Prospect: information for the user

DEPAKINE 100 mg/ml powder and solvent for injectable solution

Valproic acid

This medicine is subject to additional monitoring, which will speed up the detection of new information about its safety. You can contribute by reporting any adverse effects you may experience. The final part of section 4 includes information on how to report these adverse effects.

Read this prospect carefully before starting to take this medicine, as it contains important information for you.

• Keep this prospect, as you may need to refer to it again.
• If you have any doubts, consult your doctor or pharmacist.

-This medicine has been prescribed only for you, and you must not give it to others even if they have the same symptoms as you, as it may harm them.

• If you experience adverse effects, consult your doctor or pharmacist,even if they are adverse effects that do not appear in this prospect. See section 4.

Depakine belongs to a group of medications called antiepileptics. It is indicated for the treatment of different types of epilepsy in adults and children.

Depakine 100 mg/ml powder and solvent for injectable solution should be reserved for unconscious patients and other situations in which oral administration is not possible temporarily, and should be replaced by the oral presentation as soon as possible. It may also be resorted to in urgent situations in which rapid therapeutic induction is required.

No use Depakine

• If you are allergic (hypersensitive) to the active ingredient or to any of the other components of Depakine 100 mg/ml powder and solvent for injection, or to any other medicine, inform your doctor.

• Do not use Depakine if you are pregnant, unless no other treatment works.

• If you are a woman of childbearing potential, do not take Depakine unless you use an effective method of contraception (birth control) throughout your treatment with Depakine.Do not stop taking Depakine or your contraceptive until you have spoken to your doctor. Your doctor will advise you.
• If you have any liver or pancreas disease.
• If you have had any liver disease in the past.
• If any of your close relatives have a history of severe liver disease (hepatitis), mainly caused by medication.
• If you have a history of a family member dying from liver function alteration during treatment with sodium valproate.
• If you have porphyria of the liver (a very rare metabolic disorder).
• If you have a genetic disorder that causes a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome).
• If you have a known metabolic disorder, such as a urea cycle disorder.
• If you have untreated carnitine deficiency (a very rare metabolic disorder).

If you think you may have any of these problems or have any doubts, consult your doctor before administering Depakine.

Warnings and precautions

SEE YOUR DOCTOR IMMEDIATELY:

The risk of liver damage increases if valproate is administered to children under 3 years, to people taking other antiepileptic medicines at the same time or who have other neurological or metabolic diseases and severe forms of epilepsy.

Your doctor should review your liver function tests before you start treatment and periodically during the first 6 months, especially in high-risk patients.

If you or your child suddenly develops a disease, especially if it appears in the first few months of treatment and, in particular, if it includes repeated vomiting, extreme fatigue, abdominal pain, drowsiness, weakness, loss of appetite, upper stomach pain, nausea, jaundice (yellowing of the skin or eyes), swelling of the legs, or worsening of epilepsy or general feeling of discomfort. In this case, you should see your doctor immediately. In a very small number of patients, Depakine can affect the liver or pancreas. Liver function alteration combined with pancreatic alteration increases the risk of fatal outcome.

If you or your child taking valproate develops problems with balance and coordination, feeling drowsy or less alert, vomiting, inform your doctor immediately. This may be due to an increase in your blood ammonia levels.

A reduced number of people who have been treated with antiepileptic medicines like valproic acid have had thoughts of self-harm or suicide. If you ever have these thoughts, contact your doctor immediately.

Severe skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, and angioedema, have been reported in association with valproate treatment. Seek medical attention immediately if you notice any of the symptoms related to these severe skin reactions described in section 4.

Before taking this medicine, consult your doctor

• If you know or your doctor suspects that there is a genetic disorder caused by a mitochondrial disorder in your family, due to the risk of liver damage.

