VALPORAL CAPSULES

Israel - English - Ministry of Health

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Active ingredient:
VALPROIC ACID
Available from:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
ATC code:
N03AG01
Pharmaceutical form:
CAPSULES
Composition:
VALPROIC ACID 200 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
Therapeutic group:
VALPROIC ACID
Therapeutic area:
VALPROIC ACID
Therapeutic indications:
Sole or adjunctive therapy in the treatment of simple (petit mal) and complex absence seizures. May also be used adjunctively in patients with multiple seizure types which include absence seizures.
Authorization number:
012 05 24232 00
Authorization date:
2010-11-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

03-01-2017

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

Valporal Capsules

The active ingredient and its quantity:

Each capsule contains:

Valproic acid 200 mg

For the list of inactive ingredients, please see section 6.

WARNING

Newborns of mothers who took valproic acid during pregnancy are

at higher risk of severe developmental disturbances )approximately

30% to 40% of the cases) and birth defects )approximately 11%

of the cases).

If you are a woman of child-bearing age or if you are pregnant, the

doctor will only prescribe valproic acid for you if other treatments

are not suitable.

Women of child-bearing age should use effective methods of

contraception during the course of treatment with this preparation.

Do not stop using the preparation before first consulting with the

attending doctor. If, despite use of contraception, you become

pregnant unplanned, refer to the attending doctor immediately in

order to discuss options for an alternative treatment, if possible.

In addition to the leaflet, Valporal also comes with a Patient

Information Card.

This card contains important safety information, which you must

know, before starting and during the course of treatment with

Valporal. Read the Patient Information Card and the patient leaflet

before starting treatment with the preparation. Keep the card for

later reference, if needed.

Read this leaflet carefully in its entirety before using the

medicine.

Keep this leaflet; you may need to read it again.

This leaflet contains concise information about the medicine. If you

have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others.

It may harm them even if it seems to you that their ailment is similar.

This medicine is not intended for children weighing less than

17 kg.

1. WHAT IS THE MEDICINE INTENDED FOR?

The medicine is an anticonvulsant, given to treat certain types of

epilepsy.

Therapeutic group: the active ingredient belongs to the group of

anticonvulsants.

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

You are sensitive )allergic) to the active ingredient or to any of the

ingredients in the medicine )see section 6 – “Further Information”)

You are sensitive to another medicine from the valproic acid group

)divalproate, valpromide)

You are suffering from a liver disease )such as severe or chronic

hepatitis, or if you are suffering from hepatic porphyria)

You, or someone from your family, has suffered, or is suffering,

from a severe liver disease, especially if it was caused by use of

medicines

You are taking mefloquine

You are taking St. John’s Wort for treatment of depression

In patients suffering from mitochondrial disorders, due to a

mutation in the POLG gene, such as Alpers-Huttenlocher

syndrome, and in children under the age of two who are suspected

to have disorders related to a mutation in the POLG gene

In patients suffering from urea cycle disturbances

Special warnings regarding use of the medicine:

∙ The medicine should not be given to young girls, teenage girls,

women of child-bearing age and pregnant women, unless

alternative treatments have been found unsuitable.

∙ Women of child-bearing age being treated with the medicine must

use effective methods of contraception. If a woman taking this

medicine is planning to become pregnant, she should consult

with the attending doctor regarding the possibility of switching

to an alternative treatment.

This medicine may cause a disturbance in blood count and

bleeding, and in very rare cases, cause liver )hepatitis) or pancreatic

)pancreatitis) diseases, which may be severe and life-threatening.

Your doctor will refer you to perform blood tests to assess liver

function, especially in the first 6 months of treatment. Consult the

doctor immediately if the following effects occur:

∙ Sudden tiredness, lack of appetite, exhaustion, drowsiness,

swelling of the legs, weakness.

∙ Recurrent vomiting, nausea, abdominal pain, jaundice )yellow

eyes or skin).

∙ Recurrence of epileptic seizures, even though you are taking the

medicine correctly.

Before treatment with Valporal, tell your doctor if:

∙ You suffer from impaired liver function.

∙ You suffer from an impairment of the blood system )e.g., coagulation

etc.).

∙ You suffer from a kidney disease )kidney failure).

∙ You suffer from systemic lupus erythematosus.

∙ You suffer from a metabolic disorder, especially a hereditary disorder

such as urea cycle disorder, associated with a lack of enzymes,

which may cause an increase in blood ammonia levels.

∙ You have a family history of epilepsy, developmental impairment,

neurological problems, severe migraines.

∙ You suffer from a deficiency of the carnitine palmitoyltransferase

)CPT) type II enzyme. In this case, there is an increased risk of

muscle breakdown when taking Valporal.

∙ Your child is taking another anti-epilepsy treatment or suffers from

a neurological or metabolic disease or severe forms of epilepsy.

∙ Before performing any type of surgery )dental work or emergency

treatment), inform the doctor that you are taking Valporal.

∙ Consult a doctor immediately if there is an increase in the frequency

of seizures, or if you are experiencing a different type of seizures.

∙ This medicine may cause weight gain. Consult your doctor regarding

methods of maintaining body weight.

∙ Taking anticonvulsants may increase the risk of suicidal actions or

thoughts. You and your family members must take note of mood

changes and changes in behavior and actions. Monitor signs

indicative of risk of suicide such as: talk or thoughts of wanting to

harm yourself, introversion and withdrawal from family and friends,

depression or worsening of pre-existing depression, preoccupation

with death, abandoning or giving away prized possessions. If such

thoughts occur, refer to a doctor immediately.

