Package leaflet: Information for the user

Warning! Keep this leaflet. Information on the immediate packaging is in a foreign language.
Depakine
400 mg (400 mg/4 ml), powder and solvent for solution for injection
Natrii valproas
▼ This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can also help by reporting any side effects you experience with this medicine. For information on how to report side effects – see section 4.
WARNING
Depakine (sodium valproate) used during pregnancy can seriously harm the unborn child. Women of childbearing potential must use effective contraception (birth control) continuously throughout the entire duration of treatment with Depakine. Your doctor will discuss this with you. Please also follow the recommendations given in section 2 of this leaflet.
You must contact your doctor immediately if you are planning a pregnancy or suspect you may be pregnant.
Do not stop taking Depakine unless your doctor tells you to, as your condition may worsen.
Please read all of this leaflet carefully before using this medicine, as it contains important information for you.

Keep this leaflet, so that you can read it again if needed.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm someone else, even if their symptoms are the same.
If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents:

What Depakine is and what it is used for
What you need to know before using Depakine
How to use Depakine
Possible side effects
How to store Depakine
Contents of the pack and other information

1. What Depakine is and what it is used for

Depakine is a powder for solution for injection and contains the active substance sodium valproate. Sodium valproate belongs to a group of medicines called anticonvulsants. It has anticonvulsant activity in various types of epilepsy in humans.
Depakine is used:

in epileptic seizures when intravenous benzodiazepines are ineffective;
in cluster seizures;
for the treatment of convulsive seizures when oral treatment is temporarily impossible due to the patient's state of consciousness or inability to swallow, especially if the patient has previously been effectively treated orally with sodium valproate. This applies to generalized and partial seizures;
prophylactically in connection with neurosurgical procedures of the head when there is a risk of occurrence of epileptic seizure(s).

2. Important information before using Depakine

When not to use Depakine
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 hepatitis,
the patient has previously experienced 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 used concomitantly with mefloquine,
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 untreated,
epilepsy:
the patient is pregnant, unless no other therapy is effective,
the patient is of childbearing potential, unless she uses an effective method of contraception throughout the entire treatment period with Depakine. Do not stop taking Depakine 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, discuss this with your doctor.
CONTACT YOUR DOCTOR IMMEDIATELY IF:

Sudden onset of the following symptoms occurs: 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. Contact your doctor immediately.
Depakine 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 increases if Depakine is used in children under 3 years of age, in patients taking other antiepileptic drugs, in patients with other neurological or metabolic disorders, and in patients with severe forms of epilepsy. Sodium valproate should not be administered concomitantly with salicylates in children under 3 years of age due to the risk of hepatotoxic effects.
Severe abdominal pain occurs. Rarely, Depakine may cause severe pancreatitis, sometimes fatal.
The patient or their child taking Depakine develops problems with balance and coordination, drowsiness or reduced alertness, or vomiting. This may be due to increased blood ammonia levels.
The patient has ever had thoughts of self-harm or suicide. A small number of people taking antiepileptic medicines containing sodium valproate have had such thoughts. If these occur, contact your doctor immediately.
Serious skin reactions have been reported with valproate treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema. If the patient notices any symptoms related to these serious skin reactions described in section 4, they should seek medical advice immediately.

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

Valproate should not be used in women with epilepsy who are planning pregnancy, except when other treatments are ineffective or not tolerated. The benefits of treatment should be weighed against the risks before the first prescription or when a woman treated with valproate plans pregnancy. Women of childbearing potential must use effective contraception during treatment.
Before starting treatment, including before any surgical procedure, and in case of bruising or spontaneous bleeding, laboratory tests are recommended (complete blood count with blood smear, including platelet count, bleeding time, and coagulation tests).
Use with caution in patients with renal impairment. Your doctor may recommend a lower dose.
Use with caution in patients with systemic lupus erythematosus.
If a 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.
Weight gain may occur in patients treated with sodium valproate.
In patients with 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: Depakine and other medicines).
Sodium valproate is excreted mainly by the kidneys, partly in the form of ketone bodies; therefore, in diabetic patients, urine ketone tests may yield 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 drugs, 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 previously experienced severe skin rash, skin peeling, blistering, and/or oral ulceration after taking valproate.