• If you suspect you have any metabolic disorder, particularly hereditary enzyme deficiency disorders such as a "urea cycle disorder" due to the risk of increased blood ammonia levels.
• If you have a rare disorder called "carnitine palmitoyltransferase type II deficiency" because you have a higher risk of developing muscle disorders.
• If you have an altered dietary intake of carnitine, which is found in meat and dairy products, especially in children under 10 years.
• If you have carnitine deficiency and are taking carnitine.
• If you have kidney function impairment or hypoproteinemia (decreased blood protein levels). In this case, your doctor may want to monitor your valproate blood levels or adjust your dose.
• If Depakine is administered to children under 3 years, avoid administering it with aspirin (acetylsalicylic acid) especially.
• If you have systemic lupus erythematosus.
• If you have blood disorders (coagulation disorders or thrombocytopenia). It is recommended to perform a blood test (complete blood count) before starting treatment or before surgery and in cases of spontaneous bleeding or bruising.
• If you experience weight gain at the start of treatment.
• As with other antiepileptic medicines, seizures may worsen or occur more frequently while using this medicine. If this happens, contact your doctor immediately.
• If you have ever developed a severe skin rash or peeling, blisters, or mouth sores after taking valproate.

Use of Depakine with other medicines

Inform your doctor or pharmacist if you are using, have used recently, or may use any other medicine, including those purchased without a prescription, homeopathic, herbal, or other health-related products, as it may be necessary to stop treatment or adjust the dose of one or both of them.

Some medicines may alter the effect of Depakine or vice versa. These include:

• Carbapenem agents (antibiotics used to treat bacterial infections).

• Products containing estrogens (including some birth control pills).
• Neuroleptics (medicines used to treat mental disorders).
• Medicines used to treat depression.
• Benzodiazepines (medicines used to sleep or treat anxiety).
• Olanzapine and quetiapine (medicines used to treat mental health disorders).
• Other medicines used to treat epilepsy, including phenobarbital, phenytoin, primidone, lamotrigine (the risk of severe skin rash may increase when lamotrigine and valproic acid are administered together), carbamazepine, ethosuximide, felbamate, and topiramate. The concurrent administration of Depakine with topiramate has been associated with encephalopathy and/or hyperammonemia (brain and nervous system complications resulting from liver disorders with or without increased blood ammonia levels).
• Zidovudine (medicine used to treat HIV and AIDS).
• Mefloquine (medicine used to treat or prevent malaria).
• Salicylates (aspirin). See also "Warnings and precautions - Children under 3 years."
• Anticoagulants (medicines used to prevent blood clotting).
• Cimetidine (medicine used to treat stomach ulcers).
• Erythromycin and rifampicin (antibiotics).
• Rufinamide.
• Acetazolamide.
• Inhibitors of protease, such as lopinavir, ritonavir (used to treat HIV).
• Colestiramine.
• Propofol (anesthetic).
• Metamizol (medicine used to treat pain and fever).
• Cannabidiol (used to treat epilepsy and other diseases).
• Methotrexate (used to treat cancer and inflammatory diseases).
• Some antibiotics containing pivalate (e.g., pivampicillin, adefovir dipivoxil).
• Clozapine (used to treat mental health disorders).

Depakine may increase the effects of Nimodipino (medicine used to treat hypertension, angina, and vascular disorders).

The activity of these and other medicines may be affected by Depakine, or they may directly affect the activity of Depakine. You may need different doses of medicine or take different medicines. Your doctor or pharmacist will advise you.

Use of Depakine with food and drinks

Do not consume alcoholic beverages.

Pregnancy, breastfeeding, and fertility

Pregnancy

Consult your doctor or pharmacist before using any medicine.

Important warning for women

• Do not use Depakine if you are pregnant, unless no other treatment works.
• If you are a woman of childbearing potential, do not take Depakine unless you use an effective method of contraception (birth control) throughout your treatment with Depakine.Do not stop taking Depakine or your contraceptive until you have spoken to your doctor. Your doctor will advise you.