∙ Children under 3 years of age, especially those taking multiple

anti-epilepsy medicines, are at higher risk of: brain damage, mental

retardation, genetic metabolic degenerative disease.

∙ Long-term use of Valporal is associated with a reduction in bone

density, which may lead to osteoporosis, osteopenia and increased

risk of fractures.

∙ This medicine may cause a disturbance in blood count and bleeding.

The doctor will refer you to perform blood tests, including blood

count and coagulation function test, before and during the course

of treatment.

∙ A severe allergic reaction, including symptoms such as fever,

enlarged lymph nodes and involvement of other body systems,

with or without skin rash )called DRESS).

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

including non-prescription medicines and nutritional supplements,

tell the doctor or pharmacist. Do not take Valporal if you are taking

the following medicines:

∙ Mefloquine - a medicine to treat malaria

∙ St. John’s Wort - a herbal medicine to treat depression

Inform your doctor if you are taking lamotrigine )an additional medicine

for treatment of epilepsy) or medicines from the carbapenems group

)a group of antibiotics for the treatment of bacterial infections, such

as meropenem, imipenem, panipenem).

Avoid using medicines containing aspirin during the course of

treatment with the medicine, especially in children under 3 years

of age.

Inform the doctor or pharmacist if you are taking the following

medicines:

Medicines that affect the central nervous system such as:

Tranquilizers and hypnotics such as benzodiazepines

Medicines to treat Parkinson’s

Antidepressants )such as imipramine, monoamine oxidase

inhibitors)

Cold and cough medicines

Antiepileptics )such as phenobarbital, phenytoin, fosphenytoin,

carbamazepine, primidone, felbamate, topiramate, rufinamide)

∙ Antibiotics such as: aztreonam, rifampicin, erythromycin

∙ Vitamin K-dependent anticoagulants, such as warfarin

∙ Zidovudine, lopinavir, ritonavir – to treat patients with an HIV

infection

∙ Cimetidine – against gastric acidity

∙ Nimodipine – used for prevention of venous constriction during

cerebral bleeding

∙ Quetiapine, olanzapine – medicines for psychiatric illnesses

∙ Cholestyramine – a medicine to lower cholesterol

∙ Acetazolamide

Use of the medicine and food and alcohol consumption

If you are sensitive to any food or medicine, inform the doctor before

taking the medicine.

Drinking alcoholic beverages is not recommended during the course

of treatment with the medicine.

Swallow the medicine with or after food.

Pregnancy and breastfeeding

If you are a woman of child-bearing age, the doctor will only prescribe

this medicine for you if alternative treatments have been found

unsuitable.

∙ Valproic acid may be harmful to an unborn baby when taken during

pregnancy. The risk increases with the dosage, but exists at all

dosages.

Children exposed to valproic acid in utero are at high risk

for severe birth defects and developmental disturbances.

Birth defects which have been reported include spina bifida

)a developmental defect where the spine does not develop properly),

defects in the face, in the upper lip, palate and skull, defects in the

heart, kidneys, urinary tract and genitals, limb defects.

∙ It was observed that in women who take valproic acid, around 11

babies in every 100 are born with birth defects. This compares

to 2-3 babies among women in the rest of the population.

Approximately 30%-40% of preschool children whose

mothers took valproic acid during pregnancy may suffer

from developmental problems, such as: a delay in walking

and speech, memory disturbance, lower cognitive capacities,

language and speech difficulties.

∙ Autistic spectrum disorders are diagnosed more often )3-5 times)

in children who were exposed to valproic acid.

∙ There are some data indicating that children who were exposed

to valproic acid in utero are more likely to develop symptoms of

Attention Deficit Hyperactivity Disorder )ADHD).

Before administering the medicine, the doctor will explain to you the

possible risks to your baby in case of exposure to valproic acid during

pregnancy. If you decide later that you want to become pregnant, do

not stop taking the medicine before consulting with the attending

doctor and considering the possibility of switching the treatment,

if possible.

Consult with your doctor about taking folic acid while you are trying to

become pregnant. Taking folic acid before pregnancy can lower the risk

of spinal closure defects and early-stage miscarriages, which exists

with all pregnancies. Prevention of birth defects which may occur due

to use of valproic acid, by folic acid, has not been proven.

If this is the first time you were prescribed valproic acid, the doctor will

explain to you the possible risks to your baby in case of exposure to

valproic acid during pregnancy. If you are a woman of child-bearing

age, you must use effective contraceptive methods during the

course of treatment with the preparation. Consult with your

gynecologist regarding effective contraceptives.

Important points:

∙ Make sure you are using an effective method of contraception

∙ Tell your doctor immediately if you are pregnant or think you may

be pregnant

Continuing treatment with valproic acid when you are not planning

a pregnancy:

Make sure you are using effective methods of contraception

throughout the entire course of treatment with the preparation.

Consult with your gynecologist regarding effective methods of

contraception.

Important points:

∙ Make sure you are using effective methods of contraception

∙ Tell your doctor if you are pregnant or think you may be pregnant

If you are planning a pregnancy:

Do not stop using the preparation before consulting with the

attending doctor.

If possible, consult the attending doctor before you become pregnant

so as to reduce the risk to your baby. Your doctor may decide to lower

the dosage of valproic acid or switch you to another treatment before

you start to try to become pregnant.

If you become pregnant, you must be under close medical monitoring,

both due to your medical condition and to check the development

of the unborn baby.

Talk to your doctor about taking folic acid when you are trying to

become pregnant. Taking folic acid before pregnancy can lower the

risk of spinal closure defects and early-stage miscarriages, which

exists with all pregnancies. However, prevention of birth defects by

folic acid among women taking valproic acid has not been proven.

