Depakine chrono 300

Poland
Brand name Depakine chrono 300
Form tablets, film-coated, prolonged release
Active substance / Dosage
sodium valproate · 200 mg
valproic acid · 87 mg
Prescription type Prescription only
ATC code
N03AG01
Registration number 100017799
Manufacturer Sanofi Aventis S.A. Sanofi Winthrop Industry
Depakine chrono 300 tablets, film-coated, prolonged release

Table of Contents

Package leaflet: Information for the user

DEPAKINE CHRONO 300
200 mg + 87 mg, prolonged-release coated tablets
DEPAKINE CHRONO 500
333 mg + 145 mg, prolonged-release coated tablets
Sodium valproate + Valproic acid
This medicinal product will be subject to additional monitoring. This will allow rapid
identification of new safety information. Users of this medicine can also help by reporting any
adverse reactions that occur after using the medicine. To find out how to report adverse reactions – see section 4.
WARNING
Depakine Chrono (sodium valproate + valproic acid) used during pregnancy can seriously harm the unborn child. Women of childbearing potential must use an effective method of birth control (contraception) continuously throughout the entire duration of treatment with Depakine Chrono. This will be discussed by the treating physician with the patient, and recommendations presented in section 2 of this leaflet should also be followed.
Patients should contact their doctor immediately if they plan to become pregnant or suspect they may be pregnant.
Do not stop taking Depakine Chrono unless instructed by a doctor, as the patient's condition may worsen.
Please read all of this leaflet carefully before taking this medicine, as it contains important information for the patient.

  • 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. This medicine may harm another person, 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.

Leaflet contents:

  1. What Depakine Chrono is and what it is used for
  2. What you need to know before taking Depakine Chrono
  3. How to take Depakine Chrono
  4. Possible side effects
  5. How to store Depakine Chrono
  6. Contents of the pack and other information

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

Depakine Chrono is available as prolonged-release coated 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 is a medicine used in the treatment of epilepsy and mania.
Depakine Chrono 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 may be used when lithium cannot be administered.

2. Important information before using Depakine Chrono

When not to use Depakine Chrono
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 had 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 mefloquine is being used at the same time,
  • you have a genetic disorder causing mitochondrial disturbances (e.g. patients with Alpers-Huttenlocher syndrome),
  • you have metabolic disorders such as urea cycle disorders,
  • you have carnitine deficiency (a very rare metabolic disorder) which is not being treated.
  • for bipolar affective disorder:
    • if you are pregnant,
    • if you are of childbearing potential, unless you are using an effective method of contraception throughout treatment with Depakine Chrono. Do not stop taking Depakine Chrono or your contraception until you have discussed this with your doctor. Your doctor will give you further advice (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).
  • for epilepsy:
    • if you are pregnant, unless no other treatment is effective,
    • if you are of childbearing potential, unless you are using an effective method of contraception throughout treatment with Depakine Chrono. Do not stop taking Depakine Chrono or your contraception until you have discussed this with your doctor. Your doctor will give you further advice (see below “Pregnancy, breastfeeding and fertility – Important advice for women”).

Warnings and precautions
Talk to your doctor before starting treatment with Depakine Chrono.
CONTACT YOUR DOCTOR IMMEDIATELY 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 a recurrence of seizures, especially during the first 6 months of treatment.

Depakine Chrono may cause severe liver damage, which may occasionally be fatal.
Liver function tests should be performed regularly before starting treatment and during the first 6 months of treatment.
The risk of liver damage increases if Depakine Chrono is used 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 may cause severe pancreatitis, sometimes fatal.
  • you or your child being treated with Depakine Chrono experience problems with balance and coordination, drowsiness or reduced alertness, or vomiting. This 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 during treatment with valproate. If you notice any of the symptoms associated with these serious skin reactions described in section 4, you should contact your doctor immediately.

