Package leaflet: Information for the user

Warning! Keep this leaflet. Information on the immediate packaging is in a foreign language.
Depakine Chrono 500
333 mg + 145 mg, prolonged-release tablets
Natrii valproas + Acidum valproicum
▼ This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can also help by reporting any side effects you experience after using the medicine. To find out how to report side effects – see section 4.
WARNING
Depakine Chrono 500 (sodium valproate + valproic acid) used during pregnancy may cause serious harm to the unborn child. Women of childbearing potential must use an effective method of contraception (birth control) continuously throughout the entire duration of treatment with Depakine Chrono 500. Your doctor will discuss this with you; please also follow the recommendations provided in section 2 of this leaflet.
You must contact your doctor immediately if you are planning a pregnancy or suspect you may be pregnant.
Do not stop taking Depakine Chrono 500 unless your doctor advises you to do so, as your condition may worsen.
Please read all of this leaflet carefully before taking this medicine, as it contains important information for you.

Keep this leaflet, so that you can read it again if necessary.
If you have any further questions, please consult your doctor or pharmacist.
This medicine has been prescribed for a specific individual. Do not give it to others. It may harm someone else, even if their symptoms are similar.
If you experience any adverse effects, including any side effects not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Leaflet contents:

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

1. What Depakine Chrono 500 is and what it is used for

Depakine Chrono 500 is available as prolonged-release tablets and contains the active substances sodium valproate and valproic acid, which belong to a group of medicines called antiepileptics and act on the central nervous system. The medicine has anticonvulsant activity in various forms of epilepsy in humans.
Depakine Chrono 500 is a medicine used in the treatment of epilepsy and mania.
Depakine Chrono 500 is used to treat:

Epilepsy, in generalized seizures:
- myoclonic seizures,
- tonic-clonic seizures,
- atonic seizures,
- absence seizures; and partial seizures:
- simple or complex partial seizures,
- secondarily generalized seizures,
- Lennox-Gastaut syndrome.
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. Depakine Chrono 500 may be used when lithium cannot be administered.

2. Important information before using Depakine Chrono 500

When not to use Depakine Chrono 500
Do not use this medicine if:

you are allergic to the active substance sodium valproate or any of the other ingredients of this medicine (listed in section 6),
you have acute or chronic hepatitis,
you have previously experienced severe hepatitis, especially drug-induced hepatitis, or if there is a family history of severe hepatitis,
you have porphyria (a very rare metabolic disorder),
when used concomitantly with mefloquine,
you have a genetic disorder causing mitochondrial dysfunction (e.g. patients with Alpers-Huttenlocher syndrome),
you have metabolic disorders, e.g. urea cycle disorders,
you have carnitine deficiency (a very rare metabolic disorder) which is not being treated.
for the treatment of bipolar affective disorder:
- if you are pregnant,
- if you are of childbearing age, unless you are using an effective method of contraception throughout the entire treatment period with Depakine Chrono 500. Do not stop taking Depakine Chrono 500 or contraception without first discussing it with your doctor. Your doctor will provide further guidance (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).
for the treatment of epilepsy:
- if you are pregnant, unless no other therapy is effective,
- if you are of childbearing age, unless you are using an effective method of contraception throughout the entire treatment period with Depakine Chrono 500. Do not stop taking Depakine Chrono 500 or contraception without first discussing it with your doctor. Your doctor will provide further guidance (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).

Warnings and precautions
Talk to your doctor before starting treatment with Depakine Chrono 500.
YOU MUST IMMEDIATELY INFORM YOUR DOCTOR IF:

you experience any of the following symptoms suddenly: weakness, loss of appetite, drowsiness, repeated vomiting and abdominal pain, jaundice (yellowing of the skin and whites of the eyes), or recurrence of epileptic seizures, especially during the first 6 months of treatment.

