Package leaflet: Information for the patient

ValproLEK 500, 500 mg, prolonged-release tablets
Natrii valproas
This medicinal product will be subject to additional monitoring. This will allow rapid
identification of new safety information. Patients can help by reporting any adverse
reactions that occur after using the medicine. For information on how to report adverse
reactions – see section 4.
WARNING
ValproLEK 500 used during pregnancy may harm the unborn child. Women of childbearing
potential must use an effective method of contraception (birth control) continuously throughout
the entire duration of ValproLEK 500 treatment. The treating physician will discuss this with the
patient, but patients should also follow the recommendations provided in section 2 of this leaflet.
Patients should contact their physician immediately if they plan to become pregnant or suspect
they are pregnant.
Do not stop taking ValproLEK 500 unless instructed by a doctor, as the patient's condition may
worsen.
Read the entire leaflet carefully before using this medicine
.

Keep this leaflet, as you may need to read it again.
If you have any further questions, consult your doctor or pharmacist.
This medicine has been prescribed for a specific individual only. Do not give it to others. This medicine may harm others, even if their symptoms are the same.
If any adverse effects occur in the patient, including any adverse effects not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of the leaflet:

What ValproLEK 500 is and what it is used for
Important information before taking ValproLEK 500
How to take ValproLEK 500
Possible side effects
How to store ValproLEK 500
Contents of the package and other information

1. What ValproLEK 500 is and what it is used for

ValproLEK 500 is a medicine used in the treatment of epilepsy and mania.
ValproLEK 500 is used in certain types of epilepsy, such as:
certain forms of brief loss of consciousness due to disturbances in brain function (petit mal),
sudden muscle jerks (myoclonus),
rhythmic convulsive seizures associated with muscle rigidity (grand mal),
mixed forms of the above-mentioned disorders,
convulsive seizures without accompanying muscle rigidity (atonic seizures).
ValproLEK 500 may also be used in epilepsy where other antiepileptic medicines have not been
sufficiently effective, such as:
epilepsy occurring without convulsions or muscle rigidity,
epilepsy with symptoms affecting perception and symptoms involving voluntary movements.
ValproLEK 500 may be used as monotherapy or in combination with other antiepileptic drugs.
ValproLEK 500 is used in the treatment of mania – a condition in which the patient feels extremely
excited, elated, agitated, enthusiastic, or hyperactive. Mania occurs in a disorder known as bipolar
affective disorder. ValproLEK 500 may be used when lithium cannot be administered.

2. Important information before using ValproLEK 500

When not to use ValproLEK 500
if the patient is allergic (hypersensitive) to sodium valproate and/or valproic acid or to
any of the other ingredients of the medicine (listed in section 6);
if the patient has liver or pancreas function disorders;
if the patient has metabolic disorders (including urea cycle disorders);
if the patient or a close relative previously had severe liver damage, especially related to taking medicines;
if the patient has a disease caused by impaired production of blood pigment (porphyria);
if the patient has a tendency to bleed;
if the patient has a genetic disorder causing mitochondrial dysfunction (e.g. Alpers-Huttenlocher syndrome).

Bipolar affective disorder

In bipolar affective disorder, ValproLEK 500 must not be used if the patient is pregnant.
In bipolar affective disorder, if the patient is of childbearing age, ValproLEK 500 must not be taken unless the patient uses an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500. Do not stop taking ValproLEK 500 or contraception unless discussed with the doctor. The treating physician will provide further guidance (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).

Epilepsy

In epilepsy, ValproLEK 500 must not be used if the patient is pregnant, unless no other therapy is effective.
In epilepsy, if the woman is of childbearing age, ValproLEK 500 must not be taken unless the patient uses an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500. Do not stop taking ValproLEK 500 or contraception unless discussed with the doctor. The treating physician will provide further guidance (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).

Warnings and precautions
SEE A DOCTOR IMMEDIATELY
Severe skin reactions have been reported with valproate treatment, including
Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema.
If the patient experiences any symptoms related to these severe skin reactions described in section 4, they should contact a doctor immediately.

