Depakine chronosphere 750

Poland
Brand name Depakine chronosphere 750
Form granules, prolonged release
Active substance / Dosage
Sodium valproate · 500.06 mg
Valproic acid · 217.75 mg
Prescription type Prescription only
ATC code
N03AG01
Registration number 100157017
Manufacturer Sanofi Winthrop Industry
Depakine chronosphere 750 granules, prolonged release

Table of Contents

Package leaflet: Information for the user

DEPAKINE CHRONOSPHERE 100
6 6.66 mg + 29.03 mg, prolonged-release granules
DEPAKINE CHRONOSPHERE 250
166.76 mg + 72.61 mg, prolonged-release granules
DEPAKINE CHRONOSPHERE 500
333.30 mg + 145.14 mg, prolonged-release granules
DEPAKINE CHRONOSPHERE 750
500.06 mg + 217.75 mg, prolonged-release granules
DEPAKINE CHRONOSPHERE 1000
666.60 mg + 290.27 mg, prolonged-release granules
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. For information on how to report adverse reactions – see section 4.
WARNING
Depakine Chronosphere (sodium valproate + valproic acid) used during pregnancy can 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 Chronosphere. This will be discussed with the patient by the treating physician, and patients should also follow the recommendations provided in section 2 of this leaflet.
Patients should contact their treating physician immediately if they are planning a pregnancy or suspect they may be pregnant.
Do not stop taking Depakine Chronosphere 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 others, even if their symptoms are the same.
  • If the patient experiences any adverse effects, including any adverse effects not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of the leaflet:

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

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

Depakine Chronosphere is a prolonged-release granule formulation (containing microgranules with a diameter of 350 µm to 450 µm) and contains sodium valproate and valproic acid as active substances. Depakine Chronosphere is a medicine used in the treatment of epilepsy and mania.
Depakine Chronosphere is used in the treatment of:

  • Epilepsy, in generalized seizures:
    • Myoclonic seizures
    • Tonic-clonic seizures
    • Atonic seizures
    • Mixed seizures
      Partial seizures:
    • Simple or complex partial seizures
    • Secondarily generalized seizures
    • Specific syndromes (West syndrome, Lennox-Gastaut syndrome).
  • Mania, which is a condition in which the patient feels extremely excited, elated, overactive, enthusiastic, or hyperactive. Mania occurs in a disorder known as bipolar affective disorder. Depakine Chronosphere may be used when lithium cannot be administered.

2. Important information before using Depakine Chronosphere

When not to use Depakine Chronosphere
Do not use this medicine if:

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

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

  • You experience any of the following symptoms suddenly: recurrent vomiting, feeling tired, abdominal pain, drowsiness, weakness, loss of appetite, nausea, jaundice (yellowing of the skin or whites of the eyes), or a recurrence of epileptic seizures, especially during the first 6 months of treatment. Depakine Chronosphere may cause severe liver damage, which can sometimes 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 Chronosphere is used in children under 3 years of age, in patients taking other antiepileptic medicines, in patients with other neurological or metabolic disorders, or in patients with severe epilepsy.
  • You experience severe abdominal pain. Very rarely, Depakine Chronosphere may cause pancreatitis.
  • You or your child taking Depakine Chronosphere experience problems with balance and coordination, drowsiness, or reduced alertness, vomiting. These may be caused by increased levels of ammonia in the blood.
  • 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 therapy. 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 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 surgery, and in cases of bruising or spontaneous bleeding, laboratory tests should be performed (assessment of total blood cell and platelet counts, 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 in the patient, particularly inherited enzyme deficiencies such as "urea cycle disorders", due to the risk of increased blood ammonia levels.
  • Patients treated with sodium valproate may experience increased appetite and weight gain.
  • If the patient has a rare condition called "carnitine palmitoyltransferase II deficiency", due to an increased risk of muscle disorders.
  • Concomitant use of carbapenem antibiotics with valproic acid is not recommended (see Depakine Chronosphere and other medicines).
  • Sodium valproate is primarily excreted by the kidneys, partly in the form of ketone bodies, so urine ketone tests in diabetic patients may give false-positive results.
  • If the patient has a family history or the 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 the patient has inadequate intake of carnitine, found in meat and dairy products, particularly in children under 10 years of age.
  • If the patient has carnitine deficiency and is taking carnitine supplements.
  • If the patient has ever experienced a severe skin rash, skin peeling, blistering, and/or oral ulcers after taking valproate.

