

binding sites and reduces its hepatic

catabolism). Therefore, clinical monitoring

is recommended when phenytoin plasma

levels are determined, the free form should

be evaluated.

Topiramate and acetazolamide

Concomitant administration of valproate

and topiramate has been associated with

encephalopathy and/or hyperammonemia.

Patients treated with those two drugs

should be carefully monitored for signs and

symptoms of hyperammonemic

encephalopathy.

Zidovudine

Risk of increased adverse effects of

Zidovudine, particularly hematological

effects, due to decreased metabolism by

valporic acid.

Regular clinical and laboratory monitoring.

A blood count should be performed to test

for anemia during the first two months of

the combination.

Olanzapine

Valproic acid may decrease the olanzapine

plasma concentration.

Rufinamide

Valproic acid may lead to an increase in

plasma level of rufinamide. This increase is

dependent on concentration of valproic

acid. Caution should be exercised, in

particular in children, as this effect is larger

in this population.

.

.

.

.

Lithium:

Depalept has no effect on serum lithium

levels.

Oral contraceptives

Valproate usually has no enzyme inducing

effect, as a consequence, valproate does

not reduce efficacy of oestroprogestative

agents in women receiving hormonal

contraception.

.

Nimodipine (oral route and

by extrapolation, injectable

route)

Risk of enhanced hypotensive

effect of nimodipine due to an

increase in its plasma

concentrations (decreased

metabolism by valproic acid).

Quetiapine

Co-administration of valproate

and quetiapine may increase

the risk of

neutropenia/leucopenia.

Lithium:

Valproic acid has no effect on

serum lithium levels.

Oral contraceptives

Valproate usually has no

enzyme inducing effect, as a

consequence, valproate does

not reduce efficacy of

oestroprogestative agents in

women receiving hormonal

contraception.

Protease inhibitors

Protease inhibitors such as lopinavir,

ritonavir decrease valproate plasma level

when co-administered.

Cholestyramine

Cholestyramine may lead to a decrease in

plasma level of valproate when co-

administered.

Fertility, pregnancy and

lactation

Risk

associated

with

seizures:

During pregnancy,

maternal tonic clonic

seizures and status

epilepticus with hypoxia

carry a particular risk of

death for mother and for

the unborn child.

- Risk associated with

sodium valproate:

In animals: teratogenic

effects have been

demonstrated in the

mice, rats and rabbits.

In humans: Available

data suggest an

increased incidence of

minor or major

malformations including,

in particular, neural tube

defects, craniofacial

defects, malformation of

the limbs,

cardiovascular

malformations,

hyposapadias and

multiple anomalies

involving various body

systems in offspring

born to mothers treated

with valproate, when

Depalept should not be used in female

children, in female adolescents, in women

of childbearing potential and in pregnant

women unless other treatments are

ineffective or not tolerated. Women of

childbearing potential have to use effective

contraception during treatment.

In women planning to become pregnant all

efforts should be made to switch to

appropriate alternative treatment prior to

conception, if possible.

Pregnancy Exposure Risk related to

valproate

Both valproate monotherapy and valproate

polytherapy are associated with abnormal

pregnancy outcomes.

Available data suggest that antiepileptic

polytherapy including valproate is

associated with a greater risk of congenital

malformations than valproate monotherapy.

Congenital malformations

Data derived from a meta-analysis

(including registries and cohort studies) has

shown that 10.73% of children of epileptic

women exposed to valproate monotherapy

during pregnancy suffer from congenital

malformations (95% CI: 8.16 -13.29). This

is a greater risk of major malformations

than for the general population, for whom

the risk is about 2-3%. The risk is dose

dependent but a threshold dose below

which no risk exists cannot be established.

Available data show an increased incidence

compared to the

incidence for certain

other antiepileptic drugs.

Data from a meta-

analysis has shown an

incidence of congenital

malformations in

children born to epileptic

women exposed to

valproate monotherapy

during pregnancy at

10.73% (95% CI: 8.16-

13.29). Available data

indicate dose-

dependency of this

effect.

Data suggest an

association between in-

utero valporate

exposure and a risk of

developmental delay,

particularly of verbal IQ,

in children born to

mothers suffering from

epilepsy and treated

with valproate.

Developmental delay is

frequently associated

with malformations

and/or dysmorphic

features. However, it is

difficult to establish

causal relationship in

view of possible

confounding factors

such as low maternal or

paternal IQ, genetic,

social and

environmental factors,

and poor maternal

seizure control during

pregnancy.

Autism spectrum

disorders have also

been reported in

children exposed to

valproate in utero.

Both valproate

monotherapy and

valproate polytherapy

are associated with

abnormal pregnancy

outcome. Available data

suggest that

antiepileptic polytherapy

including valproate is

associated with higher

risk of abnormal

pregnancy outcome that

valproate monotherapy.

-In view of the above

data

This medicine should

not be used during

of minor and major malformations. The

most common types of malformations

include neural tube closure defects

(approximately 2 to 3%), facial

dysmorphism, cleft lip and palate,

craniostenosis, cardiac, renal and

urogenital defects (in particular,

hypospadias), limb defects (including

bilateral aplasia of the radius), and multiple

anomalies involving various body systems.

Neuro- disorders

Studies have shown that exposure to

valproate in utero increases the risk of

neuro-developmental disorders of the

exposed children. The risk seems to be

dose-dependent but a threshold dose below

which no risk exists, cannot be established

based on available data. The period of risk

could involve the entire pregnancy.

Studies in preschool children exposed in

utero to valproate show that up to 30-40%

experience delays in their early

development such as talking and walking

later, lower intellectual abilities, poor

language skills (speaking and

understanding) and memory problems.

Intelligence quotient (IQ) measured in

school aged children (age 6) with a history

of valproate exposure in utero was on

average 7-10 points lower than those

children exposed to other antiepileptics.

Although the role of confounding factors

cannot be excluded, there is evidence in

children exposed to valproate that the risk

of intellectual impairment may be

independent from maternal IQ.

There are limited data on the long term

outcomes.

Available data show that children exposed

to valproate in utero are at increased risk of

pervasive developmental disorders (autism

spectrum disorders) (approximately three-

fold) and childhood autism (approximately

five-fold) compared with the general study

population.

Limited data to date suggests that children

exposed to valproate in utero may be more

likely to develop symptoms of attention

deficit/hyperactivity disorder (ADHD).