Talk to your doctor before taking this medicine:

  • 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 potential must use effective contraception during treatment.
  • Before starting treatment, including before surgery and in cases 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 you are suspected of having any metabolic disorder, especially inborn 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 disorder 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 with other medicines").
  • Sodium valproate is excreted mainly by the kidneys, partly in the form of ketone bodies, so in diabetic patients, tests for ketone bodies may give false positive results.
  • If you have a family history or your doctor suspects a genetic disorder due to mitochondrial disturbances, 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 had a severe skin rash, skin peeling, blistering and/or mouth ulcers after taking valproate.

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

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

  • neuroleptics, 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 for other indications);
  • certain antiviral medicines containing pivoxil (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 some contraceptive medicines);
  • 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 use alternative medicines. Your doctor will inform you of any changes in treatment.
Your doctor will also provide additional information about medicines which should be used with caution or avoided during treatment with Depakine Chrono.

Depakine Chrono with food, drink and alcohol
This medicine should be taken with food.
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 to treat bipolar affective disorder if you are pregnant.
  • Women of childbearing potential must not take Depakine Chrono to treat bipolar affective disorder unless they are using an effective method of contraception throughout treatment with Depakine Chrono. Do not stop taking Depakine Chrono or your contraception until you have discussed this with your doctor. Your doctor will give you further advice.

Epilepsy

  • Do not use Depakine Chrono to treat epilepsy if you are pregnant, unless no other treatment is effective.
  • Women of childbearing potential must not take Depakine Chrono to treat epilepsy unless they are using an effective method of contraception throughout treatment with Depakine Chrono. Do not stop taking Depakine Chrono or your contraception until you have discussed this with your doctor. Your doctor will give you further advice.

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

  • Contact your doctor immediately if you are planning a 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 are not properly formed); 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 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 be less intellectually capable 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 (attention deficit hyperactivity disorder - ADHD) in these children.

  • Babies born to women taking valproate during pregnancy may have lower birth weight than expected for gestational age. In women taking valproate, about 11-15 out of every 100 babies may have lower than expected birth weight. For comparison, this affects about 5-10 out of every 100 babies born to women in the general population.

  • Before prescribing this medicine, your doctor will explain to you what risks may affect the 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 your contraception without first discussing it with your doctor.

  • Some contraceptive methods (contraceptive pills 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 being 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 taking folic acid will reduce the risk of congenital malformations associated with valproate treatment.

Please select the situation below that applies to you and read the information:
o STARTING TREATMENT WITH DEPAKINE CHRONO
o CONTINUING TREATMENT WITH DEPAKINE CHRONO WITHOUT TRYING FOR A CHILD
o CONTINUING TREATMENT WITH DEPAKINE CHRONO WHILE TRYING FOR A CHILD
o BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE CHRONO

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

Important information

  • Before starting treatment with Depakine Chrono, 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 treatment with Depakine Chrono.
  • Discuss the appropriate method of contraception with your doctor. Your doctor will provide you with information on preventing pregnancy and may refer you to a specialist for advice on contraception.
  • 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 well informed and understand all the risks and advice related to taking valproate 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 WITHOUT TRYING FOR A CHILD
If you continue treatment with Depakine Chrono and do not plan pregnancy, you must be certain that you are using an effective method of contraception continuously throughout treatment with Depakine Chrono. 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 treatment with Depakine Chrono.
  • Discuss contraception (method of birth control) with your doctor. Your doctor will provide you with information on preventing pregnancy and may refer you to a specialist for advice on contraception.
  • 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 well informed and understand all the risks and advice related to taking valproate 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 WHILE TRYING FOR A CHILD
If you plan to have a child, you should first schedule an appointment with your doctor. Do not stop taking Depakine Chrono or your contraception until you have discussed this with your doctor. Your doctor will give you further advice.
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 appropriately assess alternative treatment options. The specialist may take steps to ensure the best possible pregnancy outcome and minimise risks for both mother and unborn child.
The specialist may decide to change the dose of Depakine Chrono, switch to another medicine or discontinue treatment with Depakine Chrono well before conception to ensure that 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 taking folic acid will reduce the risk of congenital malformations associated with valproate treatment.