Risks of valproate when taken during pregnancy

• Talk to your doctor immediately if you are planning to have a baby or are pregnant.
• Valproate carries a risk when taken during pregnancy. The higher the dose, the greater the risk, but all doses have a risk, even when valproate is used in combination with other medicines to treat epilepsy.
• It may cause severe birth defects and may affect the physical and mental development of the child and how it grows after birth. The most commonly reported birth defects include:spina bifida(where the spinal vertebrae do not develop properly); malformations of the skull and face, heart, kidney, urinary system, reproductive organs, and limb defects, and multiple malformations affecting various organs and body parts. Birth defects may result in disabilities that can be severe.
• There have been reports of hearing or deafness problems in children exposed to valproate during pregnancy.
• There have been reports of eye malformations in children exposed to valproate during pregnancy, associated with other congenital malformations. These eye malformations may affect vision.
• If you take valproate during pregnancy, you have a higher risk than other women of having a child with birth defects that require medical treatment. As valproate has been used for many years, it is known that of the women taking valproate, about 11 out of every 100 babies will have birth defects. In comparison, 2 to 3 out of every 100 babies born to women without epilepsy will have birth defects.
• It is estimated that up to 30-40% of preschool children whose mothers took valproate during pregnancy may have developmental problems in childhood. Affected children may be slow to talk and walk, be intellectually less capable than other children, and have language and memory difficulties.
• Children exposed to valproate are more likely to be diagnosed with autism spectrum disorders, and there is some evidence that these children have a higher risk of developing Attention Deficit Hyperactivity Disorder (ADHD).
• Before prescribing this medicine, your doctor will have explained to you what may happen to your baby if you become pregnant while taking valproate. If you decide later that you want to have a baby, do not stop taking your medicine or your contraceptive until you have spoken to your doctor.
• If you are a father or caregiver of a girl being treated with valproate, contact your doctor when your daughter in treatment with valproate reaches menarche (first menstruation).
• Some birth control pills (birth control pills containing estrogens) may decrease valproate blood levels. Make sure to talk to your doctor about the most suitable birth control method for you.
• Consult your doctor about taking folic acid while trying to conceive. Folic acid may reduce the general risk ofspina bifidaand early abortion that exists during all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Choose and read the situations that affect you from the following:

• I am starting treatment with DEPAKINE
• I am taking Depakine and do not intend to have a baby
• I am taking Depakine and intend to have a baby
• I am pregnant and taking Depakine

I AM STARTING TREATMENT WITH DEPAKINE

If this is the first time you have been prescribed Depakine, your doctor will have explained the risks to the fetus if you become pregnant. Once you are of childbearing age, you will need to ensure that you use an effective method of contraception without interruption throughout your treatment with Depakine. Consult your doctor or family planning clinic if you need advice on contraception.

Important messages:

• Pregnancy must be ruled out before starting treatment with Depakine, by the result of a pregnancy test, confirmed by your doctor.
• You must use an effective method of contraception throughout your treatment with Depakine.
• You must speak to your doctor about the most suitable method of contraception. Your doctor will give you information on how to prevent pregnancy and may refer you to a specialist for advice on contraception.
• You must have regular consultations (at least annually) with a specialist experienced in treating epilepsy. During this visit, your doctor will ensure that you know and understand all the risks and warnings related to the use of valproate during pregnancy.
• Inform your doctor if you want to have a baby.
• Consult your doctor immediately if you are pregnant or think you may be pregnant.

I AM TAKING DEPAKINE AND DO NOT INTEND TO HAVE A BABY

If you continue treatment with Depakine but do not plan to have a baby, make sure to use an effective method of contraception without interruption throughout your treatment with Depakine. Consult your doctor or family planning clinic if you need advice on contraception.