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

Depakine Chronosphere and other medicines
Tell your doctor about all medicines you are currently taking, have recently taken, or plan to take.
Some medicines may interact with Depakine Chronosphere, affecting how either medicine works. These include:

  • neuroleptics, including quetiapine, olanzapine (used to treat psychotic disorders);
  • antidepressants;
  • benzodiazepines (used as sleeping aids or for treating anxiety disorders);
  • other antiepileptic medicines (phenobarbital, phenytoin, primidone, lamotrigine, carbamazepine, felbamate, topiramate, rufinamide);
  • cannabidiol (used in the treatment of epilepsy and other indications);
  • certain antibacterial medicines containing pivampicillin (such as pivampicillin, adefovir dipivoxil);
  • methotrexate (used in cancer and inflammatory diseases);
  • zidovudine, ritonavir, and lopinavir (used in HIV infection);
  • mefloquine (used for the treatment and prevention of malaria);
  • acetylsalicylic acid (commonly known as aspirin);
  • anticoagulants;
  • cimetidine (used for peptic ulcer disease);
  • 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 for pain and fever);
  • clozapine (used to treat psychiatric disorders).

Depakine Chronosphere with food, drink and alcohol
The medicine should be taken with soft food (yoghurt, fruit puree, cottage cheese, etc.) or drinks (fruit juices) – cold or at room temperature.
Food does not affect the absorption of the medicine from the gastrointestinal tract.
Do not consume alcohol while taking Depakine Chronosphere.

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

  • Do not use Depakine Chronosphere for the treatment of bipolar affective disorder if the patient is pregnant.
  • For the treatment of bipolar affective disorder, a woman of childbearing age must not take Depakine Chronosphere unless she uses an effective method of contraception throughout the entire treatment period. Do not stop taking Depakine Chronosphere or contraception without first discussing it with your doctor. Your doctor will provide further advice.

Epilepsy

  • Do not use Depakine Chronosphere for the treatment of epilepsy if the patient is pregnant, unless no other therapy is effective.
  • For the treatment of epilepsy, a woman of childbearing age must not take Depakine Chronosphere unless she uses an effective method of contraception throughout the entire treatment period. Do not stop taking Depakine Chronosphere or contraception without first discussing it with your doctor. Your doctor will provide further advice.

Risks 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 completely 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 skull developmental defects; heart, kidney, urinary tract, and genital organ malformations; limb defects; and multiple developmental abnormalities affecting several organs and body parts. Congenital malformations may lead to disabilities, which can be significant.
  • Hearing problems or deafness have been reported in children exposed to valproate in utero.
  • Eye developmental defects, often occurring together with other congenital malformations, have been reported in children exposed to valproate in utero. Eye 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 a group of children born to mothers taking valproate, about 11 out of 100 will have congenital malformations. For comparison, such malformations occur in about 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 experience early developmental problems. Affected children may start walking and talking later, may have lower intellectual abilities than other children, and may have language difficulties 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.
  • Children 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 children may have lower than expected birth weight. For comparison, this occurs in about 5–10 out of every 100 children born to women in the general population.
  • Before prescribing this medicine, your doctor will explain 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 on your own; discuss it with your doctor first.
  • Some contraceptive methods (oral contraceptives containing oestrogen) may reduce the blood concentration of valproate. Discuss with your doctor the most appropriate contraceptive method for you.
  • Parents or guardians of girls being treated with valproate should contact the doctor when their daughter starts menstruating.
  • Ask your doctor about taking folic acid when planning pregnancy. 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 the patient and read the relevant information:
o STARTING TREATMENT WITH DEPAKINE CHRONOSPHERE
o CONTINUING TREATMENT WITH DEPAKINE CHRONOSPHERE WITHOUT
PLANNING PREGNANCY
o CONTINUING TREATMENT WITH DEPAKINE CHRONOSPHERE WHILE
PLANNING PREGNANCY
o BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE
CHRONOSPHERE

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

  • Before starting Depakine Chronosphere, 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 Chronosphere.
  • Discuss with your doctor the appropriate method of contraception. 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) with 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 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 CHRONOSPHERE WITHOUT PLANNING PREGNANCY
If you are continuing treatment with Depakine Chronosphere and do not plan to become pregnant, you must ensure 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 must use an effective method of contraception throughout the entire treatment period with Depakine Chronosphere.
  • Discuss 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) with 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 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 CHRONOSPHERE WHILE PLANNING PREGNANCY
If you plan to have a child, you should first schedule an appointment with your doctor. Do not stop taking Depakine Chronosphere or contraception until you have discussed it with your doctor. Your doctor will provide 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 evaluate alternative treatment options as early as possible. The specialist may take steps to ensure the best possible pregnancy outcome and minimize risks to both mother and unborn child.
The specialist may decide to adjust the dose of Depakine Chronosphere, switch to another medicine, or discontinue Depakine Chronosphere well before conception – to ensure the condition is stable.
Ask your doctor about taking folic acid when planning pregnancy. 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 Chronosphere unless your doctor advises it.
  • Do not stop using contraceptive methods before discussing it with your doctor and jointly developing a management plan that ensures control of epilepsy/bipolar affective disorder 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 taking valproate during pregnancy.
  • Your doctor may try switching to another medicine or discontinuing Depakine Chronosphere 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 CHRONOSPHERE
Do not stop treatment with Depakine Chronosphere 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 provide 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 evaluate alternative treatment options.
In exceptional circumstances, when Depakine Chronosphere is the only available treatment option during pregnancy, you will be closely monitored for both your underlying condition and the child's 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 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 Chronosphere 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 counselling on the risks of using Depakine Chronosphere 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 any potential developmental abnormalities.