Important information

  • Do not stop treatment with Depakine Chrono unless your doctor advises you to do so.
  • 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 that you have been well informed and understand all the risks and advice related to taking valproate during pregnancy.
  • Your doctor will try switching to another medicine or discontinuing treatment with Depakine Chrono 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
Do not stop treatment with Depakine Chrono until you have discussed 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 give you further advice.
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 assess alternative treatment options.
In exceptional circumstances, when Depakine Chrono is the only available treatment option during pregnancy, you will be monitored very closely, both regarding treatment of the underlying condition and the development of the child. 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 every pregnancy. However, it is unlikely that taking folic acid 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 unless your doctor advises you to do so.
  • You should ensure that you are referred to a specialist experienced in treating epilepsy or bipolar affective disorder to assess the need for alternative treatment methods.
  • You must receive counselling on the risks of using Depakine Chrono during pregnancy, including its teratogenic effects (causing congenital malformations) and physical and mental developmental disorders in children.
  • You should ensure that you are referred to a specialist in prenatal monitoring to detect possible developmental defects.

Newborns of mothers who took Depakine Chrono during pregnancy may experience blood clotting disorders, hypoglycaemia, hypothyroidism and withdrawal symptoms such as agitation, irritability, hyperactivity, muscle 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 of taking valproate during pregnancy.

Important advice for male patients
Possible risks 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 the patient has). The risk in children whose fathers discontinued valproate treatment at least 3 months (the time required for new sperm production) before conception is not known. 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 show exactly what types of motor and mental developmental disorders in children are associated with this risk.
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 treatment;
  • 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 it.
If you are planning a child, discuss this with your doctor.
If your partner becomes pregnant while you are taking valproate within the 3 months before conception and you have questions about this, 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 taking valproate and the possibility of using alternative treatment methods 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 taking valproate.

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 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 contains sodium
Depakine Chrono 300 contains 27.65 mg of sodium (the main component of table salt) in each tablet. This corresponds to 1.38% of the maximum recommended daily sodium intake in the diet of adults.
Depakine Chrono 500 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 sodium intake in the diet of adults.

3. How to use Depakine Chrono

Depakine Chrono must always be used as directed by the physician. In case of doubt,
consult your doctor.
Girls and women of childbearing age
Treatment with Depakine Chrono should be initiated and supervised by a physician
specializing in the treatment of epilepsy or bipolar affective disorder.
Male patients
It is recommended that treatment with Depakine Chrono be initiated and supervised by a specialist
experienced in treating epilepsy or bipolar affective disorder – see section 2
Important advice for male patients.
The prolonged-release formulation allows Depakine Chrono to be administered as a single daily dose or divided into two doses per day.
If indicated, Depakine Chrono prolonged-release coated 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 should be determined according to age and body weight; additionally, the physician must always take into account the individual patient's sensitivity to valproate.
Switching therapy to prolonged-release formulations (Depakine Chrono).
When switching from conventional tablets to prolonged-release tablets, it is recommended (according to current knowledge) to maintain the same total daily dose.
Initiating treatment with Depakine Chrono in epilepsy
When starting treatment with Depakine Chrono 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 in patients already treated with other antiepileptic drugs, the dose of Depakine Chrono should be gradually increased over a period of 2 weeks to reach the average recommended dose. Subsequently, the dose of the other drugs should be gradually reduced to a level ensuring optimal seizure control or, if appropriate, discontinued.
If adding other anticonvulsant drugs 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).
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 strict clinical monitoring of the patient is maintained (see section: Exercise particular caution when using Depakine Chrono).
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 based on 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 is too strong or too weak, consult your doctor.
Patients with renal impairment
The physician may decide whether dose adjustment is necessary.
Use of a higher than recommended dose of Depakine Chrono
Symptoms of severe overdose with valproic acid derivatives include: coma, decreased muscle tone and tendon reflexes, pupillary constriction, respiratory disturbances; metabolic acidosis, reduced arterial blood pressure, 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 blood sodium concentration in case of overdose.
If a higher than recommended dose has been taken, seek immediate medical advice from a doctor or pharmacist.
Hospital treatment in cases of poisoning should include: gastric lavage (up to 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
If a dose is missed, take it as soon as possible, except when the next dose is due soon. 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
Do not discontinue treatment with Depakine Chrono 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 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 severe adverse reactions occur in the 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 an increased frequency or severity of epileptic seizures, especially when Depakine Chrono is taken concomitantly with phenobarbital or when the dose of Depakine Chrono 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)
  • Problems with balance and coordination, drowsiness or feeling less alert, combined with vomiting. This may be due to 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:
    • Blistering with skin peeling (formation of blisters, skin peeling 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 centre, which may be itchy, peeling or filled with fluid. The rash may appear especially on the 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, enlarged lymph nodes and possible damage to other organs – these may be symptoms of a condition known as "DRESS" or drug reaction with eosinophilia and systemic symptoms
  • Blood clotting disorders confirmed by laboratory tests, which may lead to spontaneous bruising and bleeding
  • Marked decrease in white blood cell count or bone marrow failure shown in blood tests, sometimes accompanied by fever and difficulty breathing
  • 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 manifest as reduced urine output