Depakine Chrono 500 may cause severe liver damage, sometimes resulting in death.
Liver function tests should be performed regularly before starting treatment and during the first 6 months of treatment.
The risk of liver damage is higher in children under 3 years of age, in patients taking other antiepileptic medicines, in patients with other neurological or metabolic disorders, and in patients with severe forms of epilepsy.

you experience severe abdominal pain – inform your doctor immediately. Very rarely, Depakine Chrono 500 may cause severe pancreatitis, sometimes resulting in death.
you or your child taking Depakine Chrono 500 experience problems with balance and coordination, drowsiness or reduced alertness, or vomiting – inform your doctor immediately. These may be caused by increased blood ammonia levels.
a small number of people taking antiepileptic medicines containing sodium valproate have had thoughts about harming or killing themselves. If you ever have such thoughts, contact your doctor immediately.
serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema, have been reported with valproate treatment. If you notice any of the symptoms associated with these serious skin reactions described in section 4, you should seek medical advice immediately.

Before starting treatment with this medicine, discuss the following with your doctor:

Valproate should not be used in women with epilepsy who are planning pregnancy, except when other treatments are ineffective or not tolerated. The benefits of treatment should be weighed against the risks before the first prescription or when a woman treated with valproate plans pregnancy. Women of childbearing age must use effective contraception during treatment.
Before starting treatment, including prior to surgical procedures, and in cases of bruising or spontaneous bleeding, laboratory tests (blood count with blood smear, including platelet count, bleeding time, and coagulation tests) are recommended.
Use with caution in patients with impaired kidney function. Your doctor may recommend a lower dose.
Depakine Chrono 500 should be used with caution in patients with systemic lupus erythematosus.
If you are suspected of having any metabolic disorder, especially inherited enzyme deficiencies such as “urea cycle disorders”, due to the risk of increased blood ammonia levels.
Weight gain may occur in patients treated with sodium valproate.
If you have a rare condition called “carnitine palmitoyltransferase II deficiency”, due to increased risk of muscle disorders.
Concomitant use of carbapenem antibiotics with valproic acid is not recommended (see section “Depakine Chrono 500 and other medicines”).
Sodium valproate is excreted mainly by the kidneys, partly in the form of ketone bodies, so urine ketone tests in diabetic patients may give false positive results.
If you have a family history of, or your doctor suspects, a genetic disorder due to mitochondrial dysfunction, due to the risk of liver damage.
As with other antiepileptic medicines, seizures may worsen in severity or frequency during treatment. If seizures worsen, consult your doctor immediately.
If you have inadequate intake of carnitine, found in meat and dairy products, particularly in children under 10 years of age,
If you have carnitine deficiency and are taking carnitine supplements.
If you have previously experienced severe skin rash, skin peeling, blistering, and/or oral ulcers after taking valproate.

Children and adolescents
Children and adolescents under 18 years of age:
Depakine Chrono 500 should not be used in children and adolescents under 18 years of age for the treatment of mania.

Depakine Chrono 500 and other medicines
Tell your doctor about all medicines you are currently taking, have recently taken, or plan to take.
Some medicines may affect the action of sodium valproate, and sodium valproate may affect the action of other medicines.
These include:

neuroleptic medicines, including quetiapine, olanzapine (used to treat psychotic disorders);
medicines used to treat depression, MAO inhibitors;
benzodiazepines (used to treat insomnia and anxiety disorders);
other medicines used to treat epilepsy, including phenobarbital, phenytoin, primidone, lamotrigine, carbamazepine, felbamate, topiramate, rufinamide;
cannabidiol (used to treat epilepsy and other conditions);
certain antimicrobial medicines containing pivampicillin (such as pivampicillin, adefovir dipivoxil);
methotrexate (used to treat cancer and inflammatory diseases);
zidovudine, ritonavir, and lopinavir (used to treat HIV infection and AIDS);
mefloquine (used to treat and prevent malaria);
salicylates (acetylsalicylic acid);
anticoagulant medicines;
cimetidine (used to treat gastric ulcers);
erythromycin, rifampicin;
carbapenems (antibiotics used to treat bacterial infections);
cholestyramine (used to lower blood cholesterol levels);
propofol (used for general anaesthesia);
nimodipine;
medicines containing oestrogen (including some contraceptive agents);
metamizole (used to treat pain and fever);
clozapine (used to treat psychiatric disorders).