Important points:

∙ Do not stop using contraception before consulting with the doctor

and summarizing with him a plan for further treatment that will

enable control of the epilepsy and reduce the risk to the unborn

baby

∙ Tell the doctor if you are pregnant or think you may be pregnant

Unplanned pregnancy during treatment with valproic acid:

Children exposed to valproic acid in utero are at high risk for

severe birth defects and developmental disturbances. If you are

taking valproic acid and you think you may be pregnant, refer to the

doctor immediately.

Talk to your doctor about taking folic acid when you are trying to

become pregnant. Taking folic acid can lower the risk of spinal

closure defects and early-stage miscarriages, which exists with all

pregnancies.

However, prevention of birth defects by folic acid among women

taking valproic acid has not been proven.

Important points:

∙ Tell your doctor immediately if you are pregnant or think you may

be pregnant

∙ Do not stop taking valproic acid until your doctor instructs you to

do so

Make sure you read and understood the patient information provided

to you by the doctor. If you have questions, consult with the doctor

or pharmacist.

Breastfeeding

Do not breastfeed during treatment with Valporal, unless recommended

otherwise by the doctor. Consult a doctor or pharmacist before

starting treatment with any medicine.

Driving and operating machinery

Use of this medicine may impair alertness, especially if the medicine

is being taken concomitantly with other antiepileptics or medicines

that cause sleepiness.

If you experience this effect or if your epilepsy is still not under control

and you continue to suffer from seizures, do not drive or operate

dangerous machinery.

Children should be cautioned against riding a bicycle or playing near

the road, and the like.

Important information about some of the ingredients in this

medicine:

The capsules contain sodium.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by the doctor

only.

The doctor may recommend dividing the required dose to twice a

day. It is preferable to take the medicine at mealtimes.

Do not exceed the recommended dose.

This medicine is not intended for children weighing less than 17 kg.

Tests and follow-up:

Before starting treatment and in the first six months of treatment with

this medicine, blood and liver function tests, should be performed.

If you accidentally took a higher dosage or if a child has accidentally

swallowed the medicine, immediately refer to a doctor or proceed

to a hospital emergency room and bring the package of the medicine

with you.

You may suffer from the following effects: coma, muscle weakness,

reduced reflexes, constriction of the pupils, impaired respiration,

metabolic acidosis, decreased blood pressure and shock.

If you forgot to take this medicine at the scheduled time, do

not take a double dose. Take the next dose at the regular time and

consult the doctor.

Adhere to the treatment regimen as recommended by the doctor.

Use this medicine at set intervals, as determined by the attending

doctor.

If you stop taking Valporal

Do not stop taking Valporal without consulting with a doctor, even if

there is an improvement in your health.

Treatment termination must be done gradually.

If you stop taking Valporal instantly, or not in accordance with your

doctor’s instructions, you may be at increased risk of seizures.

Do not take medicines in the dark! Check the label and dose

each time you take medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult

the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Valporal may cause side effects in some

users. Do not be alarmed when reading the list of side effects. You

may not suffer from any of them.

Refer to a doctor immediately if you experience the following

side effects:

∙ This medicine can cause liver )hepatitis) or pancreatic )pancreatitis)

diseases, which may be severe and life-threatening. These effects

are uncommon and can begin suddenly with weakness, tiredness,

loss of appetite, exhaustion, sleepiness, which is sometimes

associated with vomiting and stomachache.

∙ In rare cases, the appearance of skin rash, sometimes accompanied

by blisters that may involve the mouth area )erythema multiforme),

blisters with separation of the skin that can quickly spread over

the entire body and be life-threatening )toxic epidermal necrolysis,

Stevens-Johnson syndrome).

∙ An allergic reaction including sudden swelling of the face and/or

neck that causes breathing difficulty and is life-threatening

)angioedema).

∙ Severe allergic reaction that includes symptoms such as fever, skin

rash, enlargement of the lymph nodes, kidney damage, abnormal

blood test results, such as an increase in a certain type of white

blood cells )eosinophils).

∙ Strange behavior - especially if this medicine is taken concomitantly

with phenobarbital or if the dosage of this medicine was suddenly

increased.

∙ Spontaneous appearance of bruises or bleeding, blood coagulation

problems.

Additional possible side effects:

∙ Birth defects and physical and mental developmental disturbances

)see “Pregnancy and breastfeeding” section).

Very common side effects )occur in more than one in ten users):

∙ Tremor

∙ Nausea

Common side effects )occur in 1-10 in 100 users):

∙ Reduced red blood cell )anemia) and platelet )thrombocytopenia)

counts

∙ Weight gain

∙ Motor nervous system disturbances )symptoms include: tremor,

limb stiffness and walking difficulties), sometimes irreversible. In

some cases, Parkinson-like effects can be reversible

∙ Sleepiness, dizziness, memory impairment, headaches

∙ Rapid and involuntary eye movements

∙ Seizures

∙ Deafness

∙ At the beginning of treatment: diarrhea, vomiting, abdominal pain

∙ Gum problems, especially gingival hyperplasia

∙ Pain and swelling in the mouth, sores and burning sensation

)stomatitis)

∙ Hypersensitivity, hair loss

∙ Low levels of blood sodium )hyponatremia, a symptom of abnormal

secretion of antidiuretic hormone)

∙ Severe pains during menstrual period

∙ Confusion, hallucinations )seeing or hearing things that do not exist),

aggressiveness, nervousness, attention disturbances

∙ Liver damage

∙ Bleeding

Uncommon side effects )occur in 1-10 in 1,000 users):

∙ Reduced blood cell count )general and white blood cells)

