Depakine

Package leaflet: Information for the user

Warning! Keep this leaflet! The information on the immediate packaging is in a foreign language.
Depakine (Depakine 400 mg/4 ml)
400 mg (400 mg/4 ml), powder and solvent for solution for injection
Natrii valproas
Depakine and Depakine 400 mg/4 ml are different brand names for the same medicinal product.
▼ This medicinal product will be subject to additional monitoring. This will allow for rapid
identification of new safety information. Users of this medicine can also help by reporting any
adverse reactions that occur after administration. For information on how to report adverse
reactions – see section 4.
WARNING
The use of Depakine (sodium valproate) during pregnancy can cause serious harm to the unborn
child. Women of childbearing age must use an effective method of contraception (birth control)
continuously throughout the entire duration of treatment with Depakine. This will be discussed by
the treating physician with the patient, and the recommendations outlined in section 2 of this
leaflet should also be followed.
Patients should contact their physician immediately if they are planning a pregnancy or suspect
they may be pregnant.
Do not stop taking Depakine unless instructed by a doctor, as the patient's condition may worsen.
Please read all of this leaflet carefully before using 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 questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm someone else, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of the leaflet:

1. What Depakine is and what it is used for
2. Important information before using Depakine
3. How to use Depakine
4. Possible side effects
5. How to store Depakine
6. 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 antiepileptics. It has antiepileptic activity in
various types of epilepsy in humans.
Depakine is used:

• in epileptic status when intravenous benzodiazepines are ineffective;
• in clustered seizures;
• for the treatment of epileptic seizures when oral therapy is temporarily impossible due to level of consciousness or inability to swallow, especially if the patient has previously been effectively treated orally with sodium valproate. This applies to both generalized and partial seizures;
• prophylactically in association 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 is using an effective method of contraception throughout treatment with Depakine. Do not stop taking Depakine or contraception unless discussed with your doctor. Your doctor will provide further guidance (see below "Pregnancy, breastfeeding and fertility – Important advice for women").

Warnings and precautions

Talk to your doctor before starting treatment with Depakine.
CONTACT YOUR DOCTOR IMMEDIATELY IF:

• You experience sudden symptoms such as weakness, loss of appetite, drowsiness, recurrent 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 may cause severe liver damage, sometimes leading to 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 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 given concomitantly with salicylates in children under 3 years of age due to the risk of hepatotoxic effects.
• You experience severe abdominal pain. Very rarely, Depakine may cause severe pancreatitis, sometimes fatal.
• You or your child being treated with Depakine develop problems with balance and coordination, drowsiness, reduced alertness, or vomiting. These may be caused by increased blood ammonia levels.
• A small number of people taking antiepileptic medicines containing sodium valproate have had thoughts about harming themselves or suicide. If you ever have such thoughts, contact your doctor immediately.
• Serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema, have been reported with valproate treatment. If you notice any of the symptoms related to these serious skin reactions described in section 4, seek medical advice immediately.

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

• Valproate should not be used in women with epilepsy who are planning pregnancy, except when other treatments are ineffective or not tolerated. The benefits of treatment should be weighed against the risks before the first prescription or when a woman treated with valproate plans pregnancy. Women of childbearing potential must use effective contraception during treatment.
• Before starting treatment, including prior to surgery, and in cases 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 any metabolic disorder is suspected, 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.
• If the patient has a rare condition called "carnitine palmitoyltransferase II deficiency" due to increased risk of muscle disorders.
• Concomitant use of carbapenem antibiotics with valproic acid is not recommended (see: Depakine and other medicines).
• Sodium valproate is excreted mainly by the kidneys, partly in the form of ketone bodies; therefore, urine ketone tests in diabetic patients may yield false-positive results.
• If there is a family history or clinical suspicion of 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 carnitine intake (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 ulcers after taking valproate.

Depakine and other medicines

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

• neuroleptics, including quetiapine, olanzapine (used to treat psychotic disorders);
• antidepressants, including MAO inhibitors;
• benzodiazepines (used to treat insomnia and anxiety disorders);
• other antiepileptic medicines, including phenobarbital, phenytoin, primidone, lamotrigine, carbamazepine, felbamate, topiramate, rufinamide;
• cannabidiol (used in the treatment of epilepsy and other indications);
• certain antimicrobial agents containing pivampicillin (such as pivampicillin, adefovir dipivoxil);
• methotrexate (used in cancer and inflammatory diseases);
• zidovudine, ritonavir, and lopinavir (used in the treatment of 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 estrogen (including some contraceptives);
• metamizole (used to treat pain and fever);
• clozapine (used to treat psychiatric disorders).