These medicines may affect the action of sodium valproate and vice versa. Your doctor may need to adjust the dose of your medicines or prescribe alternative treatments. Your doctor will inform you about any such changes.
Your doctor will also provide additional information about medicines that should be used with caution or avoided during treatment with Depakine Chrono 500.

Depakine Chrono 500 with food, drink and alcohol
This medicine should be taken during meals.
Alcohol consumption is not recommended during treatment with valproate.

Pregnancy, breastfeeding and fertility
Pregnancy
Important advice for women
Bipolar affective disorder

Do not use Depakine Chrono 500 for the treatment of bipolar affective disorder if you are pregnant.
Women of childbearing age must not take Depakine Chrono 500 for the treatment of bipolar affective disorder unless using an effective method of contraception throughout the entire treatment period. Do not stop taking Depakine Chrono 500 or contraception without first discussing it with your doctor. Your doctor will provide further guidance.

Epilepsy

Do not use Depakine Chrono 500 for the treatment of epilepsy if you are pregnant, unless no other therapy is effective.
Women of childbearing age must not take Depakine Chrono 500 for the treatment of epilepsy unless using an effective method of contraception throughout the entire treatment period. Do not stop taking Depakine Chrono 500 or contraception without first discussing it with your doctor. Your doctor will provide further guidance.

Risk of taking valproate during pregnancy (regardless of the condition being treated with valproate)

Consult your doctor immediately if you are planning pregnancy or are pregnant.
Taking valproate during pregnancy carries risks. The higher the dose, the greater the risk, but no dose is risk-free, even when valproate is used in combination with other antiepileptic medicines.
Valproate may cause serious congenital malformations and affect the physical and mental development of the child after birth.
The most common congenital malformations include: spina bifida (when the spinal bones do not develop properly); facial and cranial developmental defects; heart, kidney, urinary tract and genital organ malformations; limb defects; and multiple associated developmental defects affecting several organs and body parts. Congenital malformations may lead to disabilities, which may be significant.
Hearing problems or deafness have been reported in children exposed to valproate in utero.
Eye developmental defects together with other congenital malformations have been reported in children exposed to valproate in utero. Eye developmental defects may affect vision.
Women taking valproate during pregnancy have an increased risk of giving birth to a child with congenital malformations requiring treatment. Valproate has been used for many years, so it is known that in the group of children born to mothers taking valproate, about 11 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 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 problems.
Various disorders within the autism spectrum are more frequently diagnosed in children exposed to valproate in utero. Some evidence suggests an increased risk of attention deficit (attention deficit hyperactivity disorder – ADHD) in these children.
Before prescribing this medicine, your doctor will explain to you the risks to the unborn child if you become pregnant while taking valproate. If you are taking this medicine and decide you want to have a child, do not stop taking the medicine or contraception without first discussing it with your doctor.
Some contraceptive methods (oral contraceptives containing oestrogen) may reduce the blood concentration of valproate. Discuss with your doctor the most appropriate method of contraception for you.
Parents or guardians of girls treated with valproate should contact the doctor when their daughter starts menstruation.
Ask your doctor about taking folic acid when trying to conceive. Folic acid may reduce the general risk of spina bifida and early miscarriage, which affects all pregnancies. However, it is unlikely that folic acid supplementation will reduce the risk of congenital malformations associated with valproate treatment.