∙ Impaired alertness, that can develop into temporary coma, which

regresses after lowering the dosage or stopping treatment

∙ Encephalopathy

∙ Paresthesia/tingling sensation in the limbs

∙ Difficulty synchronizing movements

∙ Breathing difficulties and pains, due to inflammation of the lung

tissues )pleural effusion)

∙ Skin rash

∙ Hair problems )changes in the structure, color or growth of the

hair)

∙ Cases of metabolic impairment in the bones, e.g., bones that

become more fragile )osteopenia), loss of bone mass )osteoporosis)

and fractures, have been reported. Consult a doctor or pharmacist

if you are on long-term treatment with antiepileptics, if you suffer

from osteoporosis or if you are taking corticosteroids

∙ Hyperandrogenism )symptoms include excessive hairiness,

development of male traits in women, acne, male balding and

increased androgen levels)

∙ Decreased body temperature )hypothermia)

∙ Edema in the limbs that is not severe

∙ Amenorrhea

∙ Inflammation of the blood vessels

Rare side effects )occur in less than 1 in 1,000 users):

∙ Bone marrow function failure, including decreased red and white

blood cell count, anemia )macrocytic anemia)

∙ Decrease in coagulation factors, causing abnormal coagulation test

results )such as: prolonged prothrombin and INR times)

∙ Vitamin biotin/biotinidase deficiency

∙ Dementia and cognitive disorders that occur gradually and regress

a few weeks up to a few months after stopping treatment

∙ Kidney problems, difficulty or inability to control urination )wetting

and bed-wetting)

∙ Kidney damage )tubulointerstitial nephritis)

∙ Autoimmune response, with joint pain, skin rash and fever )systemic

lupus erythematosus)

∙ Muscle pain, muscle weakness that can be severe )rhabdomyolysis)

∙ Underactive thyroid gland

∙ Bone marrow damage of the myelodysplastic syndrome type

∙ Polycystic ovaries, impaired male fertility

∙ Increased psychomotor activity, learning disorders, abnormal

behavior.

If a side effect occurs, if any of the side effects worsen, or if

you are suffering from a side effect not mentioned in the leaflet,

consult the doctor.

Side effects can be reported to the Ministry of Health by clicking on

the link "Report Side Effects of Drug Treatment" found on the Ministry

of Health homepage )www.health.gov.il) that directs you to the online

form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?

formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicine should be

kept in a safe place out of the reach and sight of children and/or

infants in order to avoid poisoning. Do not induce vomiting without

an explicit instruction from the doctor.

∙ Do not use the medicine after the expiry date )exp. date) that

appears on the package. The expiry date refers to the last day of

that month.

Store in a dark place, below 25ºC. Keep the bottle tightly

closed.

The medicine can be used for up to 60 days after first opening the

bottle, but no later than the expiry date of the preparation.

∙ Do not discard medicines via the wastewater or waste bin. Ask the

pharmacist how to dispose of medicines no longer in use. These

measures will help protect the environment.

6. FURTHER INFORMATION

In addition to the active ingredient, each capsule also contains:

Sorbitol, mannitol, glycerol, gelatin, sodium propyl hydroxybenzoate,

sodium ethyl hydroxybenzoate, titanium dioxide, FD&C Blue No.1,

90%.

The capsules contain sodium.

What the medicine looks like and what are the contents of the

package:

∙ Oval, soft, blue capsule, containing a clear light yellow liquid,

imprinted with “TEVA” on one side.

∙ The marketed package contains 40 capsules.

Manufacturer and address:

Teva Pharmaceutical Industries Ltd., P.O.B. 3190, Petach Tikva.

This leaflet was checked and approved by the Ministry of Health in

March 2016.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health:

012.05.24232.00/01

VALP CAPS PL SH 090616

VALP CAPS PL SH 090616

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This leaflet format has been determined by the Ministry of Health and the content thereof

has been checked and approved on Mar 2016.

PRESCRIBING INFORMATION

1. NAME OF THE MEDICINAL PRODUCT

Valporal Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

Valproic acid 200 mg

3. PHARMACEUTICAL FORM

Capsules

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Sole or adjunctive therapy in the treatment of simple (petit mal) and complex absence seizures.

May also be used adjunctively in patients with multiple seizure types which include absence seizures.

4.2 Posology and method of administration:

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

Valporal 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 Valporal 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.

Valporal 200 mg capsules are not suitable for children under the age of 6 years (due to 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 interindividual 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

Initiation of Valporal 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 stepwise 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

Valporal 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 Valporal 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 Valporal 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:

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

teratogenic risks and the risks of neuro-developmental disorders.

2. The need to use effective contraception.

3. The need for regular review of treatment.

4. 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:

Valporal Syrup contains 30 mg of sodium per 5 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 (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 co-administration 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 is needed. 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:

Valporal 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

Valporal 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)

Valporal 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 to the neonate

Exceptional cases of hemorrhagic syndrome have been reported in 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. 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 as, in particular, agitation, irritability, hyper-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 Valporal 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 the dosage of this medicinal product usually leads to

resolution of thrombocytopenia.

Uncommon: pancytopenia, leucopenia

Rare: bone marrow aplasia or pure red 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 4.4 and 4.6), 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

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

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

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedi

c@moh.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 muscle 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

slow wave 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 remaining 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 metabolism by glucuronic conjugation and

beta oxidation.

Valproate is dialyzable, but hemodialysis affects only the unbound fraction of plasma valproate

(about 10%).

Valproate is 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 degradation, nor that of

other substances, such as estrogen, progestogens and oral anticoagulants.