If any of the following adverse reactions worsen or persist for longer than a few days, inform your doctor or pharmacist; treatment may be necessary.

Adverse reactions are listed below according to the following frequency classification:

Very common (may affect more than 1 in 10 people):

  • tremor
  • nausea

Common (may affect 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, 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 abnormalities (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, hallucinations, aggression, agitation, attention disturbances
  • urinary incontinence

Uncommon (may affect 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 and 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 on long-term Depakine Chrono treatment
  • 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 affect fewer than 1 in 1,000 people):

  • macrocytic anaemia (low number of red blood cells), macrocytosis (abnormal increase in red blood cell size)
  • 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)

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

  • congenital disorders and inherited or genetic diseases
  • decreased carnitine levels (visible in blood and muscle tests)
  • darkened 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 reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at 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
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Depakine Chrono

Store the medicine below 25°C. Keep in the original, tightly closed packaging to protect from light and moisture.
Keep the medicine out of the reach and sight of children.
Do not use the medicine after the expiry date stated on the packaging.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What Depakine Chrono contains
Depakine Chrono 300
One prolonged-release coated tablet of Depakine Chrono 300 contains as active substances:
sodium valproate 200 mg,
valproic acid 87 mg,
corresponding in total to 300 mg of sodium valproate
and excipients: copolymer of acrylic and methacrylic acid esters with quaternary ammonium chloride, ethylcellulose (20 mPa·s), colloidal hydrated silica.
Coating composition: hypromellose (6 mPa·s), polyethylene glycol 6000, talc, titanium dioxide (E 171), polyacrylate 30%.

Depakine Chrono 500
One prolonged-release coated tablet of Depakine Chrono 500 contains as active substances:
sodium valproate 333 mg,
valproic acid 145 mg,
corresponding in total to 500 mg of sodium valproate
and excipients: copolymer of acrylic and methacrylic acid esters with quaternary ammonium chloride, ethylcellulose (20 mPa·s), colloidal hydrated silica.
Coating composition: hypromellose (6 mPa·s), polyethylene glycol 6000, talc, titanium dioxide (E 171), polyacrylate 30%.

What Depakine Chrono looks like and contents of the pack
The pack contains 30 prolonged-release coated tablets of Depakine Chrono 300 or Depakine Chrono 500.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Sanofi Sp. z o.o.
Marcina Kasprzaka 6
01-211 Warsaw
Poland

Manufacturers:
Sanofi Aventis S.A.
Ctra. C-35 (La Batlloria-Hostalric Km. 63.09)
Riells i Viabrea, 17404 Girona
Spain

Sanofi-Winthrop Industrie
1 rue de la Vierge
33 440 Ambares
France

For further information about this medicinal product, please contact the Marketing Authorisation Holder:
Sanofi Sp. z o.o.
Marcina Kasprzaka 6
01-211 Warsaw
Poland
Tel.: +48 22 280 00 00

Other sources of information
Detailed and up-to-date information on this medicinal product is available by scanning with a smartphone the QR code located on the leaflet and outer packaging. The same information is also available on the website: www.qr.walproinianija.pl