Newborns of mothers who took Depakine Chronosphere 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 patient's condition). The risk in children whose fathers discontinued valproate treatment at least 3 months (the time needed for new sperm production) before conception is unknown. The study has limitations, so it is unclear whether the increased risk of motor and mental developmental disorders suggested by this study is caused by valproate. The study was not large enough to identify the specific types of motor and mental 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 both the patient and his 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, 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. Stopping treatment may worsen your symptoms.
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 possible 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 breastfeeding is possible during treatment.

Driving and operating machinery
Some patients, especially at the beginning of treatment with Depakine Chronosphere or when treated concomitantly with other antiepileptic medicines or benzodiazepines, may experience drowsiness. Before driving or operating machinery, patients should ensure they know how they react to the treatment.

Depakine Chronosphere contains sodium
Depakine Chronosphere 100 contains less than 1 mmol (23 mg) of sodium per sachet, meaning the medicine is considered "sodium-free".
Depakine Chronosphere 250 contains 23.07 mg of sodium (a major component of table salt) in each sachet. This corresponds to 1.15% of the maximum recommended daily sodium intake in the adult diet.
Depakine Chronosphere 500 contains 46.08 mg of sodium (a major component of table salt) in each sachet. This corresponds to 2.30% of the maximum recommended daily sodium intake in the adult diet.
Depakine Chronosphere 750 contains 69.20 mg of sodium (a major component of table salt) in each sachet. This corresponds to 3.46% of the maximum recommended daily sodium intake in the adult diet.
Depakine Chronosphere 1000 contains 92.24 mg of sodium (a major component of table salt) in each sachet. This corresponds to 4.61% of the maximum recommended daily sodium intake in the adult diet.

3. How to use Depakine Chronosphere

Depakine Chronosphere must always be taken as prescribed by the doctor. If in doubt, consult your doctor.
Girls and women of childbearing age
Treatment with Depakine Chronosphere should be initiated and supervised by a doctor specialized in the treatment of epilepsy or bipolar affective disorder.
Male patients
It is recommended that treatment with Depakine Chronosphere be initiated and supervised by a specialist experienced in treating epilepsy or bipolar affective disorder – see section 2 Important advice for male patients.
The pharmaceutical form of Depakine Chronosphere, prolonged-release granules, can be used in all patients, especially in children (if the child is able to swallow liquid food), in adults with swallowing difficulties, and in elderly patients.
Depakine Chronosphere may be taken once or twice daily.
The daily dose of the medication will be determined by the doctor based on age and body weight; individual sensitivity to sodium valproate in individual patients should also be taken into account.
Initiating treatment with Depakine Chronosphere in epilepsy treatment

  • In patients not taking other antiepileptic drugs, the dose should be increased every 2 or 3 days to achieve the optimal dose within one week.
  • In patients receiving other antiepileptic drugs, treatment with Depakine Chronosphere should be introduced gradually, reaching the optimal dose over 2 weeks, after which doses of other antiepileptic drugs should be gradually reduced until discontinued.
  • If concomitant use of other antiepileptic drugs is necessary, they should be introduced gradually.