6. PHARMACEUTICAL PARTICULARS

6.1 Excipients

Sorbitol, mannitol, glycerol, gelatin, sodium propyl hydroxybenzoate, sodium ethyl hydroxybenzoate,

titanium doxide, FD&C Blue No.1, 90%

6.2 Special precautions for storage

Store in a dark place below 25°C

Make sure the package will always be tightly closed

After first opening of the bottle the product may be used for up to 60 days but no later than the

expiry date.

7. PRESENTATION

Bottle of 40 capsules

8. MANUFACTURER

Teva Pharmaceutical Industries Ltd,.

P.O.Box 3190, Petach Tikva.

Registration Number: 012-05-24232

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

עדימ עדימ עדימ ןכרצל ןולעב )תוחיטב ןכרצל ןולעב )תוחיטב ןכרצל ןולעב )תוחיטב

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

ךיראת

ראוני

2016

תילגנאב רישכת םש

םושירה רפסמו

Valporal capsules 200 mg

012.05.24232

םושירה לעב םש

.ד.ת ,מ"עב תויטבצמרפ תוישעת עבט

3110

הווקת חתפ ,

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ןולעב קרפ

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הרהזא

תושק תויתוחתפתה תוערפהל רבגומ ןוכיסב םיאצמנ ןויריהה ךלהמב טאורפלאו ולטנש תוהמיאל םידולי כ(

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.)םירקמהמ

קר טאורפלאו ךל םושרי אפורה, ןויריהב התא םא וא תוירופה ליגב השיא התא םא םירחא םילופיט םא .םימיאתמ םניא

תא קיספהל ןיא. הז רישכתב לופיטה ךלהמב םיליעי העינמ יעצמאב שמתשהל תוירופה ליגב םישנ לע ,העינמ יעצמאב שומישה תורמלו הדימב. לפטמה אפורה םע תמדקומ תוצעוויה אלל רישכתב שומישה לע לפטמה אפורל ידיימ ןפואב ינפ, ןנכותמ אל ןוירהל תסנכנ תדימב יפולח לופיטל תויורשפאב ןודל תנמ .רשפאה

.תלפוטמל עדימ ןורפס םייק לרופלאו רישכתל, ןולעל ףסונב

לרופלאוב לופיטה ךלהמבו לופיטה תלחתה ינפל, תעדל ךילעש, בושח יתוחיטב עדימ ליכמ הז ןורפס שי. רישכתב שומישה תליחת םרטב ןכרצל ןולעבו תלפוטמל עדימ ןורפסב ןייעל שי.

תא רומשל .ךרוצה תדימב ףסונ ןויעל ןורפסה

.הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק

תודחוימ תורהזא שומישל תועגונה :הפורתב

:םא הפורתב שמתשהל ןיא

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

לבוסה םילוחב ןגב היצטוממ האצותכ ,תילאירדנוכוטימ תוערפהמ םי

POLG

תנומסתמ לשמל ,

Huttenlocher

Alpers

םייתנש ליגל תחתמ םידליבו

POLG

:הפורתב שומישל תועגונה תודחוימ תורהזא

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

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

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

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

םינושאר םישדוח

:תואבה תועפותה ועיפוה םא דימ אפורב ץעוויהל ךילע .לופיטה לש

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

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

.ןוכנ הפורתה תא לטונ התאש תורמל ,םייטפליפא םיפקתה לש הרזח

:םא ךאפורל רפס ,לרופלאוב לופיטה ינפל

דבכה דוקפתב יוקילמ לבוס התא

ק ןוגכ( םדה תכרעמב יוקילמ לבוס התא )'וכו השיר

.)תוילכ תקיפס יא( תוילכ תלחממ לבוס התא

תיתנמדא תבאזמ לבוס התא

Systemic Lupus Erythematosus

ומכ תיתשרות הערפה דוחיב ,תילובטמ הערפהמ לבוס התא

Urea cycle disorder

הרושקה םדב הינומאה תומר תיילעל םורגל הלולעש םימיזנאב רסוחל

סיה ךלש החפשמב שי תונרגימ, תויגולורינ תויעב, תיתוחתפתה העיגפ, היספליפא לש הירוט תושק

םיזנאב רסחמ לבוס התא

carnitine palmitoyltransferase (CPT) type II

םייק הז הרקמב . .לרופלאו םילטונשכ רירש קוריפל רבגומ ןוכיס

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

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

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

שמב היילעל םורגל הלולע וז הפורת לע הרימש תוטיש יבגל ךאפורב ץעוויה .לק

.ףוג לקשמ

לעו ךילע .תוינדבוא תובשחמ וא תולועפל ןוכיסה תא ריבגהל הלולע תותיווע דגנ תופורת תליטנ םינמיס ירחא בוקעל שי .םישעמבו תוגהנתהה יסופדב ,חורה בצמב םייונישל בל םישל ךתחפשמ ינב וביד :ןוגכ תודבאתהל ןוכיס לע םידיעמה ךמצע ךותב תוסנכתה ,ךמצעל קיזהל ןוצר לע תובשחמ וא םיר וא הרקפה ,תוומה אשונב תוקסעתה ,םייק ןואכידב הרמחה וא ןואכיד ,םירבחו החפשממ תוקחרתהו .דימ אפורל תונפל שי ,הז גוסמ תובשחמ תועיפומו הדימב .ךרע ירקי םיסכנ לש הריסמ

ליגל תחתמ םידלי

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

genetic metabolic degenerative disease

תילובטמ הלחמ( .)תיתשרות תינווינ

תליחת ינפל ךתוא הנפי אפורה, םימומידלו םד תריפסב הערפהל םורגל הלולע וז הפורת תוקידב עוציבל וכלהמב םגו לופיטה .השירק ידוקפת תקידבו םד תריפס וללכיש םד