Important messages:

• You must use an effective method of contraception throughout your treatment with Depakine.
• You must speak to your doctor about contraception. Your doctor will give you information on how to prevent pregnancy and may refer you to a specialist for advice on contraception.
• You must have regular consultations (at least annually) with a specialist experienced in treating epilepsy. During this visit, your doctor will ensure that you know and understand all the risks and warnings related to the use of valproate during pregnancy.
• Inform your doctor if you want to have a baby.
• Consult your doctor immediately if you are pregnant or think you may be pregnant.

I AM TAKING DEPAKINE AND I INTEND TO HAVE A BABY

If you are planning to have a baby, first schedule an appointment with your doctor.

Do not stop taking Depakine or your contraceptive until you have spoken to your doctor. Your doctor will advise you.

Babies born to mothers who have been treated with valproate have significant risks of birth defects and developmental problems that can be severely debilitating. Your doctor will refer you to a specialist experienced in treating epilepsy to evaluate alternative treatment options from the start. Your specialist may decide to change your Depakine dose or switch to another medicine, or stop your treatment with Depakine well before you become pregnant - to ensure that your underlying condition is stable.

Consult your doctor about taking folic acid when trying to conceive. Folic acid may reduce the general risk ofspina bifidaand early abortion that exists in all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Important messages:

• Do not stop taking Depakine unless your doctor tells you to.
• Do not stop using your contraceptive methods until you have spoken to your doctor and worked together on a plan to ensure that your condition is controlled and the risks to your baby are reduced.
• First schedule an appointment with your doctor. During this visit, your doctor will ensure that you know and understand all the risks and warnings related to the use of valproate during pregnancy.
• Your doctor will try to switch you to another medicine or stop your treatment with Depakine well before you become pregnant.
• Schedule an urgent appointment with your doctor if you are pregnant or think you may be pregnant.

I AM PREGNANT AND I AM TAKING DEPAKINE

Do not stop taking Depakine unless your doctor tells you to, as your condition may worsen.Schedule an urgent appointment with your doctor if you are pregnant or think you may be pregnant. Your doctor will advise you.

Babies born to mothers who have been treated with valproate have significant risks of birth defects and developmental problems that can be severely debilitating.

Your doctor will refer you to a specialist experienced in treating epilepsy to evaluate alternative treatment options.

In exceptional circumstances, when Depakine is the only treatment option during pregnancy, it will be closely monitored, both for the management of your underlying condition and for checking how the fetus is developing. You and your partner may receive counseling and support regarding pregnancy with valproate exposure.

Consult your doctor about taking folic acid. Folic acid may reduce the general risk ofspina bifidaand early abortion that exists in all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Important messages:

• Schedule an urgent appointment with your doctor if you are pregnant or think you may be pregnant.
• Do not stop taking Depakine unless your doctor tells you to.
• Make sure you are referred to a specialist in prenatal monitoring to detect possible malformations.
• Make sure you are informed about the risks of Depakine during pregnancy, including teratogenicity (birth defects) and developmental disorders in children.

Make sure to read the Patient Guide that your doctor will provide you with. Your doctor will discuss the Annual Risk Knowledge Form with you and ask you to sign and keep it. Your pharmacist will also provide you with a Patient Card to remind you of the risks of valproate if you take it during pregnancy.

In babies born to mothers who have taken Depakine during pregnancy, the following may occur:

• Problems with blood clotting due to partial or complete lack of one of the substances necessary for blood clotting. In the latter case, the problem can be fatal, so in the newborn, specific blood tests and coagulation tests should be performed.
• Hypoglycemia in newborns of mothers who took Depakine during pregnancy.
• Cases of hypothyroidism have been reported in newborns of mothers who took valproate during pregnancy.
• A withdrawal syndrome (such as agitation, irritability, hyperexcitability, nervousness, hyperkinesia, muscle tone disorders, tremors, convulsions, and feeding disorders) may occur in newborns whose mothers took valproate during the last trimester of pregnancy.