Female children, female adolescents and

women of childbearing potential (see above

and Section 4.4)

Depalept should not be used in female

children, in female adolescents, in women

of childbearing potential and pregnant

women unless alternative treatments are

ineffective or not tolerated. Women of

childbearing potential must use effective

contraception during treatment.

If a woman wants to plan a pregnancy or if

she is pregnant:

pre-conception

consultation

recommended

valproate therapy should be

reassessed,

pregnancy and in

women of child-bearing

potential unless clearly

necessary (i.e. in

situation where other

treatments are

ineffective or not

tolerated). Women of

childbearing potential

should be informed of

the risks and benefits of

the use of valproate

during pregnancy.

Specialist advice is

required and physicians

are strongly encouraged

to discuss reproductive

issues with their

patients, before sodium

valproate is prescribed

for the first time or a

woman already treated

with sodium valporate is

planning a pregnancy.

If a woman plans a

pregnancy, valporate

therapy should be

reassessed whatever

the indication:

bipolar

disorders

indication, cessation of

valporate

prophylaxis

should be considered.

During

pregnancy,

valproate

therapy

should

discontinued

without

reassessment

benefit/risk.

If, in any indication,

further to a careful

evaluation of the risks

and benefits, valporate

treatment is continued

during the pregnancy,

it is recommended to

use valporate in

divided doses over the

day at the lowest

effective dose. The

use of a prolonged

release formulation

may be preferable to

any other treatment

form.

addition,

appropriate,

folate

supplementation

should

started

before pregnancy and

at relevant dosage (5

daily)

minimize

risk

neural tube defects.

Specialized

prenatal

all efforts should be made to switch

to appropriate alternative treatment

prior to conception, if possible.

-Valproate therapy should not be

discontinued without reassessment of the

benefits and risks of the treatment with

valproate for the patient by a physician

experienced in the management of

epilepsy. During pregnancy, maternal tonic-

clonic seizures and status epilepticus with

hypoxia may have serious consequences

and even be fatal for the mother and the

unborn child.

If based on a careful evaluation of the risks

and benefits, valporate treatment is

continued during the pregnancy (no

alternative), it is recommended to:

Use the lowest effective dose and

divide the daily dose valproate into

several

small

doses

taken

throughout the day. The use of a

prolonged-release formulation may

preferable

other

treatment

formulations in order to avoid high

peak plasma concentrations.

Provide

folate

supplementation

before the pregnancy, which may

decrease

risk

neural

tube

closure

defects

common

pregnancies. However the available

evidence

does

suggest

prevents the malformations due to

valproate exposure.

Institute

specialized

prenatal

monitoring in order to detect the

possible occurrence of neural tube

defects or other malformations.

Before delivery:

Coagulation tests should be performed,

including in particular a platelet count,

fibrinogen levels and coagulation time

(activated partial thromboplastin time:

aPTT) in the mother before delivery.

- Risk in the neonate

Exceptional

cases

hemorrhagic

syndrome

have

been

reported

neonates

whose

mothers

have

taken

sodium

valproate

during

pregnancy.

This hemorrhagic syndrome is related to

thrombocytopenia,

hypofibrinogenemia

and/or to decrease in other coagulation

factors; afibrinogenemia has also been

reported and may be fatal. However, this

syndrome must be distinguished from

the decrease of the vitamin-K factors

induced by phenobarbital and enzymatic

inducers. Normal hemostasis test results

in the mother do not make it possible to

rule out hemostasis abnormalities in the

neonate.

monitoring

should

instituted

order

detect

possible

occurrence

neural

tube defects or other

malformations.

- Risk in the neonate

Exceptional

cases

hemorrhagic

syndrome

have

been

reported

neonates

whose

mothers

have

taken

sodium

valproate

during

pregnancy.

This

hemorrhagic

syndrome

related

thrombocytopenia,

hypofibrinogenemia

and/or

decrease

other

coagulation

factors;

afibrinogenemia

also

been reported and may be

fatal.

However,

this

syndrome

must

distinguished

from

decrease of the vitamin-K

factors

induced

phenobarbital

enzymatic inducers.

Therefore,

platelet

count,

fibrinogen

plasma

level,

coagulation

tests

coagulation

factors

should

investigated

neonates.

Therefore,

platelet

count,

fibrinogen

plasma

level,

coagulation

tests

coagulation

factors

should

investigated

neonates.

Cases

hypoglycaemia

have been reported

in neonates whose

mothers have taken

valproate

during

third

trimester

of the pregnancy.

Cases

hypothyroidism

have been reported

in neonates whose

mothers have taken

valproate

during

pregnancy.

Withdrawal

syndrome (such as,

particular,

agitation, irritability,

heperexcitability,

jitterness,

hyperkinesia,

tonicity

disorders,

Therefore,

platelet

count,

fibrinogen

plasma

level,

coagulation

tests

coagulation

factors

should

investigated in neonates.

Cases

hypoglycaemia

have

been

reported

neonates

whose

mothers

have

taken

valproate

during

third

trimester of the pregnancy.

Cases of hypothyroidism have

been

reported

neonates

whose

mothers

have

taken

valproate during pregnancy.

Withdrawal syndrome (such as,

in particular, agitation, irritability,

heperexcitability,

jitterness,

hyperkinesia, tonicity disorders,

tremor, convulsions and feeding

disorders)

occur

neonates whose mothers have

taken valproate during the last

trimester of pregnancy.

Lactation

Sodium

valproate

excretion

breast

milk

(between

1%-10%

maternal serum levels).

Hematological disorders have been

shown in breast-fed newborns/infants of

treated women (see Section 4.8).

A decision must be made whether to

discontinue breast-feeding or to

discontinue/abstain from Depalept

therapy taking into account the benefit of

breast-feeding for the child and the

benefit of therapy for the woman

Fertility

Amenorrhoea, polycystic ovaries and

increased testosterone levels have been

reported in women using valproate (see

Section 4.8). Valproate administration

may also impair fertility in men (in

particular, decreased sperm motility)

(see Section 4.8). Case reports indicate

that fertility dysfunctions are reversible

after treatment discontinuation.

tremor, convulsions

feeding

disorders)

occur

neonates

whose

mothers

have

taken

valproate

during

the last trimester of

pregnancy.

Lactation

Sodium valproate excretion

breast

milk

(between

1%-10%

maternal serum levels).

Based on literature and

clinical experience,

breastfeeding can be

envisaged, taking into

account the valproate

safety profile, especially

hematological disorders.