These medicines may affect the action of sodium valproate and vice versa. Your doctor may need to adjust the dose of one or more of these medicines or switch to another medicine. Your doctor will inform you of any 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 you are pregnant, unless no other therapy is effective.
• If you are of childbearing potential, you must not take Depakine unless you are using an effective method of contraception throughout treatment with Depakine. Do not stop taking Depakine or contraception unless 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 you are planning pregnancy or are pregnant.

• Taking valproate during pregnancy carries risks. The higher the dose, the greater the risk, but no dose is risk-free, even when valproate is used with other antiepileptic medicines.

• Valproate may cause serious congenital malformations and affect the physical and mental development of the child after birth.

• The most common congenital malformations include: spina bifida (when the spinal bones do not develop properly); facial and cranial developmental defects; heart, kidney, urinary tract and genital organ malformations; limb defects; and multiple developmental defects affecting several organs and body parts. Congenital malformations may lead to disabilities, which may be severe.

• Hearing problems or deafness have been reported in children exposed to valproate in utero.

• Eye developmental disorders, together with other congenital malformations, have been reported in children exposed to valproate in utero. Eye developmental disorders may affect vision.

• Pregnant women taking valproate have an increased risk of giving birth to a child with congenital malformations requiring treatment. Valproate has been used for many years, and 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 experience early developmental problems. Affected children may start walking and talking later, have lower intellectual abilities than other children, and may have language and memory problems.

• Various 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.

• Pregnant women taking valproate may give birth to a child with 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 affects about 5–10 out of every 100 children born to women in the general population.

• Before prescribing this medicine, your doctor will explain to you the risks to the unborn child if you become pregnant while taking valproate. If you are taking this medicine and decide you want to have a child, do not stop taking the medicine or contraception on your own; discuss this with your doctor first.

• Some contraceptive methods (oral contraceptives containing estrogen) may reduce the blood concentration of valproate. Discuss with your doctor the most appropriate method of contraception for you.

• 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 you 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 you become pregnant. Women of childbearing potential should ensure they use an effective method of contraception continuously throughout treatment with Depakine. If you need advice on contraception, consult your doctor or a family planning clinic.
Important information

• Before starting Depakine, 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 treatment with Depakine.
• 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 epilepsy. During these visits, your doctor will ensure you have been well 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 WITHOUT PLANNING PREGNANCY
If you continue treatment with Depakine and do not plan pregnancy, you must ensure you use an effective method of contraception continuously throughout treatment with Depakine. 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 treatment with Depakine.
• 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 epilepsy. During these visits, your doctor will ensure you have been well 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 WHILE PLANNING PREGNANCY
If you plan to have a child, you should first schedule an appointment with your doctor. Do not stop taking Depakine or contraception until you have discussed it with your doctor. Your doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems that may significantly impair the child. Your doctor will refer you to a specialist experienced in treating 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, 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 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 you have been well informed and understand all risks and advice related to taking valproate during pregnancy.
• Your doctor will try switching to another medicine or discontinuing Depakine treatment well before conception.
• If you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor.

BECOMING PREGNANT WHILE CONTINUING TREATMENT WITH DEPAKINE
Do not stop treatment with Depakine unless discussed with your doctor, as your health condition may worsen. If you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor. Your doctor will provide further guidance.
Children born to mothers who took valproate have a high risk of congenital malformations and developmental problems that may significantly impair the child. You will be referred to a specialist experienced in treating epilepsy to evaluate alternative treatment options.
In exceptional circumstances, when Depakine is the only available treatment option during pregnancy, you will be closely monitored for both your underlying condition and fetal development. You and your partner will receive 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 you are pregnant or suspect you may be pregnant, schedule an urgent appointment with your doctor.
• Do not stop treatment with Depakine unless your doctor advises you to do so.
• Ensure you are referred to a specialist experienced in treating epilepsy to evaluate the need for alternative treatment methods.
• You 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.
• Ensure you are referred to a specialist in prenatal monitoring to detect possible developmental abnormalities.