לש תוברועמו הפמיל תוטולב תלדגה, םוח ןוגכ םינימסת תללוכה הפירח תיגרלא הבוגת הנוכמ( תירוע החירפ ילב וא םע, תופסונ ףוג תוכרעמ

DRESS

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

תכרעמ לע תועיפשמה תופורת

ןוגכ תיזכרמה םיבצעה

םיניפזאידוזנב ומכ הנישלו העגרהל תופורת

ןוסניקרפב לופיטל תופורת

)זדיסקואנימאונומ יבכעמ ,ןימארפימיא ןוגכ ןואכד דגנ תופורת

תוננטצהו לועיש דגנ תופורת

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

ןיצימורתיריא ,ןיציפמאפיר ,םנוארטזא :ןוגכ תוקיטויבטנא

ןימטיו ייולת השירק ידגונ

ןירפרוו ןוגכ ,

ריבנוטיר ,ריבניפול ,ןידופודיז

םוהיז םע םילוחב לופיטל

ןידיטמיס

.הביקב תויצמוח דגנ

ןיפידומינ

ד תעב םידירו תורציה דגנ שמשמ יחומ םומי

ןיפזנלוא, ןיפאיטווק

תוירטאיכיספ תולחמב לופיטל

ןימארטסלוכ

לורטסלוכ תדרוהל הפורת

דימלוזוטצא

הקנהו ןוירה

ואצמנ םייפולח םילופיט םא קר וז הפורת ךל םושרי אפורה, תוירופה ליגב השיא ךנה םא

.םימיאתמ יתלב

זב חקלנ רשאכ רבועל קיזהל לולע טאורפלאו לכב םייק ךא ,ןונימה םע הלוע ןוכיסה. ןויריה ןמ .םינונימה

םישק םידלומ םימומל הובג ןוכיסב םיאצמנ םחרב תיאורפלוו הצמוחל ופשחנש םידלי םיללוכ וחוודש םידלומ םימומ .תויתוחתפתה תוערפהלו

spina bifida

הרדשה דומע וב יתוחתפתה םגפ , ינפב םימומ, )הניקת הרוצב חתפתמ וניא תכרעמב ,תוילכב ,בלב םימומ ,תלוגלוגבו ךחב ,הנוילע הפשב, ם .םייפגב םימגפ ,ןימה ירביאבו ןתשה

ךרעב תיאורפלוו הצמוח תולטונש םישנ לצא יכ אצמנ

ךותמ תוקונית

םימגפ םע םידלונ ל האוושהב תאזו ,םידלומ

.הייסולכואה ראשב תוקונית

ל ןגה ליגב םידלימ לובסל םילולע ,ןויריה ךלהמב תיאורפלוו הצמוח ולטנש תוהמיא םיישק ,רתוי הכומנ תילכש תלוכי ,ןורכיזב הערפה ,רובידו הכילהב בוכיע :ןוגכ ,תויתוחתפתה תויעבמ .רובידבו הפשב

יפ( רתוי תובורק םיתיעל תונחבואמ יטסיטואה םורטקפסהמ תוערפה

ופשחנש םידלי לצא ) פלוו הצמוחל . תיאור

רתוי םיטונ םחרב תיאורפלוו הצמוחל ופשחנש םידליש םיארמה םימיוסמ םינותנ םימייק

ADHD

זוכירו בשק תוערפה לש םינימסת חתפל )

הצמוחל הפישח לש הרקמב ךקוניתל םיירשפאה םינוכיסה תא אפורה ךל ריבסי ,הפורתה ןתמ םרט ךשמהב יטילחתו הדימב .ןויריהה ךלהמב תיאורפלוו

קיספהל ןיא ,ןויריהל סנכיהל ךנוצרב יכ

תא לוטיל לופיטה תפלחהל תורשפא תניחבו לפטמה אפורה םע תוצעייתה םרט ,הפורתה

.רשפאה תדימב

הצמוח תליטנ .ןויריהל סנכיהל הסנמ תאש ןמזב תילופ הצמוח תליטנ יבגל ךלש אפורה םע יצעייתה ימגפל ןוכיסה תא ןיטקהל הלוכי ןויריה ינפל תילופ רשא םדקומ בלשב תולפהו הרדשה דומע תריגסב ם תרזעב תיאורפלוו הצמוח תליטנמ האצותכ רצוויהל םילולעה םידלומ םימגפ תעינמ. תונוירהה לכב םייק .החכוה אל תילופ הצמוח

ךקוניתל םיירשפאה םינוכיסה תא ךל ריבסי אפורה ,תיאורפלוו הצמוח ךל ומשרש הנושאר םעפ וז םא הפישח לש הרקמב ךילע ,תוירופה ליגב השיא ךנהו הדימב .ןויריהה ךלהמב תיאורפלוו הצמוחל יעצמא יבגל ךלש םישנ אפור םע יצעייתה .רישכתב לופיטה ךלהמב םיליעי העינמ יעצמאב שמתשהל .םיליעי העינמ