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

STARTING TREATMENT WITH DEPAKINE CHRONO 500
CONTINUING TREATMENT WITH DEPAKINE CHRONO 500 WITHOUT PLANNING PREGNANCY
CONTINUING TREATMENT WITH DEPAKINE CHRONO 500 WHILE PLANNING PREGNANCY
BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE CHRONO 500

STARTING TREATMENT WITH DEPAKINE CHRONO 500
If Depakine Chrono 500 is being prescribed for the first time, your doctor will explain the risks to the unborn child if you become pregnant. Women of childbearing age should ensure they use an effective method of contraception continuously throughout the entire treatment period with Depakine Chrono 500. If you need advice on contraception, consult your doctor or a family planning clinic.
Important information

Before starting Depakine Chrono 500, you should confirm you are not pregnant with a pregnancy test, the result of which should be confirmed by your doctor.
You must use an effective method of contraception throughout the entire treatment period with Depakine Chrono 500.
Discuss the appropriate method of contraception with your doctor. Your doctor will provide information on pregnancy prevention and may refer you to a specialist for advice on contraception.
You should have regular visits (at least once a year) to a specialist experienced in treating bipolar affective disorder or epilepsy. During these visits, your doctor will ensure you have been adequately informed and understand all risks and advice related to valproate use during pregnancy.
If you plan to have a child, inform your doctor.
If you are pregnant or suspect you may be pregnant, inform your doctor immediately.

CONTINUING TREATMENT WITH DEPAKINE CHRONO 500 WITHOUT PLANNING PREGNANCY
If you are continuing treatment with Depakine Chrono 500 and not planning pregnancy, you must be certain you are continuously using an effective method of contraception throughout the entire treatment period. If you need advice on contraception, consult your doctor or a family planning clinic.
Important information

You must use an effective method of contraception throughout the entire treatment period with Depakine Chrono 500.
Discuss contraception (method of birth control) with your doctor. Your doctor will provide information on pregnancy prevention and may refer you to a specialist for advice on contraception.
You should have regular visits (at least once a year) to a specialist experienced in treating bipolar affective disorder or epilepsy. During these visits, your doctor will ensure you have been adequately informed and understand all risks and advice related to valproate use during pregnancy.
If you plan to have a child, inform your doctor.
If you are pregnant or suspect you may be pregnant, inform your doctor immediately.

CONTINUING TREATMENT WITH DEPAKINE CHRONO 500 WHILE PLANNING PREGNANCY
If you plan to have a child, you should first schedule an appointment with your doctor. Do not stop taking Depakine Chrono 500 or contraception until you have discussed this with your doctor. Your doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems, which may significantly impair the child. Your doctor will refer you to a specialist experienced in treating bipolar affective disorder or epilepsy to evaluate alternative treatment options as early as possible. The specialist may take steps to ensure the best possible pregnancy outcome and minimise risks to both mother and unborn child.
The specialist may decide to adjust the dose of Depakine Chrono 500, switch to another medicine, or discontinue treatment with Depakine Chrono 500 well before conception – to ensure the condition is stable.
Ask your doctor about taking folic acid when trying to conceive. Folic acid may reduce the general risk of spina bifida and early miscarriage, which affects all pregnancies. However, it is unlikely that folic acid supplementation will reduce the risk of congenital malformations associated with valproate treatment.
Important information

Do not stop treatment with Depakine Chrono 500 unless directed by your doctor.
Do not stop using contraception methods before talking to your doctor and jointly developing a management plan that ensures control of your condition and reduces risks to the child.
First, schedule an appointment with your doctor. During this visit, your doctor will ensure you have been adequately informed and understand all risks and advice related to valproate use during pregnancy.
Your doctor will attempt to switch to another medicine or discontinue Depakine Chrono 500 well before conception.
If you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor.

BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE CHRONO 500
Do not stop treatment with Depakine Chrono 500 without first discussing it with your doctor, as your health condition may worsen. If you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor. Your doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems, which may significantly impair the child.
You will be referred to a specialist experienced in treating bipolar affective disorder or epilepsy to evaluate alternative treatment options.
In exceptional circumstances, when Depakine Chrono 500 is the only available treatment option during pregnancy, you will be closely monitored for both your underlying condition and fetal development. You and your partner will receive counselling and support regarding valproate-exposed pregnancy.
Ask your doctor about taking folic acid. Folic acid may reduce the general risk of spina bifida and early miscarriage, which affects all pregnancies. However, it is unlikely that folic acid supplementation will reduce the risk of congenital malformations associated with valproate treatment.
Important information

If you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor.
Do not stop treatment with Depakine Chrono 500 unless directed by your doctor.
Ensure you are referred to a specialist experienced in treating epilepsy or bipolar affective disorder to evaluate the need for alternative treatment methods.
You must receive counselling on the risks of using Depakine Chrono 500 during pregnancy, including its teratogenic effects (causing congenital malformations) and physical and mental developmental disorders in children.
Ensure you are referred to a specialist in prenatal monitoring to detect possible developmental abnormalities.

Newborns of mothers who took Depakine Chrono 500 during pregnancy may experience bleeding disorders, hypoglycaemia, hypothyroidism, and withdrawal symptoms such as agitation, irritability, hyperactivity, tremors, seizures, and feeding difficulties.
Please read the patient guide provided by your doctor.
Your doctor will discuss the annual risk acknowledgement form and ask you to sign and keep it. You will also receive a patient card from the pharmacist as a reminder of the risks associated with valproate use 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 and mental developmental 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 condition you have). The risk in children whose fathers discontinued valproate treatment at least 3 months (the time required for new sperm production) before conception is unknown. The study has limitations, so it is unclear whether the increased risk of motor and mental developmental disorders suggested by this study is caused by valproate. The study was not large enough to determine the specific types of motor and mental developmental disorders involved.
As a precaution, your doctor will discuss with you:

the possible risk in children whose fathers were treated with valproate;
the need to consider using effective contraception (birth control) by you and your partner during treatment and for 3 months after stopping;
the need to consult your doctor when planning conception and before stopping contraception;
the possibility of alternative treatment options for your condition, depending on your individual situation.

Do not donate sperm while taking valproate and for 3 months after stopping.
If you are planning to have children, discuss this with your doctor.
If your partner becomes pregnant while you were taking valproate within 3 months before conception and you have any questions, contact your doctor. Do not stop treatment without consulting your doctor, as your symptoms may worsen.
You should have regular visits with the doctor who prescribed the medicine. During these visits, your doctor will discuss precautions related to valproate use and the possibility of alternative treatments for your condition, depending on your individual situation.
Please read the patient guide provided by your doctor. You will also receive a patient card from the pharmacist as a reminder of the possible risks associated with valproate use.

Breastfeeding
Valproate is excreted in small amounts in breast milk. Discuss with your doctor whether you can breastfeed during treatment.

Driving and operating machinery
Some patients may experience drowsiness during treatment, especially when taking multiple antiepileptic medicines or when benzodiazepines are used concomitantly. Before driving or operating machinery, you should ensure you know how you react to the treatment.

Depakine Chrono 500 contains sodium
This medicine contains 46.08 mg of sodium (the main component of table salt) in each tablet. This corresponds to 2.3% of the maximum recommended daily intake of sodium in the diet for adults.