Newborns of mothers who took Depakine during pregnancy may experience blood clotting disorders, hypoglycemia, 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 acknowledgment 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 using valproate during pregnancy.

Important advice for male patients
Possible risk associated with taking valproate within 3 months before conception
A study suggests a possible risk of motor and mental developmental disorders (early childhood developmental problems) in children whose fathers were treated with valproate 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 needed for new sperm production) before conception is unknown. The study has limitations, so it is unclear whether the suggested increased risk of motor and mental developmental disorders is caused by valproate. The study was not large enough to determine the specific types of motor and mental developmental disorders involved.
As a precaution, your doctor will discuss with you:

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

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

Breastfeeding
Valproate is excreted in small amounts in breast milk. Discuss with your doctor whether breastfeeding is advisable during treatment.

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

Depakine contains sodium
Depakine contains 55.4 mg of sodium (the main component of table salt) in 400 mg of sodium valproate. This corresponds to 2.77% of the maximum recommended daily dietary sodium intake for adults.

3. How to use Depakine

This medicine should always be used exactly as prescribed by the doctor. In case of doubt, consult your doctor.
Female patients and women of childbearing potential
Treatment with Depakine should be initiated and supervised by a doctor 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.
Depakine is administered to the patient only by a doctor or nurse, because it requires slow intravenous injection or infusion (intravenously). If the patient is uncertain about why Depakine has been prescribed or has any questions regarding the dose being administered, they should discuss this with the doctor or nurse.
Dosage of Depakine
The doctor will decide what dose of Depakine should be given to the patient, depending on the type of disease. The dose administered depends on age and body weight. The daily dose, frequency, and timing of administration are determined and monitored by the doctor. The doctor will also decide on the duration of treatment.
Epilepsy:
If the patient has previously taken Depakine orally, the doctor may decide to administer the same dose of Depakine as a continuous or repeated infusion, 6 hours after the last oral dose.
If the patient has not previously taken Depakine:

• In adults, adolescents, and children over 10 years of age, the usual recommended dose is 15 mg/kg body weight, administered by slow intravenous injection over 3–5 minutes, followed by continuous or repeated infusion.
• In children under 10 years of age, the usual recommended dose is 20–30 mg/kg body weight, administered by slow intravenous injection, followed by continuous or repeated infusion. For children under 3 years of age, see section 2.

Different forms of status epilepticus:

• In adults, the recommended initial dose is 10–20 mg/kg body weight, administered by slow intravenous injection over 5–10 minutes, followed by continuous infusion.
• In children, the recommended initial dose is 15–40 mg/kg body weight, administered by slow intravenous injection, followed by continuous infusion.

Patients with impaired kidney function
The doctor may decide that dose adjustment is necessary.
Use of a higher than recommended dose of Depakine
Clinical symptoms of severe overdose include: coma, decreased muscle tone, diminished tendon reflexes, miosis (pupil constriction), and respiratory disturbances. Metabolic acidosis, hypotension, and acute cardiovascular failure may also occur. Other symptoms may occur; seizures have been reported in cases of very high blood concentrations of valproate.
The presence of sodium in valproate pharmaceutical formulations may lead to increased blood sodium levels in case 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.
In case of administration of a higher than recommended dose, seek immediate medical advice from a doctor or pharmacist.
Missed dose of Depakine
Do not administer two doses at the same time or in close succession. Continue taking the medicine as directed by the doctor.
If several doses have been missed, contact the doctor immediately.
Stopping treatment with Depakine
Do not discontinue treatment with Depakine or change the dose without consulting the doctor. Discontinuing treatment without medical advice may worsen the patient's condition.