Breastfeeding

Consult your doctor or pharmacist before using any medicine.

Valproate sodium passes into breast milk. However, the amounts of valproate sodium that pass into breast milk are small, and therefore, treatment with Depakine during lactation generally does not pose a risk to the infant and usually does not require stopping breastfeeding. However, you should consult your doctor about the advisability of continuing or stopping breastfeeding, always taking into account the safety profile of Depakine, especially blood disorders (see section "Possible side effects").

Important information for male patients

Potential risks related to the use of valproate in the 3 months before conception

A study suggests a possible risk of movement and developmental disorders (problems with development in childhood) in children born to fathers treated with valproate in the 3 months before conception. In this study, about 5 out of every 100 children had these disorders when born to fathers treated with valproate, compared to about 3 out of every 100 children born to fathers treated with lamotrigine or levetiracetam (other medicines that can be used to treat your condition). The risk for children born to fathers who stopped taking valproate 3 months (the time needed to form new sperm) or more before conception is unknown. The study has limitations, and therefore, it is unclear whether the higher risk of movement and developmental disorders suggested by this study is caused by valproate. The study was not extensive enough to demonstrate which specific type of movement and developmental disorder children may develop.

As a precaution, your doctor will discuss with you:

Do not donate sperm while taking valproate and for 3 months after stopping valproate.

Talk to your doctor if you are thinking of having a child.

If your female partner becomes pregnant while you were taking valproate in the 3 months before conception and you have any doubts, contact your doctor. Do not stop treatment without consulting your doctor. If you stop treatment, your symptoms may worsen.

You should have regular appointments with your doctor. During this visit, your doctor will discuss with you the precautions associated with the use of valproate and the possibility of other treatments that can be used to treat your condition, depending on your individual situation.

Make sure to read the patient guide that your doctor will provide you with. You will also receive a Patient Card from your pharmacist to remind you of the potential risks of valproate.

Driving and operating machinery

Depakine may cause symptoms such as drowsiness, dizziness, or visual disturbances, and may impair your ability to react. These effects, as well as the underlying condition, may make it difficult for you to drive vehicles or operate machinery. Therefore, do not drive, operate machinery, or engage in other activities that require special attention until your doctor evaluates your response to this medicine.

Important information about some of the components of DepakineThis medicine contains 55.35 mg of sodium in each vial. This is equivalent to 2.8% of the maximum daily sodium intake recommended for an adult.

Girls and women of childbearing age

The treatment with Depakine should be initiated and supervised by a specialized doctor in the treatment of epilepsy.

Male patients

It is recommended that Depakine be initiated and supervised by an expert with experience in the treatment of epilepsy - see section 2 Important information for male patients.

Depakine should be administered under the supervision of a doctor. Normally, it will be administered by a doctor or a nurse (under medical supervision).

Your doctor will decide on the most suitable dose of Depakine. Make sure to have regular check-ups with your doctor.

Depakine is prescribed on an individual basis and for a specific situation. The doses recommended in this prospectus are indicative. The doses of Depakine are established according to body weight, your specific situation, and the doctor's prescription criteria.

• Newborns and children (28 days to 11 years): The recommended dose is 20-30 mg/kg of body weight.
• Adolescents (≥12 years) and adults (≥18 years): In patients with oral treatment initiated, Depakine 100 mg/ml powder and solvent for injectable solution will be administered in continuous infusion, 4 to 6 hours after oral intake, following the same established dosage regimen, at a perfusion rate of 0.5 to 1 mg/kg/h. In the rest of patients, administer the preparation in the form of slow injection (3-5 minutes), at a rate of 15 mg/kg of body weight, to continue after 30 minutes with a continuous infusion at 1 mg/kg/h up to a maximum of 25 mg/kg/day.
• Older patients (≥65 years): 15-20 mg/kg of body weight.
• Patients with liver insufficiency: Depakine should not be administered to patients with severe liver disease.
• Patients with renal insufficiency: It may be necessary to administer lower doses to this type of patient.