Before using ValproLEK 500, discuss with the doctor or pharmacist if:
ValproLEK 500 is used in infants or children under 3 years of age with severe forms of epilepsy (especially in children with brain damage, intellectual disability, certain genetic disorders and/or diagnosed metabolic disorders), as there is an increased risk of liver toxicity during the first 6 months of treatment, particularly in very young children. The risk is higher when treatment is combined with other antiepileptic drugs;
the patient has kidney function disorders; the doctor may consider reducing the dose to lower blood levels of valproic acid;
the patient has inflammatory-like skin or internal organ diseases (systemic lupus erythematosus), as ValproLEK 500 may trigger or worsen the disease;
the patient has carnitine palmitoyltransferase (CPT) type II deficiency-related encephalopathy; during ValproLEK 500 treatment, there is an increased risk of muscle tissue breakdown with muscle cramps, fever, and reddish-brown discoloration of urine (rhabdomyolysis);
the patient previously had bone marrow damage;
the patient’s family has a genetic disorder causing mitochondrial dysfunction;
the patient ever experienced severe skin rash, skin peeling, blistering, and/or oral ulcers after taking valproate.

Consult the doctor if any of the above warnings currently apply to the patient or applied in the past.
If the patient experiences symptoms such as physical or mental fatigue, loss of appetite (anorexia), apathy, drowsiness, repeated vomiting, abdominal pain, recurrence or worsening of seizures and/or prolonged bleeding time during ValproLEK 500 treatment, contact the doctor immediately. These symptoms may indicate liver or pancreas inflammation or increased blood ammonia levels. For patients suspected of metabolic disorders, especially involving urea cycle enzymes, the doctor will order appropriate tests before starting treatment.

Due to the possibility of prolonged bleeding from wounds, inform the doctor or dentist about taking ValproLEK 500. If the patient is undergoing surgery or a dental procedure, or experiences spontaneous bruising or bleeding (see “Possible side effects”), the doctor will monitor blood cell counts.

If the patient taking ValproLEK 500 undergoes urine testing for ketones (substances produced when the body burns fat instead of sugar), test results may be unreliable due to this medicine.

If the patient’s body weight increases, especially at the beginning of treatment, inform the doctor. This may be a risk factor for polycystic ovary syndrome.
Weight gain may be due to increased appetite (see section 4 “Possible side effects”). Body weight should be monitored, and weight gain minimized.

In a small number of people taking antiepileptic drugs such as ValproLEK 500, thoughts of self-harm or suicide have occurred. If such thoughts occur, contact the doctor immediately.

Note
The tablet shell of ValproLEK 500 may be excreted in faeces.

Children and adolescents
Children and adolescents under 18 years of age:
ValproLEK 500 must not be used to treat mania in children and adolescents under 18 years of age.

ValproLEK 500 and other medicines
Inform the doctor about all medicines currently or recently taken, including those available without a prescription.

ValproLEK 500 and other medicines may interact, affecting their actions and the occurrence of side effects, so dose adjustments may sometimes be necessary. This includes, among others:
antipsychotics, monoamine oxidase inhibitors (MAO), antidepressants, and benzodiazepines (medicines used in psychiatric disorders). ValproLEK 500 may enhance the effects of these medicines;
phenobarbital (an antiepileptic medicine). Blood levels of phenobarbital may increase (especially in children);
primidone (an antiepileptic medicine). Blood levels of primidone and its side effects (such as drowsiness) may increase. This effect diminishes during long-term treatment;
phenytoin (an antiepileptic medicine). Blood levels of phenytoin (in its unbound form) may increase, leading to signs of overdose. This may particularly occur when clonazepam (an antiepileptic medicine) and valproic acid are used together in children;
carbamazepine (a medicine used to treat epilepsy and psychiatric disorders). Concurrent use of ValproLEK 500 may enhance carbamazepine’s toxic effects;
lamotrigine (an antiepileptic medicine). Combination therapy increases the risk of severe skin reactions, especially in children. Valproic acid may reduce lamotrigine metabolism in the body;
topiramate (an antiepileptic medicine);
zidovudine (a medicine used in HIV infections). Valproic acid may increase zidovudine blood levels;
other medicines used in epileptic seizures (antiepileptic drugs such as phenytoin, phenobarbital, and carbamazepine). These may reduce blood levels of valproic acid;
rifampicin (a medicine used to treat bacterial infections). It may reduce blood levels of valproic acid;
felbamate (an antiepileptic medicine). Concurrent use may increase blood levels of valproic acid and felbamate;
mefloquine (a medicine used to prevent and treat malaria). Seizures may occur during concurrent use with ValproLEK 500;
medicines that inhibit the activity of certain liver enzymes (such as cimetidine or erythromycin). These may increase blood levels of valproic acid;
carbapenem antibiotics (used to treat bacterial infections). These may reduce blood levels of valproic acid;
medicines containing quetiapine, as concurrent use with ValproLEK 500 may increase the risk of abnormal blood cell counts;
acetylsalicylic acid (a medicine used to thin the blood or relieve pain). Valproic acid may enhance its effects. Concurrent use in children under 3 years of age is not recommended due to the risk of liver damage;
valproate used with medicines such as acetylsalicylic acid, due to the possibility of increased blood valproate levels;
cholestyramine (a medicine that reduces cholesterol levels), as it reduces valproate absorption;
estrogen-containing preparations (including certain oral contraceptives), as reduced blood levels of valproate may occur; use of ValproLEK 500 should not affect the effectiveness of hormonal contraception (“the pill”);
metamizole (a medicine used to treat pain and fever);
clozapine (used to treat psychiatric disorders).