Undesirable

effects

Congenital,

familial

genetic

disorders

Congenital

malformations

neuro-

developmental disorders (see Sections

4.4 and 4.6).

Sedation

urinary incontinence

nail and nail bed disorders

obesity

.

.

menstrual irregularities

Overdose

Measures to be undertaken

in a hospital setting should

be symptomatic: gastric

evacuation may be useful

up to 10 to 12 hours

following ingestion,

monitoring of cardio-

respiratory function.

The clinical signs of massive acute

poisoning usually include a calm coma,

which may be more or less deep, with

muscule hypotonia, hyporeflexia, miosis,

reduced respiratory autonomy and

metabolic acidosis, hypotension and

collapse/ cardiovascular shock.

A few cases of intracranial hypertension

related to cerebral edema have been

described.

Patient management in a hospital setting

includes: gastric lavage if indicated,

maintenance of effective diuresis,

cardiorespiratory monitoring. In very

serious cases, extra-renal purification

may be performed if necessary.

Naloxone has been successfully used in

a few isolated cases. In case of massive

overdose, hemodialysis and

hemoperfusion have been used

successfully.

The prognosis of such poisoning is

generally favorable. However a few

deaths have been reported.

In the event of overdose, the sodium

content in formulations containing

valproate can lead to hypernatremia.

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו והצ עקר לע

ב

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב ןכרצ ןכרצ ןכרצ

ןכדועמ( ןכדועמ( ןכדועמ(

.202.20

.202.20

.202.20

ךיראת

_____________

1109/01/92

__________

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:

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מ"עב

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דעוימ הז ספוט ה טורפל דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

המדקה

דע ןולעה תא ןויעב ארק שמתשת םרטב ופוס .הפורתב ליכמ הז ןולע .הפורתה לע יתיצמת עדימ ,תופסונ תולאש ךל שי םא לא וא אפורה לא הנפ .חקורה

לופיטל המשרנ וז הפורת תוא ריבעת לא .ךתלחמב

קיזהל הלולע איה .םירחאל יכ ךל הארנ םא וליפא םהל .המוד םתלחמ

הרהזא

םידולי

תוהמיאל

ולטנש

טאורפלאו

ךלהמב

ןויריהה

םיאצמנ

ןוכיסב

רבגומ

תוערפהל

תויתוחתפתה

תושק כ(

דע

)םירקמהמ

םימומלו

םידלומ

ךרעב(

)םירקמהמ

םא

ךנה

השיא

ליגב

תוירופה

וא

םא

ךנה

יריהב ןו

אפורה

םושרי

ךל

טאורפלאו

קר

םא

םילופיט

םירחא

םניא

םימיאתמ

לע

םישנ

ליגב

תוירופה

שמתשהל

יעצמאב

העינמ

םיליעי

ךלהמב

לופיטה

רישכתב

הז

ןיא

קיספהל

תא

שומישה

רישכתב

אלל

תוצעוויה

תמדקומ

םע

אפורה

לפטמה

הדימב

תורמלו

שומישה

יעצמאב

העינמ

תסנכנ

ןוירהל

אל

ןנכותמ

ינפ

ןפואב

ידיימ

אפורל

לפטמה

לע

תנמ

ןודל

תויורשפאב

לופיטל

יפולח

תדימב

רשפאה

ףסונב

ןולעל

,

רישכתל

טפלפד

םייק

סיטרכ

עדימ

יתוחיטב

לפוטמל

.

סיטרכ

הז

ליכמ

עדימ

יתוחיטב

בושח

,

ךילעש

תעדל

,

ינפל

תלחתה

לופיטה

ךלהמבו

לופיטה

טפלפדב

.

שי

ןייעל

סיטרכב

עדימ

יתוחיטב

לפוטמל

ןולעבו

ןכרצל

םרטב

תליחת

שומישה

רישכתב

.

שי

רומשל

תא

סיטרכה

ןויעל ףסונ

תדימב

ךרוצה

.

םרטב ופוס דע ןולעה תא ןויעב ארק .הפורתב שמתשת

אורקל ךרטצתו ןכתיי ,הז ןולע לע רומש .בוש וב

.הפורתה לע יתיצמת עדימ ליכמ הז ןולע אפורה לא הנפ ,תופסונ תולאש ךל שי םא חקורה לא וא

ריבעת לא .ךרובע המשרנ וז הפורת םהל קיזהל הלולע איה .םירחאל התוא .המוד םתלחמ יכ ךל הארנ םא וליפא

הפורת

וז

הניא

תדעוימ

ךרדב

ללכ

םידליל

לקשמב

ךומנ

"

םא

תעפות

יאוול

הרימחמ

וא

םא

העיפוה

תעפות

יאוול

אלש

תניוצמ

ןולעב

הז

אנא

הנפ

אפורל

וא

חקורל

ןיא שמתשהל הפורתב

)יגרלא( שיגר התא לכל וא ליעפה רמוחל םיביכרמהמ דחא הליכמ רשא םיפסונה ףיעס האר( הפורתה

ליעפה רמוחל )יגרלא( שיגר ךנה הפורתה יביכרממ דחאל וא ףיעס האר(

)ףסונ עדימ

תרחא הפורתל שיגר ךנה ,טאורפלויד( טאורפלו תחפשממ )דימורפלו

תלחממ לבוס ךנה בכ

( ד

דבכ תקלד ןוגכ וא ,תינורכ וא הרומח והשימ וא ךנה

םא לבוס /לבס ךתחפשממ הרומח דבכ תלחממ י"ע המרגנ םא דחוימב ךנה םא וא תופורת ריפרופמ לבוס הי תידבכ

ןיווקולפמ לטונ ךנה

םע ףוריצב

St. Johns

wort

ןוגכ( דבכ תלחממ לבוס ךנה וא ,תינורכ וא הרומח דבכ תקלד ךנה

םא

לבוס

היריפרופמ )תידבכ

ךתחפשממ והשימ וא ךנה םא דבכ תלחממ לבוס וא לבס י"ע המרגנ םא דחוימב ,הרומח תופורתב שומיש

