Depakine chrono 500 mg: detailed information

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
Sodium valproate + Valproic acid
This medicinal product will be subject to additional monitoring. This will allow rapid
identification of new safety information. You can also help by reporting any adverse reactions that occur
after using the medicine. For information on how to report adverse reactions – see section 4.
WARNING
Depakine Chrono 500 (sodium valproate + valproic acid) used during pregnancy may harm the unborn
child. Women of childbearing age must use an effective method of birth control (contraception)
continuously throughout the entire duration of treatment with Depakine Chrono 500.
Your doctor will discuss this with you. You should also follow the recommendations provided in
section 2 of this leaflet.
You must contact your doctor immediately if you are planning a pregnancy or if you suspect you are
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, as you may need to read it again.
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 the same.
If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents of the leaflet:

What Depakine Chrono 500 is and what it is used for
What you need to know 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 in the form of prolonged-release tablets and contains the active substances:
sodium valproate and valproic acid, which belong to a group of medicines called antiepileptics and
exert their action on the central nervous system. The medicine shows 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, stimulated, 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 to any of the other ingredients of this medicine (listed in section 6),
you have acute or chronic hepatitis,
you have previously experienced severe hepatitis, particularly drug-induced hepatitis, or if there is a family history of severe hepatitis,
you have porphyria (a very rare metabolic disorder),
concomitant use 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) that is untreated,
for bipolar affective disorder:
you are pregnant,
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 epilepsy:
you are pregnant, unless no other therapy is effective,
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
Before starting treatment with Depakine Chrono 500, discuss this with your doctor.
YOU MUST IMMEDIATELY INFORM YOUR DOCTOR IF:

You experience any of the following symptoms: weakness, loss of appetite, drowsiness, recurrent 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 periodically before starting treatment and during the first 6 months of treatment.
The risk of liver damage is increased 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 epilepsy.
You experience severe abdominal pain. Very rarely, Depakine Chrono 500 may cause severe pancreatitis, sometimes fatal.
You or your child being treated with Depakine Chrono 500 develop problems with balance and coordination, drowsiness or decreased alertness, or vomiting. These may be due to increased blood ammonia levels.
A small number of people taking antiepileptic medicines containing sodium valproate have had thoughts of 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 symptoms related to these serious skin reactions described in section 4, 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 before surgery, and in case of bruising or spontaneous bleeding, laboratory tests are recommended (blood count with blood smear, including platelet count, bleeding time, and coagulation tests).
Use with caution in patients with impaired kidney function. Your doctor may recommend a lower dose.
Use with caution in patients with systemic lupus erythematosus.
If any metabolic disorder is suspected, 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 mainly excreted by the kidneys, partly in the form of ketone bodies, so in diabetic patients, ketone body tests may give false positive results.
If you have a family history 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, especially in children under 10 years of age.
If you have carnitine deficiency and are taking carnitine supplements.
If you have ever 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 valproate may also affect the action of other medicines.
These include:

neuroleptics, including quetiapine, olanzapine (used to treat psychotic disorders);
antidepressants, including MAO inhibitors;
benzodiazepines (used to treat insomnia and anxiety disorders);
other antiepileptic medicines, including phenobarbital, phenytoin, primidone, lamotrigine, carbamazepine, felbamate, topiramate, rufinamide;
cannabidiol (used to treat epilepsy and other conditions);
certain antiviral 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);
anticoagulants;
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 certain contraceptives);
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 of 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 if you are pregnant.
If you are of childbearing age, do not take Depakine Chrono 500 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.

Epilepsy

Do not use Depakine Chrono 500 if you are pregnant, unless no other therapy is effective.
If you are of childbearing age, do not take Depakine Chrono 500 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.

Risk of taking valproate during pregnancy (regardless of the condition for which valproate is used)

Consult your doctor immediately if you are planning a pregnancy or if you are pregnant.
Taking valproate during pregnancy carries risks. The higher the dose, the greater the risk, but no dose is completely risk-free, even when valproate is used in combination with other antiepileptic medicines.
Valproate may cause serious congenital malformations and affect the child's physical and mental development 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 defects; limb defects; and multiple 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.
Developmental eye defects, sometimes 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 whose mothers took 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, may have lower intellectual abilities than other children, and may have language and memory problems.
Various autism spectrum disorders are more frequently diagnosed in children exposed to valproate in utero. Some evidence suggests an increased risk of 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 contraceptives (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 child 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 reduces the risk of congenital malformations associated with valproate treatment.