Other medicines that may affect ValproLEK 500 or whose effects may be altered by ValproLEK 500 include those containing the following active substances: protease inhibitors such as lopinavir and ritonavir (used in HIV infection treatment), nimodipine, and propofol (used in anaesthesia).

ValproLEK 500 with food and drink
Food
Tablets can be taken 1 hour before a meal or during a meal (but always in the same way), taken with plain water (do not use carbonated drinks). Food does not significantly affect medicine absorption.

Alcohol
Alcohol consumption is not recommended during ValproLEK 500 treatment due to the risk of seizures and enhanced alcohol effects.

Pregnancy, breastfeeding and fertility
Pregnancy
Important advice for women

Bipolar affective disorder

In bipolar affective disorder, ValproLEK 500 must not be used if the patient is pregnant.
In bipolar affective disorder, if the patient is of childbearing age, ValproLEK 500 must not be taken unless the patient uses an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500. Do not stop taking ValproLEK 500 or contraception unless discussed with the doctor. The treating physician will provide further guidance.

Epilepsy

In epilepsy, ValproLEK 500 must not be used if the patient is pregnant, unless no other therapy is effective.
In epilepsy, if the woman is of childbearing age, ValproLEK 500 must not be taken unless the patient uses an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500. Do not stop taking ValproLEK 500 or contraception unless discussed with the doctor. The treating physician will provide further guidance.

Risk of taking valproate during pregnancy (regardless of the condition for which valproate is used)
Contact the treating doctor immediately if the patient plans pregnancy or is pregnant.

Taking valproate during pregnancy carries risks. The higher the dose, the greater the risk, but no dose is risk-free.

Valproate may cause serious congenital malformations and affect the child’s development. Most commonly reported congenital malformations include: spina bifida (when spinal bones are not properly developed); facial and skull developmental defects; heart, kidney, urinary tract, and genital organ malformations; limb defects and multiple associated developmental abnormalities affecting several organs and body parts. Congenital malformations may cause disabilities, which can be significant.

Hearing disorders or deafness have been reported in children exposed to valproate in utero.
Developmental eye defects, together with other congenital malformations, have been reported in children exposed to valproate in utero. Eye developmental defects may affect vision.

The risk of giving birth to a child with congenital malformations requiring treatment is increased in patients taking valproate during pregnancy. Valproate has been used for many years, so it is known that in the group of children born to mothers taking valproate, about 10 out of 100 will have congenital malformations. For comparison, such malformations occur in 2–3 out of every 100 children born to women without epilepsy.

It is estimated that up to 30–40% of preschool-aged children whose mothers took valproate during pregnancy may have early developmental problems. Affected children may start walking and talking later, have lower intellectual abilities than other children, and may have language and memory difficulties.

Various autistic disorders are more frequently diagnosed in children exposed to valproate in utero, and some evidence suggests that children exposed to the drug during pregnancy may be more prone to developing symptoms of attention deficit/hyperactivity disorder (ADHD).

In rare cases, children of mothers treated with sodium valproate during pregnancy have blood clotting disorders.

A doctor may prescribe valproate to a woman capable of becoming pregnant only if no other treatment helps.