The usual initial daily dose is 5 to 15 mg/kg body weight; this should then be gradually increased until the optimal dose is reached (see: Initiating treatment with Depakine Chronosphere).
This dose usually ranges from 20 to 30 mg/kg body weight per day. If adequate seizure control is not achieved, the dose may be increased; patients receiving doses above 50 mg/kg body weight should be closely monitored.
Children with body weight above 17 kg
The usual maintenance dose is 30 mg/kg body weight per day.
Adults
The usual maintenance dose is 20 to 30 mg/kg body weight per day.
Elderly patients
Although the pharmacokinetics of the drug may change in elderly patients, this has no significant clinical importance. 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.
Method of administration
Depakine Chronosphere is tasteless and should be administered by sprinkling it onto soft food (yogurt, fruit puree, cottage cheese, etc.) or cold or room-temperature beverages (fruit juices).
Depakine Chronosphere must not be administered with warm or hot food or drinks (e.g., soup, coffee, tea, etc.).
If necessary, the contents of the sachet can also be administered directly into the mouth, followed by rinsing the mouth with a small amount of cold drink.
Depakine Chronosphere must not be administered in a feeding bottle with a nipple, as the microgranules may block the nipple opening.
When administering Depakine Chronosphere with liquids, it is recommended to rinse the glass with a small amount of water and drink it, as microgranules may adhere to the glass walls.
The prepared medication must be taken immediately and must not be chewed.
Do not leave the medication for later use.
Duration of treatment
The medication should be taken for as long as prescribed by the doctor.
Do not discontinue treatment or change the dose without consulting your doctor.
If you feel that the effect of Depakine Chronosphere is too strong or too weak, consult your doctor.
Patients with impaired renal function
The doctor may decide that dose adjustment is necessary.
Taking more than the recommended dose of Depakine Chronosphere
Clinical symptoms of severe overdose are usually: coma with reduced muscle tone, hyporeflexia (diminished reflexes), miosis (pupil constriction), respiratory disturbances, and convulsions. Metabolic acidosis, hypotension, and acute cardiovascular failure may also occur. The presence of sodium in valproate pharmaceutical forms may lead to increased blood sodium levels in case of overdose.
Treatment of overdose is symptomatic and should be conducted in a hospital. Treatment includes gastric lavage (within 10–12 hours after ingestion) and monitoring of cardiovascular and respiratory function.
Naloxone has proven effective in several cases.
In case of ingestion of more than the recommended dose, seek immediate medical advice from a doctor or pharmacist.
Missing a dose of Depakine Chronosphere
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 once or within a short time interval.
In case of doubt, consult your doctor.
Stopping treatment with Depakine Chronosphere
Do not discontinue treatment with Depakine Chronosphere 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 Chronosphere 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 a patient, contact a doctor immediately, as the patient may urgently require medical assistance:

  • Coma, encephalopathy (brain damage), lethargy (a state of inactivity and lack of response to stimuli), changes in behaviour, with or without increased frequency or severity of epileptic seizures, especially when co-administered with phenobarbital or during a sudden increase in the dose of Depakine Chronosphere
  • 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 caused by increased levels of ammonia in the blood (hyperammonemia)
  • 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), swelling of the legs 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 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 pink/red ring and pale center, 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 swellings (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 known as "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 confirmed by blood tests, sometimes accompanied by 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, chest 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 more than a few days, inform your doctor or pharmacist; treatment may be necessary.
Adverse reactions are listed 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, convulsions, memory disturbances, nystagmus (rapid, uncontrolled eye movements), dizziness
  • hearing impairment
  • vomiting, stomach pain, diarrhoea (frequent in some patients at the beginning of treatment), usually resolves after a few days without the need to discontinue treatment
  • gum disorders (mainly gum overgrowth), inflammation of the mouth
  • transient and/or dose-dependent hair loss, nail disorders and nail bed disorders
  • weight gain, which should be monitored as it is associated with polycystic ovary syndrome
  • irregular menstrual cycles
  • confusion (disorientation), hallucinations, aggression, agitation, attention disturbances
  • urinary incontinence

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

  • leukopenia (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 Depakine Chronosphere treatment
  • 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 affect up to 1 in 1,000 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 familial and/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 those not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw,
Tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to gather more information on the safety of the medicine.

5. How to store Depakine Chronosphere

Depakine Chronosphere sachets should be stored below 25°C in the
original packaging, in a dry place.
The medicine should be kept 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 in use. This will help
protect the environment.

6. Contents of the pack and other information

What the medicine contains
Depakine Chronosphere 100
Each sachet contains as active substances:
sodium valproate 66.66 mg
valproic acid 29.03 mg
corresponding in total to 100 mg of sodium valproate.
Depakine Chronosphere 250
Each sachet contains as active substances:
sodium valproate 166.76 mg
valproic acid 72.61 mg
corresponding in total to 250 mg of sodium valproate.
Depakine Chronosphere 500
Each sachet contains as active substances:
sodium valproate 333.30 mg
valproic acid 145.14 mg
corresponding in total to 500 mg of sodium valproate.
Depakine Chronosphere 750
Each sachet contains as active substances:
sodium valproate 500.06 mg
valproic acid 217.75 mg
corresponding in total to 750 mg of sodium valproate.
Depakine Chronosphere 1000
Each sachet contains as active substances:
sodium valproate 666.60 mg
valproic acid 290.27 mg
corresponding in total to 1000 mg of sodium valproate.
The medicine also contains: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

What Depakine Chronosphere looks like and contents of the pack
Depakine Chronosphere is a prolonged-release granulate.
The pack contains 30 sachets of Depakine Chronosphere medicine.

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

Manufacturer:
Sanofi-Winthrop Industrie
196, avenue du Marechal Juin
45200 Amilly
France

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

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