Depakine with other medicines
Tell your doctor about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
Some medicines may affect the action of sodium valproate, and valproate may also affect the action of other medicines.
These include:

neuroleptic medicines, including quetiapine, olanzapine (used to treat psychotic disorders);
medicines used to treat depression, MAO inhibitors;
benzodiazepines, used to treat insomnia and anxiety disorders;
other medicines used to treat epilepsy, including phenobarbital, phenytoin, primidone, lamotrigine, carbamazepine, felbamate, topiramate, rufinamide;
cannabidiol (used to treat epilepsy and for other indications);
certain antimicrobial agents containing pivampicillin (such as pivampicillin, adefovir dipivoxil);
methotrexate (used to treat cancer and inflammatory diseases);
zidovudine, ritonavir, and lopinavir (used to treat HIV infection and AIDS);
mefloquine (used to treat and prevent malaria);
salicylates (acetylsalicylic acid);
anticoagulant medicines;
cimetidine (used to treat gastric ulcers);
erythromycin, rifampicin;
carbapenems (antibiotics used to treat bacterial infections);
cholestyramine (used to lower blood cholesterol levels);
propofol (used for general anaesthesia);
nimodipine;
medicines containing estrogen (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. The patient may require dose adjustments of individual medicines or alternative treatments. Your doctor will inform the patient about any such changes in treatment.
Your doctor will also provide additional information about medicines that should be used with caution or avoided during treatment with Depakine.

Depakine with food, drink and alcohol
Alcohol consumption is not recommended during treatment with valproate.

Pregnancy, breastfeeding and fertility
Pregnancy
Important advice for women

Do not use Depakine if the patient is pregnant, unless no other therapy is effective.
If the patient is of childbearing potential, she must not take Depakine unless she uses an effective method of contraception (birth control) throughout the entire treatment period with Depakine. Do not stop taking Depakine or contraception until this has been discussed with your doctor. Your doctor will provide further guidance.

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

Consult your doctor immediately if the patient is planning pregnancy or is 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 drugs.
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 associated developmental defects 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 together with other congenital malformations have been reported in children exposed to valproate in utero. Eye defects may affect vision.
Pregnant patients taking valproate have an increased risk of giving birth to a child with congenital malformations requiring treatment. Valproate has been used for many years, so it is known that in the group of children born to mothers taking valproate, about 11 out of 100 will have congenital malformations. For comparison, such malformations occur in 2–3 out of every 100 children born to women without epilepsy.
It is estimated that up to 30–40% of preschool-aged children whose mothers took valproate during pregnancy may have early developmental problems. Affected children may start walking and talking later, may have lower intellectual abilities than other children, and may have language and memory problems.
Children exposed to valproate in utero are more frequently diagnosed with various disorders within the autism spectrum. Some evidence suggests an increased risk of attention deficit (attention deficit hyperactivity disorder – ADHD) in these children.
Before prescribing this medicine, your doctor will explain to the patient what risks the unborn child may face if she becomes pregnant while taking valproate. If the patient taking this medicine decides she wants to have a child, she should not stop taking the medicine or contraception on her own, but must discuss it with her doctor first.
Some contraceptive methods (contraceptive pills containing estrogen) may reduce the blood concentration of valproate. Discuss with your doctor the most appropriate method of contraception (birth control) for the patient.
Parents or caregivers 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 will reduce the risk of congenital malformations associated with valproate treatment.

Please select the situation below that applies to the patient and read the information:
○ STARTING TREATMENT WITH DEPAKINE
○ CONTINUING TREATMENT WITH DEPAKINE WITHOUT PLANNING PREGNANCY
○ CONTINUING TREATMENT WITH DEPAKINE WHILE PLANNING PREGNANCY
○ BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE

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

Before starting Depakine, the patient should confirm she is not pregnant with a pregnancy test, the result of which should be confirmed by the doctor.
The patient must use an effective method of birth control (contraception) throughout the entire treatment period with Depakine.
Discuss the appropriate method of contraception (birth control) with the doctor. The doctor will provide information on pregnancy prevention and may refer the patient to a specialist for advice on birth control.
Visit a specialist experienced in epilepsy treatment regularly (at least once a year). During this visit, the doctor will ensure that the patient has been adequately informed and understands all risks and advice related to using valproate during pregnancy.
If the patient plans to have a child, she should inform her doctor.
If the patient is pregnant or suspects she may be pregnant, she should inform her doctor immediately.