םע ףוריצב שמתשהל ןיא

Johns wort

וא )ןואכדב לופיטל( )הירלמב לופיטל( ןיווקולפמ םע

תוערפהמ םילבוסה םילוחב האצותכ ,תילאירדנוכוטימ

היצטוממ

ןגב

POLG

שמל

תנומסתמ

Alpers

Huttenlocher

םידליבו

תחתמ

ליגל

םייתנש

םידושחש

תוערפהב

תורושקה

היצטומל

ןגב

POLG

תוערפהמ םילבוסה םילוחב )האירוא( ןנתש לגעמב

תודחוימ תורהזא שומישל תועגונה :הפורתב

הפורתב שמתשהל ןיא ינפל אפורב ץעוויהל ילבמ לופיטה תלחתה

םא

ךניה

ירה תננכתמ ,ןו ןוירהב תאש תבשוח

הקינמ וא ןוירהב

תנתינ הפורתה םא ליגל תחתמ דליל

תופורת םע בולישב תויטפליפאיטנא דליל שיש וא תורחא וא תיגולוריונ הלחמ תרחא תילובטמ הרומח היספליפאו

וא לבוס ךניה םא יוקילמ רבעב תלבס ,דבכה :דוקפתב םדה תכרעמ ,הילכה ,)'וכו השירק ןוגכ(

רובע קר( תרכו ,)פוריסב שומישה תיתנמדא תבאז

SYSTEMIC

LUPUS

ERYTHEMATOSU

,תילובטמ הערפה הערפה דוחיב הרושקה תיתשרות יזנאב רסוחל םימ

: ומכ

Urea cycle

disorder

תורהזא

תופסונ

:

הפורתה תא תתל ןיא ליגב םישנ ,תורענ ,תודליל אלא ,ןוירהב םישנו תוירופה ואצמנ םייפולח םילופיט םא .םימיאתמ יתלב

תוירופה ליגב םישנ תוכירצ הפורתב תולפוטמה הל העינמ יעצמאב שמתש השיאש הרקמב .םיליעי הפורתה תא תלטונש הילע ,ןוירה תננכתמ אפורה םע ץעייתהל תורשפא יבגל לפטמה .יפולח לופיטל רובעל

םד תריפסב הערפהל םורגל הלולע וז הפורת םורגל ,דואמ םירידנ םירקמבו ,םימומידלו בלבלב וא )דבכ תקלד( דבכב תולחמל לולעש ,)בלבל תקלד( תורומח תויהל תו .םייח ןכסלו

םד תוקידב עוציבל ךתוא הנפי ךאפור ב דוחייב ,דבכ ידוקפת תכרעהל

םישדוח .לופיטה לש םינושאר

ועיפוה םא דימ אפורב ץעוויהל ךילע :תואבה תועפותה

,תושישת ,ןובאית רסוח ,תימואתפ תופייע .השלוח ,םיילגרב תוחיפנ ,םונמנ

אכ ,תוליחב ,תורזוח תואקה תבהצ ,ןטב ב .)בוהצ רוע וא תובוהצ םייניע(

ךנהש תורמל ,םייטפליפא םיפקתה לש הרזח

ןוזמל שיגר ךנה םא הפורתל וא והשלכ עידוהל ךילע ,יהשלכ אפורל ךכ לע

תליטנ ינפל

רתה .הפו

תולבקמה םישנש עודי ןוכיסב ןה וז הפורת דלי תדלל הובג רתוי םישנ תמועל םומ םע םומל ןוכיסה .תורחא תחקול ךנה םא לדג תופורת תויטפליפאיטנא ליבקמב תורחא .וז הפורת תחיקלל

םורגל לולע הז רישכת הז רישכת.רבועל קזנל תויעבל םורגל לולע םדה תשירקב ודלונש תוקוניתב יאל ולטנש תוהמ רישכת לש תוחתפתהה.הז םאל םידלונש םידלי הפורתה תא הלטנש הלולע ןויריהה ךלהמב ךנה םא ןכל.עגפיהל שמתשהל ןיא ןוירהב ילבמ הפורתב ינפל אפורב ץעוויהל םא .לופיטה תלחתה וז הפורתל תפשחנ ,ןויריהה ךלהמב שילשב דחוימב ץעוויהל ךילע ,ןושארה יזכרממ דחא םע ועייה םייגולוטרטה ץ ןוכיסה תכרעה םשל .רבועב העיגפל

םא וא ןוירה תננכתמ ךנה דשח ךלצא םייק אפורב יצעוויה ןוירהל .דימ

תא לוטיל קיספהל ןיא תוצעוויה אלל הפורתה .אפור םע

ליגב םישנל ץלמומ תא תולטונש תוירופה שמתשהל הפורתה העינמ יעצמאב לופיטה ךלהמב .הפורתב

ינ עוציב ינפל גוסמ חות םייניש לופיט( והשלכ .ןוכנ הפורתה תא לטונ

רפס ,טפלפדב לופיטה ינפל :םא ךאפורל

דבכה דוקפתב יוקילמ לבוס ךנה

םדה תכרעמב יוקילמ לבוס ךנה )'וכו השירק ןוגכ(

יא( תוילכ תלחממ לבוס ךנה .)תוילכ תקיפס

מ לבוס ךנה תיתנמדא תבאז

SYSTEMIC LUPUS

ERYTHEMATOSUS

,תילובטמ הערפהמ לבוס ךנה תיתשרות הערפה דוחיב : ומכ םימיזנאב רסוחל הרושקה

Urea cycle disorder

הלולעש הינומאה תומר תיילעל םורגל .םדב

שי

החפשמב

ךלש

הירוטסיה

לש

היספליפא

העיגפ

תיתוחתפתה

תויעב

תויגולורינ

תונרגימ

שק תו

ךנה

לבוס

רסחמ

יזנאב

carnitine

palmitoyltransferase (CPT)

type II

הרקמב

הז

םייק

ןוכיס רבגומ

קוריפל

רירש

םילטונשכ

טפלפד

דגנ ףסונ לופיט לטונ ךדלי תלחממ לבוס וא היספליפא תורוצ וא תילובטמ וא תיגולוריונ .היספליפא לש תורומח

ץעוויהל ילבמ הפורתב שמתשהל ןיא

םא לופיטה תלחתה ינפל אפור

ינפל והשלכ גוסמ חותינ עוציב שי )ףוחד לופיט וא םייניש לופיט( טפלפד לטונ ךנהש אפורל חוודל

םא ידיימ ןפואב אפורב ץעוויהל שי םא וא ,םיסוכרפה תורידתב היילע שי .הנוש םיסוכרפ גוס הווח ךנה