Choose 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 that 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 that you are not pregnant with a pregnancy test, the result of which should be confirmed by your doctor.
You should 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 contraceptive advice.
You should have regular visits (at least once a year) with a specialist experienced in treating bipolar affective disorder or epilepsy. During these visits, your doctor will ensure that you have been properly 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 continue treatment with Depakine Chrono 500 and do not plan pregnancy, you must ensure that you continuously use 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 should 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 contraceptive advice.
You should have regular visits (at least once a year) with a specialist experienced in treating bipolar affective disorder or epilepsy. During these visits, your doctor will ensure that you have been properly 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 without first discussing it 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 that 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 minimize risks for both mother and unborn child.
The specialist may decide to change the dose of Depakine Chrono 500, switch to another medicine, or discontinue Depakine Chrono 500 treatment well before conception to ensure the disease 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 reduces the risk of congenital malformations associated with valproate treatment.
Important information:

Do not stop treatment with Depakine Chrono unless your doctor advises it.
Do not stop using contraceptive 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 that you have been properly informed and understand all risks and advice related to valproate use during pregnancy.
Your doctor will try switching to another medicine or discontinuing Depakine Chrono 500 treatment 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 that 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 advice 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 reduces 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 your doctor advises it.
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 advice 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 have bleeding disorders, hypoglycaemia, hypothyroidism, and withdrawal symptoms such as agitation, irritability, hyperactivity, tremors, seizures, and feeding difficulties.

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 of valproate use during pregnancy.
Important advice for male patients
Possible risks associated with taking valproate within 3 months before conception
Studies suggest a possible risk of motor and psychological developmental disorders (early developmental problems in childhood) 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 psychological developmental disorders suggested by this study is caused by valproate. The study was not large enough to determine the specific types of motor and psychological developmental disorders involved.
As a precaution, your doctor will discuss with you:

the possible risks for children whose fathers were treated with valproate;
the need to consider using effective contraception 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 using alternative treatment methods 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 a family, discuss this with your doctor.
If your partner becomes pregnant while you are taking valproate within 3 months before conception and you have any questions, contact your doctor. Do not stop treatment without consulting your doctor. If you stop treatment, 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 treatment methods for your condition, depending on your individual situation.
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.

Breast-feeding
Valproate is excreted in small amounts in breast milk. Consult your doctor whether you can breast-feed during treatment.

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

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

3. How to use Depakine Chrono 500

Depakine Chrono must always be used as directed by the physician.
If in doubt, consult your doctor.

Female patients and women of childbearing potential
Treatment with Depakine Chrono 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 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 in two divided doses per day.

If clinically indicated, Depakine Chrono 500 prolonged-release tablets may be used in children weighing over 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 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 drug, the dose should be increased every 2–3 days so that the average recommended dose is reached within one week.

When introducing Depakine Chrono 500 in patients already receiving other antiepileptic drugs, the dose of Depakine Chrono 500 should be gradually increased over a period of two weeks to reach the average recommended dose. Subsequently, the dose of the remaining antiepileptic drugs should be gradually reduced to a level ensuring optimal seizure control or possibly discontinued.

If additional antiepileptic drugs need to be added to the therapy, 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").

The usual daily dose is 20 to 30 mg/kg body weight, administered as a single dose or in two divided doses.

If necessary, the daily dose may exceed 50 mg/kg body weight, provided close clinical monitoring of the patient is maintained (see section 2: "Important information before using Depakine Chrono 500").

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.

Overdose of Depakine Chrono 500
Symptoms of severe overdose with valproic acid derivatives include coma, reduced muscle tone and tendon reflexes, constricted pupils, and 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 increased serum sodium levels in cases of overdose.

In case of ingestion of more than the recommended dose, seek immediate medical advice from a doctor or pharmacist.
Hospital treatment for poisoning should include gastric lavage (within 10–12 hours after 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. If in doubt, consult your doctor.