CONTINUING TREATMENT WITH DEPAKINE WITHOUT PLANNING PREGNANCY
If the patient continues treatment with Depakine and does not plan pregnancy, she must be certain that she uses an effective method of contraception continuously throughout the entire treatment period with Depakine. If the patient needs advice on contraception, she should consult her doctor or a family planning clinic.
Important information:

The patient must use an effective method of birth control (contraception) throughout the entire treatment period with Depakine.
Discuss contraception (birth control method) with the doctor. The doctor will provide information on pregnancy prevention and may refer the patient to a specialist for advice on birth control.
Visit a specialist experienced in epilepsy treatment regularly (at least once a year). During this visit, the doctor will ensure that the patient has been adequately informed and understands all risks and advice related to using valproate during pregnancy.
If the patient plans to have a child, she should inform her doctor.
If the patient is pregnant or suspects she may be pregnant, she should inform her doctor immediately.

CONTINUING TREATMENT WITH DEPAKINE WHILE PLANNING PREGNANCY
If the patient plans to have a child, she should first schedule an appointment with her doctor. Do not stop taking Depakine or contraception until this has been discussed with the doctor. The doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems, which may significantly impair the child. The doctor will refer the patient to a specialist experienced in epilepsy treatment to appropriately assess alternative treatment options. The specialist may take steps to ensure the best possible pregnancy outcome and minimize risks for both mother and unborn child.
The treating specialist may decide to change the dose of Depakine, switch to another medicine, or discontinue Depakine 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 will reduce the risk of congenital malformations associated with valproate treatment.
Important information:

Do not stop treatment with Depakine unless advised by the doctor.
Do not stop using birth control methods (contraception) before talking to the doctor and jointly developing a management plan that ensures control of the patient's condition and reduces risks to the child.
First, schedule an appointment with the doctor. During this visit, the doctor will ensure that the patient has been adequately informed and understands all risks and advice related to using valproate during pregnancy.
The doctor will attempt to switch to another medicine or discontinue Depakine treatment well before conception.
If the patient is pregnant or suspects she may be pregnant, she should schedule an urgent appointment with her doctor.

BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE
Do not stop treatment with Depakine until this has been discussed with the doctor, as the patient's health condition may worsen. If the patient is pregnant or suspects she may be pregnant, she should schedule an urgent appointment with her doctor. The doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems, which may significantly impair the child. The patient will be referred to a specialist experienced in epilepsy treatment to assess alternative treatment options.
In exceptional circumstances, when Depakine is the only available treatment option during pregnancy, the patient will be closely monitored, both regarding the treatment of the underlying disease and the development of the fetus. The patient and her partner will receive counseling 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 will reduce the risk of congenital malformations associated with valproate treatment.
Important information:

If the patient is pregnant or suspects she may be pregnant, she should schedule an urgent appointment with her doctor.
Do not stop treatment with Depakine unless advised by the doctor.
The patient should ensure she is referred to a specialist experienced in epilepsy treatment to assess the need for alternative treatment methods.
The patient must receive counseling on the risks of using Depakine during pregnancy, including its teratogenic effects (causing congenital malformations) and physical and mental developmental disorders in children.
The patient should ensure she is referred to a specialist specializing in prenatal monitoring to detect possible developmental abnormalities.

In newborns of mothers who took Depakine during pregnancy, disorders of blood clotting, hypoglycemia, hypothyroidism, and withdrawal symptoms such as agitation, irritability, hyperactivity, tremors, seizures, and feeding difficulties may occur.
Please read the patient guide provided by your doctor.
Your doctor will discuss the annual risk acknowledgment form and ask the patient to sign and keep it. The patient will also receive a patient card from the pharmacist as a reminder of the risks associated with valproate use during pregnancy.