Before prescribing this medicine, the treating doctor will explain to the patient what risks the unborn child may face if she becomes pregnant while taking valproate. If the patient taking this medicine decides she wants to have a child, she must not stop taking the medicine or contraception independently until she discusses it with her treating doctor.

Parents or guardians of girls treated with valproate should contact the treating doctor when menstruation begins in their child.

Ask the doctor about taking folic acid during attempts to conceive. Folic acid may reduce the general risk of spina bifida and early miscarriage, which applies to all pregnancies. However, it is unlikely that folic acid use reduces the risk of congenital malformations associated with valproate treatment.

Please select the situation below that applies to the patient and read the information:

STARTING TREATMENT WITH ValproLEK 500
CONTINUING TREATMENT WITH ValproLEK 500 WITHOUT PLANNING PREGNANCY
CONTINUING TREATMENT WITH ValproLEK 500 WHILE PLANNING PREGNANCY
UNPLANNED PREGNANCY DURING CONTINUATION OF TREATMENT WITH ValproLEK 500

STARTING TREATMENT WITH ValproLEK 500
If ValproLEK 500 is prescribed for the first time, the treating doctor will explain the risks to the unborn child if the patient becomes pregnant. A patient of childbearing age should ensure she continuously uses an effective method of contraception throughout the entire treatment period with ValproLEK 500. Consult the treating doctor or a family planning clinic if advice on contraception is needed.

Important information:
Before starting ValproLEK 500, pregnancy must be excluded using a pregnancy test confirmed by the treating doctor.
The patient should use an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500.
Discuss the appropriate method of birth control (contraception) with the treating doctor.
The treating doctor will provide information on pregnancy prevention and may refer the patient to a specialist for contraception advice.
Regular visits (at least once a year) to a specialist experienced in treating bipolar affective disorder or epilepsy are recommended. During these visits, the treating doctor will ensure the patient has been adequately informed and understands all risks and advice related to valproate use during pregnancy.
Inform the doctor if the patient plans to have a child.
Inform the doctor immediately if the patient is pregnant or suspects she may be pregnant.

CONTINUING TREATMENT WITH ValproLEK 500 WITHOUT PLANNING PREGNANCY
If the patient continues ValproLEK 500 treatment and does not plan pregnancy, she must ensure she continuously uses an effective method of contraception throughout the entire treatment period with ValproLEK 500. Consult the doctor or a family planning clinic if advice on contraception is needed.

Important information:
The patient should use an effective method of birth control (contraception) throughout the entire treatment period with ValproLEK 500.
Discuss contraception (birth control method) with the treating doctor. The treating doctor will provide information on pregnancy prevention and may refer the patient to a specialist for contraception advice.
Regular visits (at least once a year) to a specialist experienced in treating bipolar affective disorder or epilepsy are recommended. During these visits, the treating doctor will ensure the patient has been adequately informed and understands all risks and advice related to valproate use during pregnancy.
Inform the doctor if the patient plans to have a child.
Inform the doctor immediately if the patient is pregnant or suspects she may be pregnant.

CONTINUING TREATMENT WITH ValproLEK 500 WHILE PLANNING PREGNANCY
If the patient plans to have a child, she should first schedule an appointment with her treating doctor. Do not stop ValproLEK 500 treatment or contraception unless discussed with the treating doctor. The treating doctor will provide further guidance.

Children born to mothers who took valproate are seriously at risk of congenital malformations and developmental problems that may significantly impair the child.

The treating doctor will refer the patient to a specialist experienced in treating bipolar affective disorder or epilepsy to appropriately assess alternative treatment options early. The specialist may take actions to ensure the best possible pregnancy course and minimize risks for both mother and unborn child.

The specialist may decide to change the dose of ValproLEK 500, switch to another medicine, or discontinue ValproLEK 500 treatment well before conception to ensure the condition is stable.

Important information:
Do not stop ValproLEK 500 treatment unless advised by the doctor.
Do not stop birth control methods (contraception) before discussing with the treating doctor and jointly developing a plan that ensures control of the patient’s condition and reduces risks to the child.
First, schedule an appointment with the treating doctor. During this visit, the treating doctor will ensure the patient has been adequately informed and understands all risks and advice related to valproate use during pregnancy.
The treating doctor will attempt to switch to another medicine or discontinue ValproLEK 500 treatment well before conception.
Schedule an urgent appointment with the treating doctor if the patient is pregnant or suspects she may be pregnant.