4. Possible adverse reactions

Like all medicines, 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 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 worsening of epileptic seizures, particularly when co-administered with phenobarbital or during a rapid increase in the dose of Depakine
• Confusion, weakness, dizziness, nausea, vomiting, which may be caused by low sodium blood levels or a condition called "SIADH" (SIADH, Syndrome of Inappropriate Secretion of ADH) or inappropriate antidiuretic hormone secretion syndrome
• Problems with balance and coordination, drowsiness or reduced alertness, combined with vomiting. This may be due to increased blood ammonia levels (hyperammonaemia)
• Increase in frequency and severity of seizures
• Extreme fatigue, weakness, loss of appetite, drowsiness, recurrent vomiting and abdominal pain, severe upper abdominal pain, nausea, jaundice (yellowing of the skin and whites of the eyes), leg swelling or increased frequency of epileptic seizures, or general malaise – these symptoms may indicate liver or pancreas damage
• Allergic reactions, which may manifest as:
• Blisters with skin peeling (formation of blisters, skin sloughing or bleeding from various parts of the body including lips, eyes, mouth, nose, genitals, palms or soles), with or without rash, sometimes accompanied by flu-like symptoms such as fever, chills or muscle pain – these may be symptoms of conditions known as "toxic epidermal necrolysis" or "Stevens-Johnson syndrome"
• Skin rash or skin lesions with a red/pink ring and pale center, which may be itchy, scaly or filled with fluid. The rash may appear especially on palms or soles. These may be symptoms of a disease called "erythema multiforme"
• Swelling caused by allergy with painful, itchy 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 called "DRESS" or drug reaction with eosinophilia and systemic symptoms
• Blood clotting disorders confirmed by laboratory tests, which may cause spontaneous bruising and bleeding
• Significant decrease in white blood cell count or bone marrow failure shown in 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, impaired body movement coordination (parkinsonism, extrapyramidal disorders, ataxia)
• Muscle pain and weakness (rhabdomyolysis – breakdown of striated muscles)
• Breathing difficulties, chest pain or pressure sensation (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 the 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 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, nystagmus (rapid, uncontrolled eye movements), dizziness (may occur within minutes after intravenous administration and usually resolves spontaneously within minutes)
• hearing impairment
• vomiting, stomach pain, diarrhoea (common in some patients at the beginning of treatment), usually resolving within a few days without the need to discontinue treatment
• gum disorders (mainly gingival hyperplasia), stomatitis (inflammation of the mouth)
• transient and/or dose-dependent hair loss, nail 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 occur in 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 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 treatment
• hyperandrogenism (excessive male-pattern hair growth, virilization, acne, male-pattern baldness and/or elevated androgen levels)
• vasculitis (inflammation of blood vessels)
• low body temperature, mild oedema of feet and legs
• amenorrhoea (absence of menstruation)

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

• macrocytic anaemia (low number of red blood cells), macrocytosis (abnormal increase in size of red blood cells)
• biotin deficiency / biotinidase deficiency
• excessive urination and thirst (Fanconi syndrome)
• involuntary urination (nocturnal enuresis)
• 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 inherited and/or genetic diseases
• decreased carnitine concentration (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 symptoms occur, including any not listed in this leaflet, inform a 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, phone: +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 this medicine.

5. How to store the medicine Depakine

Keep the medicine out of sight and reach of children.
Do not use the medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the stated month.
Unopened vial of powder: no special storage precautions required.
After reconstitution: use the solution within 24 hours.
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 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 further information about this medicine, contact the marketing authorisation holder or the parallel importer.

Marketing Authorisation Holder in Slovakia, country of export:
Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, France

Manufacturer:
Sanofi S.r.l., Via Valcanello 4, 03012 Anagni (FR), Italy
Glaxo Wellcome Production, 1 Rue de l'Abbaye, 76960 Notre Dame de Bondeville, France

Parallel Importer:
InPharm Sp. z o.o., ul. Strumykowa 28/11, 03-138 Warsaw, Poland

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

Marketing Authorisation Number in Slovakia, country of export: 21/0674/96-S
Parallel Import Authorisation Number: 331/25

Other sources of information
A patient guide for women and a patient guide for men are available by scanning the QR code located on the package leaflet using a smartphone. The same information is also available on the website: https://inpharm.pl/narzedzia-edukacyjne/#walproiniany

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Information intended exclusively for medical professionals

The vial and ampoule contain an overage to allow for withdrawal of the specified amount:

• Vial: 415 mg of lyophilized powder of sodium valproate (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 complete dissolution.
• 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 colorless.
Preparation of the intravenous form of Depakine should be performed immediately before use, and
the solution should be used within 24 hours.
The infusion solution may be administered from containers made of polyvinyl chloride, polyethylene, or
glass.
Physicochemical compatibility has been demonstrated with the following solutions:

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

using 400 mg of the intravenous form of Depakine in 500 ml of each of the above solutions (except for tromethamine: 250 ml).