Important advice for male patients
Possible risk associated with taking valproate within 3 months before conception
A study suggests a possible risk of motor disorders and psychological developmental disorders (early childhood developmental problems) in children whose fathers were treated with valproate during the 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 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, the doctor will discuss with the patient:

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

Do not donate semen while taking valproate and for 3 months after discontinuation.
If planning parenthood, discuss this with your doctor.
If the patient's partner becomes pregnant while the patient is taking valproate within the 3 months before conception and the patient has questions, he should contact his doctor. Do not stop treatment without consulting the doctor. If the patient stops treatment, symptoms may worsen.
The patient should attend regular appointments with the prescribing doctor. During such visits, the doctor will discuss precautions related to valproate use and the possibility of alternative treatment methods for the patient's condition, depending on the individual situation.
Please read the patient guide provided by your doctor. The patient 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
In some patients, drowsiness may occur during treatment, especially when taking multiple antiepileptic drugs or when benzodiazepines are used concomitantly. Before driving or operating machinery, the patient should ensure how they react to the treatment.

Depakine contains sodium
Depakine contains 55.35 mg of sodium (the main component of table salt) in 400 mg of sodium valproate. This corresponds to 2.8% of the maximum recommended daily sodium intake in the adult diet.

3. How to use Depakine

The medicine should always be used as directed by the physician. In case of doubt, consult your doctor.

Girls and women of childbearing age
Treatment with Depakine should be initiated and supervised by a physician specialized in the treatment of epilepsy.

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

In patients who have previously been successfully treated with oral Depakine, the current dose may be administered as a continuous intravenous infusion or repeated intravenous injections; for example, if the patient was taking 25 mg/kg body weight per day, treatment may be continued for 2–3 days as a continuous infusion at a rate of 1 mg/kg body weight/hour. Dose and duration of administration are interdependent.

For other patients, the medicine may initially be given as a slow intravenous injection (over more than 3 minutes), usually at 15 mg/kg body weight, followed by continuation as an intravenous infusion at a rate usually of 1 to 2 mg/kg body weight/hour, adjusted according to clinical response.

Studies have shown that outcomes do not depend on gender, duration of injection, prior use of other antiepileptic drugs, or previous dose of valproic acid within the range of 5.3–28 mg/kg body weight/day.

General notes
The daily dose is determined based on age and body weight; however, individual sensitivity should also be taken into account.

The optimal dose is determined by clinical response to treatment; serum valproic acid concentration measurements should be considered an additional monitoring tool, necessary only when clinical seizure control is inadequate or adverse effects occur. The average effective serum concentration is usually 50–120 mg/litre (375–840 μmol/l).

Depakine may be administered intravenously either as a direct slow intravenous injection or as a continuous infusion. If other medicines are administered simultaneously, Depakine should be given through a separate catheter.

Whenever possible, treatment should be continued with the oral formulation at generally recommended doses.

Duration of treatment
The medicine should be used for as long as directed by the physician.

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

Patients with renal impairment
The physician may decide that dose adjustment is necessary in the patient.

Use of a higher than recommended dose of Depakine
Clinical symptoms of severe overdose include: coma, decreased muscle tone, diminished tendon reflexes, constricted pupils, and respiratory disturbances. Metabolic acidosis, reduced arterial blood pressure, and acute circulatory failure may also occur. Other symptoms may occur; seizures have been reported in cases of very high blood valproate concentration.

The presence of sodium in valproate pharmaceutical forms may lead to increased blood sodium concentration in cases of overdose.

Hospital treatment of overdose is symptomatic and should include monitoring of cardiovascular and respiratory function.

In the most severe cases, hemodialysis or even exchange transfusion may be required.

In isolated cases, naloxone has been effective.

If a higher than recommended dose of the medicine has been used, seek immediate medical advice from a physician or pharmacist.

Missed dose of Depakine
Do not administer two doses at the same time or in close succession. Continue treatment according to the physician's instructions.

If several doses have been missed, contact your physician immediately.

Stopping treatment with Depakine
Do not discontinue treatment with Depakine or change the dose without consulting your physician. Discontinuing treatment without medical consultation may worsen the patient's condition.

4. Possible adverse reactions

Like any medicine, Depakine 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 an increased frequency or severity of epileptic seizures, especially when phenobarbital is used concomitantly or during a sudden increase in the dose of Depakine
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 detachment (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 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 changes with a red/pink ring and pale centre, which may be itchy, peeling or fluid-filled. 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
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, impaired 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 several days, inform your doctor or pharmacist; treatment may be necessary.
Adverse reactions are listed according to the following frequency classification:
Very common (may occur in more than 1 in 10 people):

tremor,
nausea.