UNPLANNED PREGNANCY DURING CONTINUATION OF TREATMENT WITH ValproLEK 500
Do not stop ValproLEK 500 treatment unless discussed with the treating doctor, as the patient’s health condition may worsen. Schedule an urgent appointment with the doctor if the patient is pregnant or suspects she may be pregnant. The treating doctor will provide further guidance.

Children born to mothers who took valproate are seriously at risk of congenital malformations and developmental problems that may significantly impair the child.

The patient will be referred to a specialist experienced in treating bipolar affective disorder or epilepsy to assess alternative treatment options.

In exceptional circumstances, when ValproLEK 500 is the only available treatment option during pregnancy, the patient will be closely monitored for both the treatment of the underlying condition and fetal development. The patient and her partner will receive counselling and support regarding valproate-exposed pregnancy.

Ask the doctor about taking folic acid. Folic acid may reduce the general risk of spina bifida and early miscarriage, which applies to all pregnancies. However, it is unlikely that folic acid use reduces the risk of congenital malformations associated with valproate treatment.

Important information:
Schedule an urgent appointment with the treating doctor if the patient is pregnant or suspects she may be pregnant.
Do not stop taking ValproLEK 500 unless advised by the doctor.
The patient must be referred to a specialist experienced in treating epilepsy or bipolar affective disorder to assess the need for alternative treatment options.
The patient must receive counselling on the risks of using ValproLEK 500 during pregnancy, including teratogenic effects and impact on child development.
The patient must be referred to a specialist in prenatal monitoring to detect possible developmental abnormalities.

Read the patient information leaflet provided by the treating doctor. The treating doctor will discuss the annual risk acknowledgement form and ask the patient to sign and keep it. The patient will also receive a Patient Card from the pharmacist as a reminder of the risks of using valproate during pregnancy.

Important advice for male patients
Possible risk associated with taking valproate within 3 months before conception
A study suggests a possible risk of motor disorders and psychological development disorders (early childhood developmental problems) in children whose fathers were treated with valproate within 3 months before conception. In this study, about 5 out of 100 children whose fathers were treated with valproate had such disorders, compared to about 3 out of 100 children whose fathers were treated with lamotrigine or levetiracetam (other medicines that may be used to treat the patient’s condition). The risk for children whose fathers discontinued valproate treatment at least 3 months (the time needed for new sperm production) before conception is unknown. The study has limitations, so it is unclear whether the increased risk of motor and psychological developmental disorders suggested by this study is caused by valproate. The study was not large enough to show exactly which types of motor and psychological developmental disorders in children are associated with this risk.

As a precaution, the doctor will discuss with the patient:
the possible risk for children whose fathers were treated with valproate;
the need to consider using effective birth control (contraception) by the patient and his partner during treatment and for 3 months after stopping treatment;
the need to consult the doctor when planning conception and before stopping contraception;
the possibility of using other treatment methods for the condition, depending on the individual situation.

Do not donate sperm during valproate treatment and for 3 months after stopping it.

If planning parenthood, discuss this with the doctor.

If the patient’s partner becomes pregnant while the patient is taking valproate within 3 months before conception and the patient has related questions, he should contact the doctor. Do not stop treatment without consulting the doctor. If the patient stops treatment, symptoms may worsen.

The patient should have regular visits with the doctor prescribing the medicine. During these visits, the doctor will discuss precautions related to valproate use and the possibility of using other treatment methods for the patient’s condition, depending on the individual situation.

Read the patient guide provided by the treating doctor. The patient will also receive a Patient Card from the pharmacist as a reminder of the possible risks associated with valproate use.

Breastfeeding
Sodium valproate passes partially into breast milk. If the patient wishes to breastfeed, the doctor will consider the benefits of breastfeeding against the risk of side effects in the infant. Breastfeeding may be possible if the infant is carefully monitored for side effects (such as drowsiness, feeding difficulties, vomiting, skin rashes).

Before taking any medicine, consult a doctor or pharmacist.

Driving and operating machinery
ValproLEK 500 may cause side effects (such as dizziness, sluggishness, and drowsiness) that impair reaction ability. This should be considered when driving or operating machinery.