היילעל םורגל הלולע וז הפורת ל ךאפורב ץעוויה .לקשמב תוטיש יבג .ףוג לקשמ לע הרימש

הלולע תותיווע דגנ תופורת תליטנ וא תולועפל ןוכיסה תא ריבגהל ינב לעו ךילע .תוינדבוא תובשחמ בצמב םייונישל בל םישל ךתחפשמ .םישעמבו תוגהנתהה יסופדב ,חורה לע םידיעמה םינמיס ירחא בוקעל שי וא םירוביד :ןוגכ תודבאתהל ןוכיס ןוצר לע תובשחמ

,ךמצעל קיזהל תוקחרתהו ךמצע ךותב תוסנכתה הרמחה וא ןואכיד ,םירבחו החפשממ אשונב תוקסעתה ,םייק ןואכידב םיסכנ לש הריסמ וא הרקפה ,תוומה שי )ףוחד לופיט וא ךנהש אפורל חוודל טפלפד ת/לטונ

לופיטה ךשמב םיכירצ וז הפורתב תחיקלמ ענמיהל תוליכמה תופורת הצמוח( ןיריפסא )תיליצילס ליטצא

דגנ תופורת תליטנ ריבגהל הלולע תותיווע וא תולועפל ןוכיסה תא .תוינדבוא תובשחמ ינב לעו ךילע

בל םישל ךתחפש ,חורה בצמב םייונישל תוגהנתהה יסופדב בוקעל שי .םישעמבו םידיעמה םינמיס ירחא תודבאתהל ןוכיס לע וא םירוביד :ןוגכ ןוצר לע תובשחמ ,ךמצעל קיזהל ךמצע ךותב תוסנכתה החפשממ תוקחרתהו וא ןואכיד ,םירבחו ,םייק ןואכידב הרמחה אשונב תוקסעתה וא הרקפה ,תוומה יסמ ירקי םיסכנ לש הר .ךרע

ליגל תחתמ םידלי

םילטונה דחוימב לופיטל תופורת רפסמ היספליפאב

םיאצמנ :ל רתוי הובג ןוכיסב רוגיפ ,תיחומ העיגפ ,ילכש

genetic

metabolic

degenerative

disease

הלחמ( . תינווינ תילובטמ )תיתשרות

ןטב באכ עיפומ םא תונפל שי ףירח לש הרקמב .אפורל בלבלב הפירח תקלד לופיט קיספהל שי טפלפדב

ןוכיסה ( בלבלב הפירח תקלדל ןוכיסה .םידליב רקיעב )ליגב הילעה םע דרוי

תכירצמ ענמיהל שי ךלהמב לוהוכלא תובשחמ תועיפומו הדימב .ךרע ירקי .דימ אפורל תונפל שי ,הז גוסמ

ליגל תחתמ םידלי

דחוימב , לופיטל תופורת רפסמ םילטונה ,היספליפאב הובג ןוכיסב םיאצמנ ,ילכש רוגיפ ,תיחומ העיגפ :ל רתוי

genetic metabolic

degenerative disease

הלחמ( . )תיתשרות תינווינ תילובטמ

רושק ,טפלפדב חווט ךורא שומיש היושעש ,םצעה תופיפצב הדיריל הינפואטסוא ,סיזורפואטסואל ליבוהל .םירבשל ןוכיסב הילעו

הפורת

וז

הלולע

םורגל

הערפה

תריפסב

םד

םימומידלו

אפורה

הנפי

ךתוא

ינפל

תליחת

לופיטה

םגו וכלהמב

עוציבל

תוקידב

םד

וללכיש

תריפס

םד

תקידבו

ידוקפת

השירק

הבוגת

תיגרלא

הפירח

תללוכה

םינימסת

ןוגכ

םוח

תלדגה

תוטולב

הפמיל

תוברועמו

לש

תוכרעמ

ףוג

תופסונ

םע

וא

ילב

החירפ

תירוע הנוכמ(

DRESS

.הפורתב שומיש

חווט ךורא שומיש רושק ,טפלפדב תופיפצב הדיריל היושעש ,םצעה ליבוהל ,סיזורפואטסואל הילעו הינפואטסוא ןוכיסב .םירבשל

יאמ לבוס התא םא שי,תוילכ תקיפס ןוויכמ אפורל תונפל תמאתהב ךרוצ ןכתייש .ןונימ

זורכוס ליכמ פוריסה

תויצקרטנא

םיטליצילסו ןיריפסא

לע תועיפשמה תופורת םיבצעה תכרעמ :ןוגכ( תיזכרמה ,העגרהל תופורת ומכ הנישל ,םיניפזאידוזנב תופורת תופורת,ןוסניקרפל גוסמ היספליפאל , ,לטיברבונפ ,ןיאוטינפ

ןודימיריפו ןיפזמברק

תשירק דגנ תופורת )ןירפרוו( םד

ןואכד דגנ תופורת פימיא( ןימאר

לועיש דגנ תופורת תוננטצהו

תכרעמל תופורת ימלוב גוסמ םיבצעה זדיסקואנימאונומ

ןיגירטומל

םנפיברק ,טמבלפ , ,םנפינפ ,םנפימיא ומכ םנפאברק ,םנפורמו םנוארטזא

,)תוקיטויביטנא ,טרמיפוט

, ןיפידומינ ,ןידופודיז ,ןיציפמאפיר ,ןידיטימיס

ידגונ ,ןיצימורתיריא ת השירק ןימטיו ייול

)ןירפרוו(

תא לטונ התא םא ,טפלפד לוטיל ןיא :תואבה תופורתה

ןיווקולפמ

הירלמב לופיטל הפורת

St John`s wort

אפרמ חמצ .ןואכידב לופיטל

לטונ התא םא ךלש אפורה תא ןכדעל ךילע גירטומל

לופיטל תפסונ הפורת( ןי םימנפה תצובקמ תופורת וא )היספליפיאב הצובק(

םימוהיזב לופיטל תוקיטויביטנא לש .)םנפינפ ,םנפימיא ,םנפורמ ןוגכ ,םייקדייח

ליגל תחתמ םידליב דוחייב

ענמיהל שי , ךשמב ןיריפסא תוליכמה תופורתב שומישמ .הפורתב לופיטה

התא םא חקורה וא אפורה תא עדייל שי :תואבה תופורתה תא חקול

תכרעמ לע תועיפשמה תופורת רמה םיבצעה תיזכ

הנישלו העגרהל תופורת :ןוגכ םיניפזאידוזנב ומכ

ןוסניקרפב לופיטל תופורת

ןוגכ ןואכד דגנ תופורת יבכעמ ,ןימארפימיא )זדיסקואנימאונומ

תוננטצהו לועיש דגנ תופורת

ןוגכ היספליפאב לופיטל תופורת ,ןיאוטינפ ,לטיברבונפ ןיאוטינפסופ ןודימיריפ ןיפזמברק , טמריפוט ,טאמבלפ,