3. How to use Depakine Chrono 500

Depakine Chrono 500 must always be used as directed by the physician. In case of
doubt, consult your doctor.
Depakine Chrono is available in the following strengths: 200 mg + 87 mg (Depakine Chrono
300) and 333 mg + 145 mg (Depakine Chrono 500).
Girls and women of childbearing potential
Treatment with Depakine Chrono 500 should be initiated and supervised by a physician
specializing in epilepsy or bipolar affective disorder.
Male patients
It is recommended that treatment with Depakine Chrono 500 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.
The prolonged-release formulation allows Depakine Chrono 500 to be administered as a single
daily dose or divided into two doses per day.
If clinically indicated, Depakine Chrono 500 prolonged-release tablets may be used in children
weighing more than 17 kg, provided the child is able to swallow the tablet.
This formulation is not suitable for children under 6 years of age (risk of choking).
The daily dose of Depakine Chrono 500 should be determined according to age and body weight;
additionally, the physician should always consider the individual patient's sensitivity to valproate.
Switching therapy to prolonged-release formulations (Depakine Chrono 500)
When switching from conventional tablets to prolonged-release tablets (Depakine Chrono 500),
it is recommended (based on current knowledge) to maintain the same total daily dose.
Initiating treatment with Depakine Chrono 500 in epilepsy
When starting treatment with Depakine Chrono 500 as the sole antiepileptic medication,
the dose should be increased every 2–3 days so that the average recommended dose is reached
after one week.
When introducing Depakine Chrono 500 in patients already receiving other antiepileptic
medications, the dose of Depakine Chrono 500 should be gradually increased over 2 weeks to
reach the average recommended dose. Subsequently, the dose of concomitant antiepileptic drugs
should be gradually reduced to a level ensuring optimal seizure control or possibly discontinued.
If it becomes necessary to add other antiepileptic drugs to the treatment regimen, they should
be introduced gradually.
The initial daily dose is usually 5 to 15 mg/kg body weight and should be gradually increased
every 2–3 days by 5 mg/kg body weight until the optimal dose is achieved (see: Initiating
treatment with Depakine Chrono 500 in epilepsy).
The usual daily dose is 20 to 30 mg/kg body weight, administered as a single dose or divided into
two doses.
If necessary, the daily dose may exceed 50 mg/kg body weight, provided strict clinical monitoring
of the patient is maintained (see section: Warnings and precautions).
Children weighing over 17 kg
The average dose is 30 mg/kg body weight per day.
Adults
The average dose is 20 to 30 mg/kg body weight per day.
Elderly patients
Dosing should be adjusted according to the degree of seizure control.
Mania
Adults:
The daily dose should be individually determined and monitored by the treating physician.
Initial dose:
The recommended initial daily dose is 750 mg.
Average daily dose:
The average daily dose is usually between 1000 mg and 2000 mg.
Duration of treatment
The medicine should be taken for as long as directed by the physician.
If you feel that the effect of Depakine Chrono 500 is too strong or too weak, consult your doctor.
Patients with renal impairment
The physician may decide whether dose adjustment is necessary.
Taking more than the recommended dose of Depakine Chrono 500
Symptoms of severe overdose with valproic acid derivatives include: coma, decreased muscle
tone and tendon reflexes, pupillary constriction, respiratory disturbances; metabolic acidosis,
hypotension and acute circulatory failure may also occur. Other symptoms may appear; seizures
have been reported in cases of very high plasma concentrations of the drug.
Cases of increased intracranial pressure associated with cerebral edema have been reported.
The presence of sodium in valproate pharmaceutical formulations may lead to elevated blood
sodium levels in cases of overdose.
If an overdose has been taken, seek immediate medical advice from a doctor or pharmacist.
Hospital treatment in cases of poisoning should include: gastric lavage (within 10–12 hours after
drug ingestion), continuous monitoring of cardiovascular and respiratory function. In the most
severe cases, hemodialysis or even exchange transfusion may be required.
Missed dose of Depakine Chrono 500
If a dose is missed, take it as soon as possible, except when the next scheduled dose is
approaching. Do not take two doses at the same time or within a short interval. In case of doubt,
consult your doctor.
Stopping treatment with Depakine Chrono 500
Do not discontinue treatment with Depakine Chrono 500 or change the dose without consulting
your doctor.
Discontinuing treatment without medical consultation may worsen the patient's condition.