Epilepsy itself also requires caution when performing these activities, especially in patients who have not been seizure-free for a long time. Consult the doctor beforehand.

Taking multiple antiepileptic drugs or medicines with sedative, hypnotic, and/or muscle-relaxing effects (benzodiazepines) may enhance these effects.

Important information about some ingredients of ValproLEK 500
This medicine contains 49.2 mg of sodium (main component of table salt) per tablet. This corresponds to 2.5% of the maximum recommended daily sodium intake in the diet for adults. Consult a doctor or pharmacist if the patient needs to take 8 or more tablets per day for a prolonged period, especially if on a low-salt (low-sodium) diet.

3. How to use ValproLEK 500

Girls and women of childbearing age
Treatment with ValproLEK 500 should be initiated and supervised by a physician specialized in the treatment of epilepsy or bipolar affective disorder.

Male patients
It is recommended that treatment be initiated and supervised by a specialist experienced in the treatment of epilepsy or bipolar affective disorder – see section 2 Important advice for male patients.

ValproLEK 500 must always be taken exactly as prescribed by the doctor.
If in doubt, consult your doctor or pharmacist.

The tablets (or their halves) should be swallowed whole, with water (not with carbonated drinks such as soft drinks). If gastrointestinal irritation occurs at the beginning or during treatment, the tablets should be taken during or after meals.

ValproLEK 500 tablets may be divided into equal doses.

The doctor determines the dose of the medicine for each individual patient.

Treatment usually starts with a low dose of ValproLEK 500, which is gradually increased until the appropriate dose for the patient is reached.

Typical dosing:
Epilepsy
Adults and children
Initial dose of sodium valproate: 10 to 20 mg/kg body weight per day. This dose should be taken in two or more divided doses, preferably with meals.
(Example: a patient weighing 75 kg is prescribed the drug at a dose of 10 mg/kg body weight (milligrams per kilogram of body weight) per day, i.e. 1½ extended-release tablets of ValproLEK 500 per day).
If necessary, the doctor may increase the dose weekly by 5 to 10 mg/kg body weight per day until the desired therapeutic effect is achieved.
Maintenance dose of sodium valproate: usually 20 to 30 mg/kg body weight per day.
Adults: 9 to 35 mg/kg body weight per day.
Children: 15 to 60 mg/kg body weight per day.
The optimal maintenance daily dose is usually taken with meals, in one or two divided doses.
The maximum dose of sodium valproate, which is 60 mg/kg body weight per day, should not be exceeded.

Children weighing less than 20 kg
In this patient group, sodium valproate should be administered in another pharmaceutical form due to the need for precise dose adjustment.

Mania
The daily dose should be determined and monitored by the treating physician.
Initial dose
The recommended initial daily dose is 750 mg.
Average daily dose
Recommended daily doses usually range from 1000 mg to 2000 mg.

If you feel that the effect of ValproLEK 500 is too strong or too weak, consult your doctor or pharmacist.

Elderly patients
The doctor may decide to modify the dose.

Patients with renal function impairment
The doctor may decide to modify the dose.

Duration of treatment
The doctor will inform the patient how long ValproLEK 500 should be taken. Do not discontinue treatment prematurely, as symptoms of the disease may recur.

Taking more than the recommended dose of ValproLEK 500
If you take more ValproLEK 500 than prescribed, contact your doctor or pharmacist immediately. Symptoms of overdose may include: coma with reduced muscle tone, diminished reflexes, constricted pupils, low blood pressure, drowsiness, metabolic acidosis, elevated blood sodium levels, and impaired respiratory or cardiac function.
Additionally, in adults and children, large doses may cause neurological disturbances such as increased susceptibility to convulsive seizures and behavioral changes.

Missing a dose of ValproLEK 500
Do not take a double dose to make up for a missed dose.
If a patient forgets to take the medicine, they should take it as soon as possible, unless it is almost time for the next dose. In that case, the patient should continue taking the medicine according to the previously established schedule.

Stopping treatment with ValproLEK 500
Do not stop taking this medicine without consulting your doctor.