דימניפור

:ןוגכ תוקיטויבטנא ,םנוארטזא

ןיציפמאפיר

ןיצימורתיריא

ןימטיו ייולת השירק ידגונ

ןוגכ ןירפרוו

ןידופודיז ריבנוטיר ,ריבניפול ,

םוהיז םע םילוחב לופיטל

ןידיטמיס

.הביקב תויצמוח דגנ

ןיפידומינ

םידירו תורציה דגנ שמשמ יחומ םומיד תעב

ןיפאיטווק

לוא ןיפזנ

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שפנ

ןימארטסלוכ

הפורת

תדרוהל

לורטסלוכ

דימלוזוטצא

הקנהו ןוירה

ילבמ הפורתב שמתשהל ןיא תלחתה ינפל אפורב ץעוויהל לופיטה

ךניה םא

תננכתמ ,ןוירהב תאש תבשוח ,ןוירה הקינמ וא ןוירהב

תורהזא" ףיעסב םג יאר .ליעל "תופסונ

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ךנה

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.

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םידלומ

וחוודש

םיללוכ

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םגפ

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םימומ

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.

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.

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שומישו הגיהנ תונוכמב

לולע וז הפורתב שומישה ב םוגפל בייחמ ןכ לעו תונרע ,בכרב הגיהנב תוריהז תונכוסמ תונוכמ תלעפהב .תונרע תבייחמה תוליעפ לכבו

םריהזהל שי םידליל רשאב וא םיינפוא לע הביכרמ שיבכה תברקב םיקחשממ .המודכו

תונרעב םוגפל לולע וז הפורתב שומיש םע בולישב תחקלנ איהו הדימב דוחייב א היספליפא דגנ תורחא תופורת תופורת ו .תוינונשיל תומרוגה

הדימב וא וז העפות הווח התא םא התאו הטילשב אל ןיידע ךלש היספליפאהו וא גוהנל ןיא ,םיסוכרפמ לובסל ךישממ .תונכוסמ תונוכמב שמתשהל

לע הביכרמ םריהזהל שי םידליל רשאב שיבכה תברקב םיקחשממ וא םיינפוא .המודכו

שמתשת דציכ ?הפורתב

ב תלטנ םא ןונימ תועט םידליל ללכ ךדב תדעוימ הניא וז הפורת מ ךומנ לקשמב

.ג"ק

רתוי הובג

םיללוכ םינמיסה ,ילוח תשוחת :רתיה ןיב םייניעה ינושיא ,תוליחב ,רתוי םינטק תויהל םיכפוה ,הרכה ןדבוא ,תרוחרחס ,םישלחומ םיסקלפר תויעב ,םירירש תשלוח ,שאר יבאכ ,המישנ ןדבוא ,לובלב ,םיסוכרפ תאצוי תוגהנתהו ןורכיז הדירי ,תמלוה יתלב וא ןפוד ץחלב תויעב ,םדה /םדה ילכ/בלה תכרעמב ,קוש

בצמב רופיש לח םא םג לופיטה קיספהל ןיא ,ךתואירב םע תוצעייתה אלל הפורתב .חקורה וא אפורה

רתוי הובג ןונימ תועטב תלטנ םא

םא וא אפורל דימ הנפ ,הפורתה ןמ דלי עלב תועטב

תזירא אבהו םילוח תיב לש ןוימ רדחל וא .ךתיא הפורתה

:תואבה תועפותהמ לובסל לולע ךנה ,םיסקלפרב הדירי ,םירירש תשלוח ,תמדרת תצמח ,המישנב העיגפ ,םינושיא תוצווכתה .םלהו םד ץחלב הדירי ,תילובטמ

שורדה ןמזב וז הפורת לוטיל תחכש םא

ןיא האבה הנמה תא חק .הלופכ הנמ לוטיל ןמזב .אפורב ץעוויהו ליגרה

ידי לע ץלמוהש יפכ לופיטב דימתהל שי םינמזב וז הפורתב שמתשהל שי .אפורה .לפטמה אפורה ידי לע עבקנש יפכ םיבוצק

טפלפד לוטיל קיספמ ךנה םא

ץתעייתהל ילבמ טפלפדב לופיט קיספהל ןיא .ךתואירב בצמב רופיש לח םא םג ,אפור םע בתהל הכירצ לופיטה תקספה ןפואב עצ .יתגרדה

הדימב

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תויהל

ןוכיסב

םיסוכרפל רבגומ

יאוול תועפות

התא םא אפורל דימ תונפל שי יאוולה תועפות תא הווח תואבה

תיגרלא הבוגת

לולכל םילולע םינמיסה ,המישנ יישק ,החירפ ה תוחפנתה ,םייתפש וא ןורגה ,םינפה ןושלה

הרזומ תוגהנתה

וז הפורת םא דחוימב םע בולישב תחקלנ םא וא לטיברבונפ הלעוה וז הפורת ןונימ ימואתפ ןפואב

לש תינאטנופס העפוה ,םימומיד וא תורובח םד תשירקב תויעב

לש הדרפה םע תועוב רועה

הפורת תורידנ םיתיעל םורגל הלוכי וז בכב תולחמל וא ד ולא תועפות .בלבלב ב תושחרתמ ברל

לופיטה ישדוח .םינושארה תועפותה :תוללוכ ,לובלב ,םירזוח םיסוכרפ רסוח ,םונמנ ,תופייע תא הווח התא םא אפורל דימ תונפל שי תואבה יאוולה תועפות

-

תולחמל םורגל הלוכי וז הפורת תקלד( בלבלב וא )דבכ תקלד( דבכב בלבלב תורומח תויהל תולולעש ,) תוחיכש ןניא ולא תועפות .םייח ןכסלו םע תוימואתפב ליחתהל תולוכיו ,ןובאית ןדבוא ,תופייע ,השלוח םיתיעלש ,תוינונשי ,תושישת .ןטב באכו האקה םע תרשוקמ