4. Possible adverse effects

Like all medicines, Depakine Chrono 500 can cause adverse effects, although not everyone experiences them. However, patients may require appropriate treatment if certain adverse effects occur.
If any of the following severe adverse effects occur in a patient, contact a doctor immediately, as the patient may urgently require medical assistance:

Coma, encephalopathy (brain damage), lethargy (a state of inertia and lack of response to stimuli), changes in behaviour, with or without increased frequency or severity of epileptic seizures, especially when phenobarbital is used concomitantly or when the dose of Depakine Chrono 500 is abruptly increased
Confusion, weakness, dizziness, nausea, vomiting, which may be caused by low sodium levels in the blood or a condition known as “SIADH” (SIADH, Syndrome of Inappropriate Secretion of ADH) or inappropriate antidiuretic hormone secretion syndrome
Problems with balance and coordination, drowsiness or reduced alertness, combined with vomiting. This may be due to increased levels of ammonia in the blood (hyperammonaemia)
Increase in frequency and severity of seizures
Extreme fatigue, weakness, loss of appetite, drowsiness, recurrent vomiting and abdominal pain, severe upper abdominal pain, nausea, jaundice (yellowing of the skin and whites of the eyes), leg swelling or increased frequency of epileptic seizures, or general malaise – these symptoms may indicate liver or pancreas damage
Allergic reactions, which may manifest as:
- Blisters with skin peeling (formation of blisters, skin sloughing or bleeding from various parts of the body, including lips, eyes, mouth, nose, genital organs, palms or soles), with or without rash, sometimes accompanied by flu-like symptoms such as fever, chills or muscle pain – these may be symptoms of conditions known as “toxic epidermal necrolysis” or “Stevens-Johnson syndrome”
Skin rash or skin lesions with a red/pink ring and pale center, which may be itchy, scaly or fluid-filled. The rash may appear especially on the palms or soles. These may be symptoms of a disease called “erythema multiforme”
Allergy-induced swelling with painful, itchy swellings (most commonly around the eyes, lips, throat, and sometimes hands and feet) – these may be symptoms of “angioedema”
Syndrome with skin rash, fever, enlarged lymph nodes and possible damage to other organs – these may be symptoms of a condition called “DRESS” or drug reaction with eosinophilia and systemic symptoms
- Blood clotting disorders confirmed by laboratory tests, which may cause spontaneous bruising and bleeding
- Marked decrease in white blood cells or bone marrow failure (myelodysplastic syndrome) shown in blood tests, sometimes presenting with fever and breathing difficulties
- Hypothyroidism, which may cause fatigue or weight gain
- Joint pain, fever, fatigue, rash. These may be symptoms of systemic lupus erythematosus
- Tremors, gait disturbances, muscle stiffness, disturbances in body coordination (parkinsonism, extrapyramidal disorders, ataxia)
- Muscle pain and weakness (rhabdomyolysis – breakdown of striated muscles)
- 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)
- Kidney disease (renal failure, interstitial nephritis), which may present as reduced urine output

If any of the following adverse effects worsen or persist for longer than a few days, inform your doctor or pharmacist; treatment may be necessary.
Adverse effects are listed according to the following frequency classification:
Very common (may occur in more than 1 in 10 people):

tremor
nausea

Common (may occur in up to 1 in 10 people):

anaemia (reduced number of red blood cells), thrombocytopenia (reduced number of platelets, increasing the risk of bleeding and bruising)
stupor, drowsiness, convulsions, memory disturbances, headache, nystagmus (rapid, uncontrolled eye movements), dizziness
hearing impairment
vomiting, stomach pain, diarrhoea (frequent in some patients at the beginning of treatment), usually transient and resolving after a few days without the need to discontinue treatment
gum abnormalities (mainly gum overgrowth), oral inflammation
transient and/or dose-dependent hair loss, nail disorders and nail bed abnormalities
weight gain, which should be monitored as it may be associated with polycystic ovary syndrome
irregular menstrual cycles
confusion (disorientation), hallucinations, aggression, agitation, attention disturbances
urinary incontinence