If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
If any of the following serious adverse reactions occur, seek medical advice immediately – urgent treatment may be necessary:

Common (may affect less than 1 in 10 people)
Liver damage. This can be very serious, especially in children, and usually occurs within the first 6 months of treatment. Early recognition is important. Sometimes symptoms occur together with drowsiness and high levels of ammonia in the blood (which can be detected by an ammonia-like odour of urine). For more information, see section “Warnings and precautions”.

Spontaneous development of bruises or bleeding due to reduced platelet count (thrombocytopenia). This occurs more frequently in women and elderly individuals.

Extrapyramidal disorders, which may be irreversible (movement disorders such as stiffness, tremor, or abnormal involuntary movements of the mouth and tongue).

Lethargy and immobility with reduced response to stimuli (stupor), marked drowsiness and sleepiness, followed by temporary disturbances in consciousness. Sometimes increased seizure frequency may also occur. These symptoms usually occur after sudden intake of a higher dose or when the patient is taking multiple antiepileptic medicines simultaneously (especially phenobarbital or topiramate).

Uncommon (may affect less than 1 in 100 people)
Pancreatitis, which may be severe and associated with nausea, vomiting, and severe upper abdominal pain radiating to the back.

Severe allergic reaction causing swelling of the face or throat (angioedema).

Reduction in white blood cell count with increased susceptibility to infections (leukopenia).

Excessive fluid accumulation in the body due to excessive secretion of antidiuretic hormone. This leads to reduced sodium concentration in the blood; confusion may occur.

Renal failure.

Worsening of epileptic seizures.

Breathing difficulties, pain or pressure in the chest (especially during inhalation), shortness of breath, and dry cough due to fluid accumulation around the lungs (pleural effusion).

Rare (may affect less than 1 in 1,000 people)
Severe hypersensitivity reaction with (high) fever, red skin lesions, skin blistering and skin peeling, joint pain and (or) eye inflammation (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Drug-induced hypersensitivity reaction, known as DRESS syndrome, with skin rash, fever, lymph node enlargement and possible involvement of other organs.

Bone marrow suppression, which may lead to serious changes in blood cell counts, such as red cell aplasia and white blood cell deficiency with sudden high fever, severe sore throat and mouth ulcers (agranulocytosis).

Hypothyroidism (reduced thyroid function, which may cause fatigue or weight gain).

Autoimmune disease with skin rash and joint inflammation (systemic lupus erythematosus).

Unusual muscle breakdown, which may lead to kidney damage (rhabdomyolysis).

Seek medical advice if any of the following adverse reactions worsen or persist for longer than a few days:

Very common (may affect more than 1 in 10 people)
Uncontrolled tremor
Nausea (common at the beginning of treatment and usually resolves within a few days)

Common (may affect less than 1 in 10 people):
Anaemia
Low sodium concentration in the blood
Hypersensitivity (allergic reaction)
Confusion
Aggressive behaviour, agitation, attention disorders (these adverse reactions occur mainly in children)
Seeing or hearing non-existent things (hallucinations)
Dizziness
Seizure attacks
Headache
Drowsiness
Memory disturbances
Uncontrolled rapid eye movements (nystagmus)
Hearing loss (temporary or permanent)
Bleeding
Upper abdominal pain, diarrhoea, vomiting
Swelling or inflammation of the gums, inflammation of the oral mucosa
Hair loss
Nail and nail bed disorders
Irregular menstruation, painful menstruation
Weight gain (see also section “How to take ValproLEK 500”), weight loss
Urinary incontinence

Uncommon (may affect less than 1 in 100 people)
Reduction in all types of blood cells (pancytopenia)
Increased levels of male hormones, leading to excessive growth of body and facial hair (hirsutism), male appearance in women (virilisation), acne, hair loss
Fatigue, lack of energy
Coma
Brain disease characterised by seizures and loss of consciousness (encephalopathy)
Temporary symptoms of Parkinson’s disease (tremor, movement disorders, so-called masked face, etc.)
Coordination disorders (ataxia), e.g. unsteady gait
Tingling or numbness (paraesthesiae)
Inflammation of blood vessels in the skin
Hair disorders (including abnormal hair structure, changes in hair colour, abnormal hair growth)
Skin rash
Absence of menstruation
Fluid accumulation in hands and feet (peripheral oedema)
Low body temperature