Stopping 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 reactions

Like any medicine, Depakine Chrono 500 may cause adverse reactions, although not everyone experiences them. However, patients may require appropriate treatment if certain adverse reactions occur.
If any of the following serious adverse reactions 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 used concomitantly with phenobarbital or during a sudden increase in the dose of Depakine Chrono 500
Confusion, weakness, dizziness, nausea, vomiting, which may be caused by low sodium levels in the blood or a condition called "SIADH" (SIADH, Syndrome of Inappropriate Secretion of ADH) or syndrome of inappropriate antidiuretic hormone secretion
Problems with balance and coordination, drowsiness or reduced alertness combined with vomiting. This may be caused by increased levels of ammonia in the blood (hyperammonaemia)
Increased 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 peeling or bleeding from various body parts including lips, eyes, mouth, nose, genital organs, palms or soles), with or without rash, sometimes with 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 pink/red ring and pale centre, which may be itchy, scaly or filled with fluid. The rash may appear especially on palms or soles. These may be symptoms of a disease called "erythema multiforme"
- Swelling caused by allergy with painful, itchy oedema (most commonly around the eyes, lips, throat, and sometimes hands and feet) – these may be symptoms of "angioedema"
- Syndrome with skin rash, fever, swollen 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
Significant decrease in white blood cell count 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 rigidity, disturbances in body coordination (parkinsonism, extrapyramidal disorders, ataxia)
Muscle pain and weakness (rhabdomyolysis – breakdown of striated muscles)
Breathing difficulties, pain or a feeling of 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 reactions worsen or persist for longer than a few days, inform a doctor or pharmacist; treatment may be necessary.
Adverse reactions are presented according to the following frequency classification:
Very common (may occur in more than 1 in 10 people):

tremor
nausea

Common (may occur in no more than 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, seizures, 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 resolving after a few days without the need to discontinue treatment
gum disorders (mainly gingival hyperplasia), stomatitis (inflammation of the mouth)
transient and/or dose-dependent hair loss, nail and nail bed disorders
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 no more than 1 in 100 people):

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

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

macrocytic anaemia (low number of red blood cells), macrocytosis (abnormal increase in size of red blood cells)
biotin deficiency / biotinidase deficiency
excessive urination and thirst (Fanconi syndrome)
involuntary urination (nocturnal enuresis)
obesity
male infertility, which is usually reversible after discontinuation of treatment and may be reversible after dose reduction. Do not discontinue treatment without prior consultation with 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 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 disturbances, abnormal behaviour, hyperactivity and learning disorders.
Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed in this leaflet, inform a doctor or pharmacist. Adverse reactions 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, phone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Depakine Chrono 500

Al/Al blisters: Store below 30°C. Keep in the original
packaging, in a dry place, to protect from moisture.
PVC/PVDC/Al blisters: Store below 25°C. Keep in the original
packaging, in a dry place, to protect from moisture.
Keep this medicine out of sight and reach of children.
Do not use this 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. These measures will help
protect the environment.

6. Contents of the package and other information

What Depakine Chrono 500 contains
1 prolonged-release tablet of Depakine Chrono 500 contains the following active substances:
sodium valproate 333 mg,
valproic acid 145 mg,
corresponding in total to 500 mg of sodium valproate,
and the following excipients: copolymer of acrylic and methacrylic acid esters with a quaternary ammonium group, ethylcellulose, colloidal anhydrous silica.
Coating composition: hypromellose, macrogol 6000, talc, titanium dioxide (E 171), polyacrylate dispersion 30%.

What Depakine Chrono 500 looks like and contents of the pack
The pack contains 30 prolonged-release tablets.
For more detailed information, please contact the marketing authorization holder or the parallel importer.

Marketing Authorization 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:
InPharm Sp. z o.o.
ul. Strumykowa 28/11
03-138 Warsaw
Poland

Repackaged in:
InPharm Sp. z o.o. Services sp. k.
ul. Chełmżyńska 249
04-458 Warsaw
Poland

Marketing Authorization Numbers in Greece, country of export: 41972/10/21-06-2011
9081/18-02-2013

Parallel Import Authorization Number: 435/15

Patient information leaflets for women and men are available by scanning the QR code on the package leaflet using a smartphone. The same information is also available on the website: https://inpharm.pl/materialy-edukacyjne/#walproiniany
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