The usual daily dose is 0.2 – 0.3 ml (equivalent to 20-30 mg of valproate sodium) per kilogram of body weight, administered by intravenous perfusion. Oral therapy should replace intravenous as soon as possible.

Patients with renal problems

Your doctor may decide to adjust your dose.

In children under 11 years, it is considered more appropriate to administer Depakine 200 mg/ml oral solution.

Depakine 100 mg/ml powder and solvent for injectable solution should not be administered by any route other than intravenous.

The dose is always adjusted individually, according to the response of each patient.

If you use more Depakine than you should

If this medication is administered by a doctor or nurse (under medical supervision), it is unlikely that you will be given more than you should. They will monitor your progress. Always ask if you are unsure why you are being given a dose of medication.

A Depakine overdose can be hazardous. Among the symptoms of intoxication are confusion, sedation, or even coma with hypotonia, muscle weakness, and lack of reflexes. Therefore, go to the nearest hospital where you will be treated for symptoms and cardio-respiratory monitoring will be performed. In some cases, hypotension, miosis, cardiovascular and respiratory alterations, circulatory collapse/shock, metabolic acidosis, hypocalcemia, and hypernatremia have also been observed. Cases of death after massive overdose have been reported; however, a favorable outcome is usually expected.

However, symptoms may be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension associated with cerebral edema have been reported.

The presence of sodium in the presentations with valproate may lead to hypernatremia in the event of an overdose.

It is recommended to bring the packaging and prospectus of the medication to the healthcare professional.

If you forgot to use Depakine

Do not proceed.

If you interrupt treatment with Depakine

Stopping treatment with Depakine abruptly without explicit indication from your doctor may be harmful to you, as seizures may occur with severe consequences.

Like all Depakine medicines, Depakine can cause side effects, although not everyone will experience them.

Inform your doctor immediately if any of the following serious side effects occur. You may need urgent medical attention:

• Drowsiness, change in level of consciousness (including coma), confusion, abnormal or slow behavior, and memory loss associated with or not associated with an increased frequency or severity of seizures, particularly if you are taking phenobarbital or topiramate (medicines used to treat seizures) at the same time or if the Depakine dose has been suddenly increased.
• Confusion caused by a decrease in blood sodium levels or a condition called Syndrome of Inadequate Antidiuretic Hormone Secretion (SIADH).
• Problems with balance and coordination, feeling tired or less alert, associated with vomiting. This may be due to an increase in your blood ammonia levels.
• Increased number and severity of seizures.
• Repeated vomiting, extreme fatigue, abdominal pain, drowsiness, weakness, loss of appetite, severe upper stomach pain, nausea, jaundice (yellowing of the skin or white of the eyes), swelling of the legs or worsening of epilepsy or general feeling of discomfort. These may be symptoms of severe liver and pancreas disorders.
• Reactions to allergens that may manifest as:

• Blisters with skin peeling (blisters, peeling, or bleeding on any part of the skin, including lips, eyes, mouth, nose, genitals, hands, or feet) with or without rash, with symptoms sometimes similar to the flu, such as fever, chills, or muscle pain - these may be signs of conditions called 'toxic epidermal necrolysis' or 'Stevens-Johnson syndrome'.
• Allergic inflammation with painful itchy rashes that cause discomfort (often around the eyes, lips, throat, and sometimes on hands and feet) - these may be symptoms of 'angioedema'.
• Syndrome involving skin rash, fever, swollen lymph nodes, and possible failure of other organs - these may be signs of a condition called 'DRESS' or 'drug reaction with eosinophilia and systemic symptoms'.