:תובושח תודוקנ

םיליעי העינמ יעצמאב תשמתשמ תאש יאדוו

ןויריהב תא םא ידימ ןפואב אפורל ירפס

ןויריהב תויהל היושע תאש תבשוח וא

ןויריה תננכתמ אל תאשכ טאורפלוב לופיט ךשמה

.רישכתב לופיטה תפוקת לכ ךלהמב םיליעי העינמ יעצמאב תשמתשמ תא יכ יאדוו

.םיליעי העינמ יעצמא יבגל ךלש םישנה אפור םע יצעייתה

:תובושח תודוקנ

םיליעי העינמ יעצמאב תשמתשמ תאש יאדוו

רפס ןויריהב תויהל היושע תאש תבשוח וא ןויריהב תא םא אפורל י

:ןוירה תננכתמ ךנהו הדימב

.לפטמה אפורה םע תוצעייתה םרט רישכתב שומישה תא קיספהל ןיא

.ךקוניתל ןוכיסה תא ןיטקהל תנמ לע ,רשפאה תדימב ןוירהל הסינכה םרט לפטמה אפורה םע ץעוויהל שי יטקהל טילחהל יושע ךלש אפורה ינפל רחא לופיטל ךריבעהל וא תיאורפלוו הצמוח לש ןונימה תא ן .תורהל תוסנל יליחתתש

תא קודבל תנמ לע םגו יאופרה ךבצמ לשב םג דומצ יאופר חוקיפב תויהל ךילע ,ןויריהל תסנכנ םא .רבועה תוחתפתה

צמוח תליטנ .ןויריהל סנכיהל הסנמ תאשכ ,תילופ הצמוח תליטנ לע ךלש אפורה םע ירבד ינפ תילופ ה לכב םייק רשא, םדקומ בלשב תולפהו הרדשה דומע תריגסב םימגפל ןוכיסה תא ןיטקהל הלוכי ןויריה .החכוה אל תיאורפלוו הצמוח תולטונה לצא תילופ הצמוח תרזעב םידלומ םימגפ תעינמ ךא .תונוירהה

:תובושח תודוקנ

רה םע תצעייתמ תאש ינפל העינמ יעצמאב שמתשהל יקיספת לא תינכת דחי ותא תמכסמו, אפו .רבועל ןוכיסה תא ןיטקהלו היספליפאה לע טולשל רשפאיש לופיט ךשמה

ןויריהב תויהל היושע תאש תבשוח וא ןויריהב תא םא אפורל ירפס

טאורפלאוב לופיטה ןמזב ןנכותמ אל ןויריה

הלו םישק םידלומ םימומל הובג ןוכיסב םיאצמנ םחרב טאורפלול ופשחנש םידלי םא .תויתוחתפתה תוערפ .דימ אפורל ינפ, ןויריהב תויהל היושע תאש תבשוח תאו טאורפלו תלטונ תא

ינפל תילופ הצמוח תליטנ .ןויריהל סנכיהל הסנמ תאשכ ,תילופ הצמוח תליטנ לע ךלש אפורה םע ירבד ק רשא, םדקומ בלשב תולפהו הרדשה דומע תריגסב םימגפל ןוכיסה תא ןיטקהל הלוכי ןויריה לכב םיי .םויה דע החכוה אל טאורפלו תולטונה לצא תילופ הצמוח תרזעב םידלומ םימגפ תעינמ ךא .תונוירהה

:תובושח תודוקנ

ןויריהב תויהל היושע תאש תבשוח וא ןויריהב תא םא דימ אפורל ירפס

תאז תושעל ךל הרוי אל אפורהש דע טאורפלו תליטנ תא יקיספת לא

תא תנבהו תארקש יאדוו

וא אפור םע יצעייתה תולאש לש הרקמב .אפורה י"ע ךל ןתינש תלפוטמל עדימה חקור

:יאוול תועפות

:תואבה יאוולה תועפות תא הווח התא םא אפורל דימ תונפל שי

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

ברעל תולולעש תויחופלש תעפוהב םיתעל הוולמה ,רועה לע החירפ תעפוה, םירידנ םירקמב ( הפה רוזא תא

erythema multiforme

ה םע תויחופלש תעפוה ,) סרפתהל הלוכיש רועה תודרפי םייח ןכסלו ףוגה לכ ינפ לע תוריהמב

Johnson syndrome

Toxic epidermal necrolysis, Steven

המישנב ישוקל תמרוגש ראווצה וא/ו םינפה לש תימואתפ תוחיפנ תללוכה תיגרלא הבוגת )המדאויגנא( םייח תנכסמו

כ םינימסת תללוכה הפירח תיגרלא הבוגת העיגפ ,הפמיל תוטולב תלדגה ,תירוע החירפ ,םוח ןוג )םיליפוניזואא( םינבל םד יאת גוסב היילע ןוגכ ,תוניקת ןניאש םד תוקידב תואצות ,תיתיילכ

הרזומ תוגהנתה

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

לש תינאטנופס העפוה

.םד תשירקב תויעב ,םימומיד וא תורובח

:תופסונ תוירשפא יאוול תועפות

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

דואמ תוחיכש יאוול תועפות

-

:הרשעמ דחא שמתשממ רתויב תועיפומש יאוול תועפות

דער

תוליחב

תוחיכש יאוול תועפות

-

תועיפומ

ב

-

1-11

ךותמ םישמתשמ

111

:

)הימנא ( םימודא םד יאת תריפסב הדירי תויסטו

הינפוטיצובמורט

לקשמב היילע

,)הכילה יישקו םייפג תושקונ ,דער :םיללוכ םינימסתה( תירוטומ םיבצע תכרעמב תוערפה יהל תויושע תולוכי ןוסניקרפ תויומד תועפות םירקמהמ קלחב .תוכיפה יתלב םימעפל .תוכיפה תו