Uncommon (may occur in up to 1 in 100 people):

leukopenia (marked decrease in white blood cell count), pancytopenia (marked decrease in blood cells, which may cause weakness, easy bruising or increased susceptibility to infections)
tingling or numbness in hands or feet
rash, hair abnormalities (such as abnormal hair structure, changes in hair colour, abnormal hair growth)
decreased bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long-term treatment with Depakine Chrono 500
hyperandrogenism (excessive male-pattern hair growth, virilization, acne, male-pattern baldness and/or elevated androgen levels)
vasculitis
decreased body temperature, mild to moderate swelling of feet and legs
absence of menstruation

Rare (may occur in less than 1 in 1000 people):

macrocytic anaemia (low number of red blood cells), macrocytosis (abnormal enlargement of red blood cells)
biotin deficiency/biotinidase deficiency
excessive urination and thirst (Fanconi syndrome)
involuntary urination (nocturnal enuresis)
obesity
male infertility, which is usually transient after discontinuation of treatment and may be transient after dose reduction. Do not stop treatment without first consulting a doctor
polycystic ovary syndrome
unusual behaviour, psychomotor hyperactivity, learning disorders (observed in children and adolescents)
transient dementia associated with transient brain atrophy, cognitive disturbances, double vision

Frequency not known (frequency cannot be estimated from available data):

congenital disorders and hereditary and/or genetic diseases
decreased carnitine levels (visible in blood and muscle tests)
darker areas of skin and mucous membranes (hyperpigmentation)

Additional adverse effects in children
Some adverse effects of valproate occur more frequently or are more severe in children than in adults. These include liver damage, pancreatitis, aggression, agitation, attention disturbances, abnormal behaviour, hyperactivity and learning disorders.
Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions of the 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
Reporting adverse effects helps to provide more information on the safety of the medicine.

5. How to store Depakine Chrono 500

Store below 30°C in a dry place.
Keep the medicine out of sight and reach of children.
Do not use the medicine after the expiry date stated on the packaging.
The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required.
This helps protect the environment.

6. Contents of the packaging and other information

What Depakine Chrono 500 contains
One prolonged-release tablet contains as active substances:

sodium valproate 333 mg,
valproic acid 145 mg, equivalent to a total of 500 mg of sodium valproate.
Excipients: copolymer of acrylic and methacrylic acid esters with quaternary ammonium salt, ethylcellulose, colloidal hydrated silica. Coating: hypromellose, macrogol 6000, talc, titanium dioxide (E 171), polyacrylate dispersion 30%.

What Depakine Chrono 500 looks like and contents of the pack
Pack contains 30 prolonged-release tablets.
For more detailed information, please contact the responsible or parallel importer.
Marketing Authorisation Holder in Greece, country of export:
Sanofi-Aventis Monoprósopi AEBE
Leof. Siggrou 348 - Building A, 176 74 Kallithea – Athens, Greece
Manufacturer:
Sanofi Winthrop Industrie
1, rue de la Vierge, Ambarès et Lagrave, 33565 Carbon Blanc CEDEX, France
Sanofi Aventis S.A.
Ctra. C-35 (La Batlloria-Hostalric Km. 63,09)
Riells i Viabrea, 17404 Girona
Spain
Parallel Importer:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź
Repackaged in:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź
Marketing Authorisation Numbers in Greece, country of export: 2057/06/28-02-2007
41972/10/21-06-2011
9081/18-02-2013
Parallel Import Licence Number: 84/15
Other sources of information
Detailed and up-to-date information on this medicine is available by scanning with a smartphone
the QR code located on the leaflet. The same information is also available on the website:
https://sirpl.org/walproinian

Depakine chrono 500