םירקמב

םירידנ

תעפוה

החירפ

לע

רועה

הוולמה

םיתעל

תעפוהב

תויחופלש

תולולעש

ברעל

תא

רוזא הפה

,(erythema multiforme)

תעפוה

תויחופלש

םע

תודרפיה

רועה

הלוכיש

סרפתהל

תוריהמב

לע

ינפ

לכ

ףוגה

םייח ןכסלו

.(toxic epidermal necrolysis,

Johnson syndrome)

Steven

:תללוכה תיגרלא הבוגת

םינפה לש תימואתפ תוחיפנ ישוקל תמרוגש האווצה וא/ו םייח תנכסמו המישנב מדאויגנא(

הפירח תיגרלא הבוגת ןוגכ םינימסת תללוכה םוח

,תירוע החירפ תלדגה העיגפ ,הפמיל תוטולב תוקידב תואצות ,תיתיילכ היילע ןוגכ ,תוניקת ןניאש םד תואקה ,ןובאית ,ןטב באכ ,תורזוח ,ןואכיד

,תובצע תבהצ ,הליחב ,השלוח רוע וא תובוהצ םייניע( תקצב , )בוהצ

לש הרמחה וא היספליפאה תיללכ השגרה אל הבוט

טילחי אפורה תוקידבב ךרוצ שי םא ךרוצ שי םא וא םד ףילחהל וא קיספהל .לופיטה תא

:דואמ תוחיכש יאוול תועפות

ליחב ,תו

דער

:תוחיכש יאוול תועפות

לושלש

,םישוח תוהק ,ןטב יבאכ תוינונשי ,םונמנ

דורי ןורכיז

תוינוצר אל תועונת ,שאר יבאכ םייניעה לש תוריהמ

נופיה

הימנר

תוכומנ תומר םדב ןרתנ לש

לקשמב היילע

העימשב הדירי

,הימנא תונפקות

רעיש תרישנ תינמז םייכינחב תולחמ , , תויזה

:תוחיכש אל יאוול תועפות

תויומד תועפות ,תמדרת ןוסניקרפ

היסקטא

החירפ

ישדוחה רוזחמב םייוניש

תומצעב תילובטמ העיגפ ,הינפואטסוא(

ורפואטסוא ,סיז

)םירבש ,יתיילכ לשכ ,

רועיש םיירבג םינייפאמ תעפוה ,רתי החרקה ,הנקא ,השיאה לצא םינומרוה תומרב הילע ,תירבג םייוניש ,םיינגורדנא

רעישב ,)..וכו החימצ ,עבצ,םקרמ( הדירי ( הימרתופיה ,)ףוגה תרוטרפמטב

:תורידנ יאוול תועפות

תוליעפ ,תרבגומ תירוטומוכיספ דימל תוערפה

העיגפ הליל תובטרה ,רבגה תוירופב ןתש ןתמב הטילש רסוח וא

הילכ תויעב

הכיפה היצנמד

בשק תוערפה

אקה ,תו יבאכ ןתש םע םירבסומ אל םירירש ההכ

קוריפ ,סיזילוימודבר( )רירש תמקר

אל תוחיכשב יאוול תועפות :העודי

ןובאיתב היילע

הילע

ןתש תלטהל ךרוצב

תוערפה תכרעמב

כיעה לו

םינבל םד יאת גוסב םיליפוניזואא(

הרזומ תוגהנתה

םא דחוימב םע בולישב תחקלנ וז הפורת וז הפורת ןונימ םא וא לטיברבונפ וה .ימואתפ ןפואב הלע

וא תורובח לש תינאטנופס העפוה .םד תשירקב תויעב ,םימומיד

:תופסונ תוירשפא יאוול תועפות

תינפוג תוחתפתהב תוערפהו םידלומ םימומ )"הקנהו ןוירה" קרפ האר( תישפנו

:תופסונ יאוול תועפות

דואמ תוחיכש יאוול תועפות

(very common)

ב תועיפומש יאוול תועפות דחא שמתשממ רתוי :הרשעמ

תוליחב ,דער

תוחיכש יאוול תועפות

(common)

תועפות ב תועיפומש

ךותמ םישמתשמ

הדירי

תריפסב

יאת

םד

םימודא

)הימנא

תויסטו

(Thrompocytopenia)

היילע

לקשמב

( תירוטומ םיבצע תכרעמב תוערפה תושקונ ,דער :םיללוכ םינימסתה ילה יישקו םייפג יתלב םימעפל ,)הכ .תויכפה קלחב

םירקמהמ

תועפות

תויומד

ןוסניקרפ

תולוכי

תויהל

תוכיפה

תוינונשי

תרוחרחס

העיגפ

ןורכיזב

יבאכ

שאר

תועונת

תוריהמ

אלו

תוינוצר

םייניעב

םיסוכרפ

תושריח

תליחתב

לופיטה

לושלש

תואקה

יבאכ

ןטב

תויעב

םייכינחב

דחוימב

תלדגה

לדוג

ייכינחה

(gingival

hyperplasia )

םיבאכ

תוחיפנו

הפב

םיעצפ

תשוחתו

הבירצ

(stomatitis)

תושיגר

רתי

תרישנ

רעיש

תומר

תוכומנ

לש

ןרתנ

םדב הימרתנופיה(

ןימסת

לש

השרפה

אל

הניקת

לש

antidiuretic hormone

םיבאכ

םישק

ןמזב

רוזחמ

לובלב

היאר( תויזה

וא

העימש

לש

םירבד

אלש

םימייק

תונפקות

תונבצע

תוערפה

בשק

העיגפ

תידבכ

םומיד

תוחיכש ןניאש יאוול תועפות

(Uncommon)

ב תועיפומש תועפות

ךותמ םישמתשמ

ללכ ךרדב תופלוח ולא תועפות תפוקת רחאל רצק ןמז ךות .רישכתל תולגתסהה

תוכשמתמ ןהש הדימב םלוא .אפורל י/הנפ ,דרטמ תווהמ וא

ןיב תובוגתו יאוול תועפות :תוקוניתו םידליב תויתפורת

אפורל חוודל םירוהה לע ןכו יאוול תעפות לכ לע לפטמה תנתינה תפסונ הפורת לכ לע /דליל

וז הפורתב לופיטה ךשמב תחיקלמ ענמיהל םיכירצ םידלי ןיריפסא תוליכמה תופורת

)תיליצילס ליטצא הצמוח(

םייתנש ליגל תחתמ תוקונית הפורתמ רתוי םילטונה םידליו ויהי םיסוכרפה דגנכ תחא חתפל תרבגומ היטנ ילעב .תויניצר יאוול תועפות