Rare (may affect less than 1 in 1,000 people)
Deficiency of blood coagulation factor VIII
Disease caused by disturbances in the production of haemoglobin (porphyria)
Increased ammonia concentration in the blood (hyperammonaemia)
Obesity
Abnormal behaviour, hyperkinesia/excessive activity, learning disorders (these adverse reactions occur mainly in children)
Temporary mental disturbances associated with transient brain shrinkage, cognitive disorders
Double vision
Skin rash with red (moist), irregular patches (erythema multiforme)
Nocturnal enuresis
Fanconi syndrome
Kidney inflammation
Polycystic ovary syndrome
Male infertility

Very rare (may affect less than 1 in 10,000 people)
Enlargement of breasts in men (gynaecomastia)

Frequency unknown (cannot be estimated from available data):
Excessive number of white blood cells in the blood (lymphocytosis)
Prolonged bleeding time due to disorders in blood clot formation and (or) disorders affecting platelets (deficiency of factor VIII/von Willebrand factor)
Gastrointestinal disorders (usually transient, occurring at the beginning of treatment)
Constipation
Increased or decreased appetite
Apathy (in case of concomitant treatment with other antiepileptic medicines)
Sedation
Congenital malformations and developmental disorders in children of mothers who took this medicine during pregnancy. More information is available in section 2 “Pregnancy, breastfeeding and fertility”.

Darker areas of skin and mucous membranes (hyperpigmentation)

There have been reports of bone disorders, including bone thinning (osteopenia, osteoporosis) and bone fractures. Patients on long-term antiepileptic therapy, with a history of osteoporosis or taking steroids, should consult their doctor.

If any adverse reaction worsens or if any adverse reactions not listed in this leaflet occur, consult a doctor or pharmacist.

Additional adverse reactions in children
Some adverse reactions of valproate occur more frequently or are more severe in children than in adults. These include liver damage, pancreatitis, aggression, agitation, attention disorders, unusual behaviour, hyperactivity and learning disorders.

Reporting of adverse reactions
If any adverse effects occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse.
Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301 / fax: +48 22 49 21 309 / website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store ValproLEK 500

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and blister after "EXP". The expiry date refers to the last day of the specified month.
No special storage conditions are required.
Medicines must not be disposed of via the sewage system or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What ValproLEK 500 contains
The active substances in this medicine are sodium valproate and valproic acid.
Each prolonged-release tablet contains 333 mg of sodium valproate and 145 mg of valproic acid, which together correspond to 500 mg of sodium valproate.
The other ingredients are: anhydrous colloidal silica, hydrated colloidal silica, ethylcellulose, hypromellose, sodium saccharin (E954), macrogol 6000, copolymer of methacrylic acid and ethyl acrylate (1:1), 30% dispersion, talc, titanium dioxide (E171).

What ValproLEK 500 looks like and contents of the pack
ValproLEK 500 prolonged-release tablets are white, bean-shaped, with a score line on both sides to facilitate breaking.
Prolonged-release tablets are packed in blisters made of aluminium/aluminium foil and placed in a cardboard carton.
Pack sizes:
30, 50 prolonged-release tablets

Marketing Authorisation Holder
Sandoz GmbH
Biochemiestrasse 10
6250 Kundl, Austria

Manufacturer
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
39179 Barleben, Germany
Lek S.A.
ul. Domaniewska 50 C
02-672 Warsaw, Poland
Lek Pharmaceuticals d.d.
Verovškova 57
1526 Ljubljana, Slovenia

This medicinal product is authorised in the member countries of the European Economic Area under the following names:
Belgium: Valproate Sandoz 500 mg tabletten met verlengde afgifte
Czech Republic: Valproat Chrono Sandoz
Germany: Valproat - 1 A Pharma 500 mg Retardtabletten
Estonia: Valproate sodium Sandoz 500 mg
Finland: Valproat Sandoz 500 mg depottabletti
Lithuania: Valproate sodium Sandoz 500 mg pailginto atpalaidavimo tabletės
Netherlands: Natriumvalproaat Sandoz Chrono 500, tabletten met verlengde afgifte 500 mg
Poland: VALPROLEK 500, 500 MG, PROLONGED-RELEASE TABLETS
Slovakia: Valproát chrono Sandoz 500 mg tablety s predĺženým uvoľňovaním

For further information about this medicine, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warsaw, Poland
tel. 22 209 70 00

Valpro lek 500