תוינונשי

, תרוחרחס, .שאר יבאכ, ןורכיזב העיגפ

םייניעב תוינוצר אלו תוריהמ תועונת

םיסוכרפ

תושריח

ןטב יבאכ ,תואקה ,לושלש :לופיטה תליחתב

( םייכינחה תלדגה דחוימב, םייכינחב תויעב

gingival hyperplasia

הבירצ תשוחתו םיעצפ, הפב תוחיפנו םיבאכ

stomatitis

רעיש תרישנ ,רתי תושיגר

לש הניקת אל השרפה לש ןימסת ,הימרתנופיה( םדב ןרתנ לש תוכומנ תומר

antidiuretic

hormone

רוזחמ ןמזב םישק םיבאכ

.בשק תוערפה ,תונבצע ,תונפקות ,)םימייק אלש םירבד לש העימש וא היאר( תויזה ,לובלב

תידבכ העיגפ

םומיד

ת

תוחיכש ןניאש יאוול תועפו

-

ב תועיפומ

-

1-11

ךותמ םישמתשמ

1111

:

)תונבל תוירודכו תיללכ( םד תוירודכ תריפסב הדירי

תקספה וא ןונימה תתחפה רחאל הגיסנ םע ,תינמז תמדרתל חתפתהל הלוכיש ,תונרעב העיגפ לופיטה

היתפולפצנא

םייפגב ץוצקע /לומינ תשוחת

ת ןורכנסב םיישק תועונ

תואירב תומקר לש תקלד בקע ,םיבאכו המישנ יישק

pleural effusion)

רועה לע החירפ

.)רעיש תחימצב וא רעיש עבצב, רעישה הנבמב םייוניש( רעישב תויעב

רתוי תוריבש תויהל תוכפוהש תומצע ומכ, תומצעב תילובטמ העיגפ לש םירקמ וחווד

צעה תסמב הדירי ,)הינפואטסוא( לטונ התא םא חקורה וא אפורב ץועייה .םירבשו )סיזורופאוטסא( ם התא םא וא סיזורופואטסואמ רבעב תלבס וא לבוס םא ,תויטפליפא יטנא תופורת םע חווט ךורא לופיט .םידיאורטסוקיטרוק לטונ

,הנקא ,השיא לצא םיירבג םינייפאמ תוחתפתה, רתי רועיש םיללוכ םינימסת( םזינגורדנארפיה שנ .)ןגורדנא תומר תיילעו תירבג רעיש תרי

)הימרתופיה( ףוג םוחב הדירי

םייפגב תורומח אל תוקצב

תסוו רדעיה

םדה ילכב תקלד

תורידנ יאוול תועפות

-

מ תוחפב תועיפומ

1

ךותמ םישמתשמ

1111

:

( הימנא ,םינבלו םימודא םד יאת תוריפסב הדירי ללוכ םצעה חמ דוקפתב לשכ

ytic

macroc

anemia

ןיבמורטורפ ןמז תכראה :ןוגכ( תוניקת ןניאש השירק תוקידבל םימרוגה השירק ימרוגב הדירי ה ןמזו

זאדיניטויב/ ןיטויב ןימטיו תומרב רסח

םישדוח רפסמ דע תועובש רפסמ תוגוסנו הגרדהב תועיפומש תויביטינגוק תוערפהו היצנמד .לופיטה תקספה ירחא

תויעב הילכ )הליל תובטרהו תובטרה( ןתש ןתמב הטילש תלוכי רסוח וא םיישק ,

( תוילכל קזנ

tubulointerstitial nephritis

וטוא הבוגת

( םוחו תירוע החירפ ,םיקרפמב םיבאכ םע ,תינומיא

systemic lupus

erythematosus

( השק תויהל הלוכיש םירירש תשלוח, םירירש יבאכ

rhabdomyolysis

.סירתה תטלב תוליעפ תת

גוסמ םצעה חומב העיגפ

Myelodysplastic syndrome

רבגה תוירופב העיגפ ,תויטסיצילופ תולחש

.הניקת אל תוגהנתה ,הדימל תוערפה ,תרבגומ תירוטומוכיספ תוליעפ

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

ךיראת

אוני

2016

םושירה רפסמו תילגנאב רישכת םש

Valporal capsules 200 mg

012.05.24232

םושירה לעב םש

.ד.ת ,מ"עב תויטבצמרפ תוישעת עבט

3110

הווקת חתפ ,

ה טורפל דעוימ הז ספוט דבלב תורמחה

ןולעב קרפ

שדח טסקט

Contraindications

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)

4.4 Special

warnings and

special precautions

for use

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 Valporal

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 Valporal 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 Valporal 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:

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

teratogenic risks and the risks of neuro-developmental disorders.

2. The need to use effective contraception.

3. The need for regular review of treatment.

4. 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).

[…]

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 (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).

4.5 Interactions

with other

medicinal products

and other forms of

interaction

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.

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.

[…]

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.

[…]

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

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.

[…]

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).

Quetiapine

Co-administration of valproate and quetiapine may increase the risk of

neutropenia/leucopenia.

[…]

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.

4.8 Undesirable

effects

Investigations

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 4.4 and 4.6), Biotin deficiency/biotinidase

deficiency.

[…]

Respiratory, thoracic and mediastinal disorders

Uncommon: pleural effusion.

Gastrointestinal disorders

[…]

Common: gingival disorder (mainly gingival hyperplasia),

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

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

Endocrine disorders

Uncommon: …hyperandrogenism (hirsutism, virilism, acnea, androgenic alopecia, and/or

increase in androgen hormone levels)

Rare: hypothyroidism

Metabolism and nutrition disorders

Common: hyponatraemia

Rare: hyperammonaemia* (see section 4.4), obesity

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

Rare: myelodysplastic syndrome.

Reproductive system and breast disorders

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

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