• Spontaneous bruising or bleeding due to blood clotting problems that appear in blood tests.
• Severe decrease in white blood cells or bone marrow insufficiency that appears in blood tests, which may manifest with fever and difficulty breathing.
• Underactive thyroid gland, which may cause fatigue or weight gain (hypothyroidism).
• Pain in the joints, fever, fatigue, and rash. These may be signs of systemic lupus erythematosus.
• Agitation (trembling), uncontrollable muscle contractions, instability while walking (parkinsonism, extrapyramidal disorder, ataxia). Muscle pain and muscle weakness (rhabdomyolysis). Sedation, extrapyramidal disorders.
• Rare: difficulty breathing, chest pain (especially when inhaling), dry cough due to fluid accumulation around the lungs (pleural effusion).
• Kidney disease (renal insufficiency, tubulointerstitial nephritis) that may manifest as reduced urine output.

Inform your doctor or pharmacist if any of the following side effects worsen or last more than a few days; you may need medical treatment:

The very common side effects that may affect more than 1 in 10 patients are:

-Nervous system disorders: tremor.

-Gastrointestinal disorders: nausea (also observed a few minutes after intravenous injection and resolves spontaneously in a few minutes).

The common side effects that may affect up to 1 in 10 patients are:

-Blood and lymphatic system disorders: reduction in red blood cells (anemia) and reduction in platelets (thrombocytopenia).

-Nervous system disorders: involuntary movements (extrapyramidal disorders), stupor, drowsiness, seizures, memory loss, headache, rapid and uncontrolled eye movements (nystagmus), may appear dizziness a few minutes after intravenous injection that disappears spontaneously in a few minutes. In isolated cases or associated with an increase in seizure frequency during treatment, cases of confusion have been described that decrease after treatment suspension and dose reduction.

Renal and urinary disorders: urinary incontinence..

-Auditory disorders: hearing problems or deafness.

-Gastrointestinal disorders: vomiting, gum problems (mainly hypertrophy), mouth pain and swelling, ulcers, and burning sensation in the mouth (stomatitis), upper abdominal pain, and diarrhea, which often appear in some patients at the beginning of treatment and usually disappear within a few days without interrupting treatment.

-Skin and subcutaneous tissue disorders: nail and skin changes under the nail, hypersensitivity, hair loss (transient and/or dose-related).

-Metabolism and nutrition disorders: low sodium levels in the blood (hyponatremia), weight gain.

-Vascular disorders: hemorrhage.

-Hepatobiliary disorders: liver damage.

-Reproductive system and breast disorders: painful menstruation (dysmenorrhea).

-Psychiatric disorders: confusion, seeing, feeling, or hearing things that do not exist (hallucinations), aggression*, agitation*, attention disorders* (*mainly observed in children).

The uncommon side effects that may affect up to 1 in 100 patients are:

-Blood and lymphatic system disorders: pancytopenia (scarcity of blood components) and decrease in white blood cells in the blood (leucopenia).

-Nervous system disorders: coma, encephalopathy, lethargy, disorder characterized by tremor, difficulty walking, movement, and coordination (reversible parkinsonism), incoordination of movements (ataxia), numbness or tingling in the feet or hands (paresthesia), worsening of seizures.

-Renal and urinary disorders: renal insufficiency.

-Gastrointestinal disorders: pancreatitis that can be fatal.

-Skin and subcutaneous tissue disorders: inflammation of feet, hands, throat, lips, and respiratory tract (angioedema) and rash, abnormal hair growth and texture, and changes in hair color.

-Musculoskeletal and connective tissue disorders: bone changes, including osteopenia and osteoporosis (bone decalcification) and fractures. Consult your doctor or pharmacist if you are on long-term antiepileptic treatment, have a history of osteoporosis, or take steroids.

-Endocrine disorders: Syndrome of Inadequate Antidiuretic Hormone Secretion (fluid retention and decrease in certain electrolyte levels in the blood), hyperandrogenism (increased hair, virilization, acne, male pattern alopecia, and/or increased androgens).

-Vascular disorders: inflammation of small blood vessels (vasculitis).