יאוול תועפות ליעל האר רת ןיב תובוגתו תויתפו .וטרופש תורהזא /תודחוימ

יאוולה תועפותמ תחא םא לבוס התא רשאכ וא ,הרימחמ הרכזוה אלש יאוול תעפותמ םע ץעייתהל ךילע ,ןולעב .אפורה

1000

תיללכ( םד תוירודכ תריפסב הדירי )תונבל תוירודכו

העיגפ

תונרעב

הלוכיש

חתפתהל

תמדרתל

תינמז

םע

הגיסנ

רחאל

תתחפה

ןונימה

וא

קספה

לופיטה

היתפולפצנא

תשוחת

לומינ

ץוצקע

םייפגב

םיישק

ןורכנסב

תועונת

יישק

המישנ

םיבאכו

בקע

תקלד

לש

תומקר

תונגמ

תואירב

(pleural

effusion )

החירפ

לע

רועה

תויעב

רעישב

םייוניש(

הנבמב

רעישה

עבצב

רעיש

וא

תחימצב

)רעיש

וחווד

םירקמ

לש

העיגפ

תילובטמ

תומצעב

ומכ

צע תומ

תוכפוהש

תויהל

תוריבש

רתוי

הינפואטסוא(

תסמב הדירי

םצעה

)סיזורופאוטסא(

םירבשו

ץועייה

אפורב

וא

חקורה

םא

התא

לטונ

לופיט

ךורא

חווט

םע תופורת

יטנא

תויטפליפא

םא

לבוס

וא

תלבס

רבעב

סיזורופואטסואמ

וא

םא

התא

לטונ

םידיאורטסוקיטרוק

םזינגורדנארפיה

םינימסת(

ללוכ םי

רועיש

רתי

תוחתפתה

םינייפאמ

םיירבג

לצא

השיא

הנקא

תרישנ רעיש

תירבג

תיילעו

תומר

ןגורדנא

הדירי

םוחב

ףוג

הימרתופיה

תוקצב

אל

תורומח

םייפגב

רדעיה

תסוו

תקלד

ילכב

םדה

תורידנ יאוול תועפות

(rare)

תועיפומש תועפות , דעב

ךותמ םישמתשמ

1000

לשכ

דוקפתב

חמ

עה םצ

ללוכ

הדירי

תוריפסב

יאת

םד

םימודא

,םינבלו

הימנא

.( macrocytic)

הדירי

ימרוגב

השירק

םימרוגה

תוקידבל

השירק

ןניאש

תוניקת

ןוגכ

תכראה

ןמז

ןיבמורטורפה

ןמזו

.(INR

רסח

תומרב

ןימטיו

ןיטויב

זאדיניטויב

היצנמד

תוערפהו

תויביטינגוק

תועיפומש

הגרדהב

תוגיסנו

פסמ

תועובש

דע

רפסמ

םישדוח

ירחא

לופיטה תקספה

תויעב

הילכ

םיישק

וא

רסוח

תלוכי

הטילש

ןתמב

ןתש

תובטרה(

תובטרהו

)הליל

קזנ

תוילכל

(tubulointerstitial

nephritis )

הבוגת

וטוא

תינומיא

םע

םיבאכ

םיקרפמב

החירפ

תירוע

םוחו

(systemic lupus

erythematosus )

יבאכ

םירירש

תשלו

םירירש

הלוכיש

תויהל

השק

(rhabdomyolysis)

תת

תוליעפ

תטלב

סירתה

העיגפ

חומב

םצעה

גוסמ

Myelodysplastic syndrome

תולחש

תויטסיצילופ

העיגפ

תוירופב

רבגה

תוליעפ

תירוטומוכיספ

תרבגומ

תוערפה

הדימל

תוגהנתה

אל

הניקת

לכב

הרקמ

ובש

ךנה

שיגרמ

תועפות

יאוול

אלש

יוצ ונ

ןולעב

הז

םא

תעפות

יאוול

הווהמ

דרטמ

וא

הרימחמ

וא

לח םא

יוניש

ךתשגרהב

תיללכה

ךילע

ץעייתהל

םע

אפורה

דימ

ןתינ

חוודל

לע

תועפות

יאוול

דרשמל

תואירבה

תועצמאב

ספוטה

ןווקמה

חווידל

לע

תועפות

יאוול

אצמנש

ףדב

תיבה

לש

רתא

דרשמ

תואירבה

www.health.gov.il

וא

"

סינכ

רושיקל

https://forms.gov.il/globaldata/getseq

uence/getsequence.aspx?formType=

AdversEffectMedic@moh.gov.il

@moh.gov.il

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו בוהצ עקר לע

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב(

ו יתוהמ ןכות קר ןמסל שי .הנוש עבצב םוקימב םייוניש אל .טסקטה

..........ךיראתב ינורטקלא ראודב רבעוה

1111111/11

......

תוכיאה תדועת ,םושירה תדועת( םושירה יאנת םע דחא הנקב םילוע םייונישה לכ

.)ינכדעה רישכתה יטרפ ספוטו

אות ,ןולעה תעצהב בותכה לכ .םושירה יאנת תא ם

ל ןולע םייק אפור .םאתהב ןכדועמ אוהו

:השקבל אתכמסא ןכרצל ןולעה ונורכ טפלפד רישכתל רשואמה

לארשי

.ב"צמ אתכמסאה

נה יונישה ב תואירבה תויושר ידי לע רשוא ל"

לארשי

חקורה ,ינא

_ תרבח לש הנוממה טצכ

תוישעת

תוימיכ

מ"עב ןיא יכ הזב ריהצמ_____ , םיפסונ םייוניש .ןולעה תעצהב ונמוסש הלא דבלמ

תימינפ הריתס םירצוי םניא םייונישה יכ ריהצמ ינא

ןולעב עדימב

)'וכו הרמחה ,היוותה תפסותל השקב תרגסמב ןולע ןוכדע :ןוגכ( תרחא תרגסמב ליבקמב לפוטמ אל הז ןולע

תרחא תרגסמב ליבקמ לופיט םייקו הדימב

.תאז ןייצל שי

:)המיתחו םש( הנוממה חקורה תמיתח

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