Common (may occur in not 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 impairment, nystagmus (rapid, uncontrolled eye movements), dizziness (may occur within minutes after intravenous administration and usually resolves spontaneously within a few minutes),
hearing impairment,
vomiting, stomach pain, diarrhoea (frequent in some patients at the beginning of treatment, usually transient and resolves within a few days without the need to discontinue treatment),
gum disorders (mainly gum hyperplasia), stomatitis (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 may be associated with polycystic ovary syndrome,
irregular menstrual cycles,
confusion (disorientation), hallucinations, aggression, agitation, attention disturbances,
urinary incontinence.

Uncommon (may occur in not more than 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 or numbness in hands or feet,
rash, hair abnormalities (such as abnormal hair structure, changes in hair colour, abnormal hair growth),
decreased bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long-term Depakine treatment,
hyperandrogenism (excessive male-pattern hair growth, virilization, acne, male-pattern baldness and/or elevated androgen levels),
vasculitis (inflammation of blood vessels),
decreased body temperature, mild oedema of feet and legs,
absence of menstruation.

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

macrocytic anaemia (low number of red blood cells), macrocytosis (abnormally large 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 difficulties (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 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 difficulties.
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can also be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C, 02-222 Warsaw, tel: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Reporting adverse reactions helps to gather more information on the safety of the medicine.

5. How to store the medicine Depakine

No special storage instructions are required.
The solution should be stored at 2–8°C and used within 24 hours.
Keep the medicine out of the sight and reach of children.
Do not use the medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month indicated.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This helps protect the environment.

6. Contents of the package and other information

What Depakine contains
Each vial of powder contains 400 mg of sodium valproate.
After reconstitution, each 1 ml of solution contains 100 mg of sodium valproate.

What Depakine looks like and contents of the pack
Depakine is a white to off-white powder. The solvent is a clear, colourless liquid.
Depakine is available in packs containing:

1 vial of powder and 1 ampoule of solvent (4 ml),
4 vials of powder and 4 ampoules of solvent (4 ml each).

For more detailed information, please contact the marketing authorisation holder or the parallel importer.

Marketing Authorisation Holder in the Czech Republic, country of export:
Sanofi s.r.o.
Generála Píky 430/26, 160 00 Prague 6, Czech Republic

Manufacturer:
Sanofi S.r.l.
Via Valcanello 4, 03012 Anagni (FR), Italy

Parallel Importer:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź, Poland

Repackaged in:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź, Poland

Marketing Authorisation Number in the Czech Republic, country of export: 21/265/96-C
Parallel Import Licence Number: 412/22

Other sources of information
Detailed and up-to-date information about this medicinal product is available by scanning the QR code on the package leaflet with a smartphone. The same information is also available at the website:
https://sirpl.org/walproinian
[QR code]

Information intended for healthcare professionals only:
The vial and ampoule contain an overage to allow withdrawal of the labeled amount:

Vial: 415 mg of lyophilized sodium valproate powder (displacement factor: 8.65%).
Ampoule: 4.25 ml of solvent (water for injections).

Reconstitution

Using a graduated syringe, withdraw 3.8 ml of solvent (water for injections) from the ampoule and inject it into the vial containing the lyophilized powder.
Allow the powder to dissolve completely.
The total volume of the reconstituted solution is 4.15 ml with a concentration of 100 mg/ml.
4 ml of the reconstituted injection solution (100 mg/ml) can be withdrawn from the vial.

The reconstituted solution is clear and almost colourless.
Preparation of the intravenous form of Depakine should be carried out immediately before use, and the solution should be used within 24 hours.
The intravenous infusion solution may be administered from containers made of polyvinyl chloride, polyethylene, or glass.

Physicochemical compatibility has been demonstrated with the following solutions when 400 mg of intravenous Depakine is added to 500 ml of each (except for tromethamine: 250 ml):

Sodium chloride solution (0.9 g in 100 ml)
Glucose (5 g in 100 ml)
Glucose (10 g in 100 ml)
Glucose (20 g in 100 ml)
Glucose (30 g in 100 ml)
Glucose (2.55 g) + NaCl (0.45 g) in 100 ml
Sodium bicarbonate (0.14 g in 100 ml)
Tromethamine (THAM) (3.66 g) + NaCl (0.172 g) in 100 ml