-General disorders: peripheral edema (non-severe swelling of legs, feet, and ankles), low body temperature.

-Reproductive system and breast disorders: irregular menstruation or absence of menstruation (amenorrhea).

The rare side effects that may affect up to 1 in 1,000 patients are:

• Blood and lymphatic system disorders: bone marrow insufficiency including pure red cell aplasia (cessation or decrease in red blood cell production. This causes severe anemia, whose symptoms include unusual fatigue and lack of energy), agranulocytosis (decrease in white blood cells), decrease in red blood cells with larger-than-normal size (anemia macrocítica, macrocitosis).
• Complementary examinations: decrease in coagulation factors, biotin/biotinidase deficiency (low levels of vitamin B8).

-Nervous system disorders: worsening of mental function causing confusion and changes in intellect or reasoning (reversible dementia), disorder of knowledge, double vision.

-Renal and urinary disorders: involuntary urination (enuresis), tubulointerstitial nephritis, urinating more frequently and feeling thirsty (Fanconi syndrome).

-Skin and subcutaneous tissue disorders: skin lesions with red patches, blisters, and even peeling that can be severe (Stevens-Johnson syndrome), DRESS syndrome (severe skin lesion characterized by generalized rash, fever, lymph node inflammation, blood abnormalities, and internal organ damage).

-Musculoskeletal and connective tissue disorders and connective tissue disorders: systemic lupus erythematosus, rhabdomyolysis (muscle pain and weakness).

-Endocrine disorders: hypothyroidism.

-Metabolism and nutrition disorders: obesity and increased ammonia levels in the blood (hyperammonemia).

-Cancer: myelodysplastic syndrome (disease in which the bone marrow does not function normally).

-Reproductive system and breast disorders: male infertility (usually reversible after treatment discontinuation and may be reversible after dose reduction. Do not stop your treatment without consulting your doctor first), polycystic ovaries.

-Psychiatric disorders: abnormal behavior*, hyperactivity*, learning disorders* (*mainly observed in children).

Other side effects of unknown frequency (cannot be estimated from available data) are:

-Genetic and congenital disorders: autism spectrum disorders, congenital malformations, and developmental disorders.

-Complementary examinations: false positives in the urine ketone elimination test in diabetic patients.

-Decreased carnitine levels (detected in blood or muscle test).

-Skin and subcutaneous tissue disorders: darker skin patches and mucous membranes (hyperpigmentation).

Additional side effects in children

Some side effects of valproate occur more frequently in children or are more severe compared to adults. These include liver damage, pancreatitis, aggression, agitation, attention disorders, abnormal behavior, hyperactivity, and learning disorders.

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Store the vial of the solvent and the vial with the lyophilized powder in the original packaging until the time of use.

No special conservation conditions are required.

Keep out of the sight and reach of children.

Do not useDepakine after the expiration date that appears on the packaging and on the labels of the vial and the ampoule. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through the drains or in the trash. Ask your pharmacist how to dispose of the packaging and medicines that you no longer need. In this way, you will be helping the environment.

Composition of Depakine 100 mg/ml powder and solvent for injectable solution

The active ingredient is valproate sodium. Each vial contains 400 mg of valproate sodium.

The other components are water for injection.

Appearance of the product and contents of the packaging

Depakine 100 mg/ml powder and solvent for injectable solution is presented in packaging containing 1 vial and 1 ampoule. Each ampoule contains 4 ml of water for injection.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization:

Sanofi-aventis, S.A

C/ Rosselló i Porcel, 21

08016 Barcelona

Spain

Responsible for manufacturing:

Sanofi S.r.l.

Via Valcanello, 4

03012 Anagni (FR)

Italy

This leaflet was approved in January 2025

You can access detailed and updated information about this medicine by scanning the QR code included in the leaflet with your smartphone. You can also access this information at the following internet address:https://cima.aemps.es/info/60352.

Detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/