PATIENT INFORMATION LEAFLET

Depakine 200 mg gastro-resistant tablets

valproate sodium

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

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

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

-This medicine has been prescribed for you only, 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 side effects, consult your doctor or pharmacist,even if they are side effects that do not appear in this leaflet. See section 4.

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

Do not take Depakine 200 mg

• If you are allergic (hypersensitive) to the active ingredient or to any of the other components of Depakine, or to any other medication, you must inform your doctor.

• You should not use Depakine if you are pregnant, unless no other treatment is effective.

• If you are a woman of childbearing potential, do not take Depakine unless you use an effective method of birth control (contraception) 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 (see "Pregnancy, breastfeeding and fertility - Important warning for women" below).
• If you have any liver or pancreas disease currently.
• If you have had any liver disease previously.
• 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 a carnitine deficiency (a very rare metabolic disorder) without treatment.

If you think you may have any of these problems or have any doubts, consult your doctor before taking 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 medications 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 develop 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 may affect the liver or pancreas. The combination of liver dysfunction and pancreatic dysfunction increases the risk of fatal outcome.

If you or your child taking valproate develop 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 medications 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 medication, 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 old.
• If you have a 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, especially avoid concurrent administration with aspirin (acetylsalicylic acid).
• 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 medications, seizures may worsen or occur more frequently while taking this medication. If this happens, contact your doctor immediately.
• If you have ever developed a severe skin rash or blistering, peeling, or ulcers in the mouth after taking valproate.

Use of Depakine 200 mg with other medications

Inform your doctor or pharmacist if you are taking, have taken recently, or may take any other medication, including those purchased without a prescription, homeopathic, herbal, or other health-related products, as it may be necessary to interrupt treatment or adjust the dose of one of them.

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

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

• Products containing estrogens (including some birth control pills).
• Neuroleptics (medications used to treat mental disorders).
• Medications used to treat depression.
• Benzodiazepines (medications used to sleep or treat anxiety).
• Olanzapine and quetiapine (medications used to treat mental disorders).
• Other medications used to treat epilepsy, including phenobarbital, phenytoin, primidone, lamotrigine (the risk of severe skin rash may increase when lamotrigine and valproic acid are taken 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 disorder that occurs as a complication of liver disorders with or without increased blood ammonia levels).
• Zidovudine (medication used to treat HIV and AIDS).
• Mefloquine (medication used to treat or prevent malaria).
• Salicylates (aspirin). See also "Warnings and precautions - Children under 3 years".
• Anticoagulants (medications used to prevent blood clotting).
• Cimetidine (medication used to treat stomach ulcers).
• Erythromycin and rifampicin (antibiotics).
• Rufinamide.
• Acetazolamide.
• Protease inhibitors, such as lopinavir, ritonavir (used to treat HIV).
• Colestiramine.
• Propofol (anesthetic).
• Metamizol (medication used to treat pain and fever).
• Cannabidiol (used to treat epilepsy and other disorders).
• Methotrexate (used to treat cancer and inflammatory disorders).
• Some antibiotics containing pivalate (e.g., pivampicillin, adefovir dipivoxil).

Clozapine (used to treat mental disorders).

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

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

Taking Depakine 200 mg with food and drinks

Do not consume alcoholic beverages.

Pregnancy, breastfeeding, and fertility

Pregnancy

Consult your doctor or pharmacist before using any medication.

Important warning for women

• You should not use Depakine if you are pregnant, unless no other treatment is effective.
• If you are a woman of childbearing potential, do not take Depakine unless you use an effective method of birth control (contraception) 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 become pregnant 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 medications 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); cranial and facial malformations, heart malformations, kidney malformations, genital malformations, and limb malformations, 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 hearing loss 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 100 babies will have birth defects. In comparison, 2 to 3 out of 100 babies born to women without epilepsy will have birth defects.
• It is estimated that up to 30-40% of children in preschool age whose mothers took valproate during pregnancy may have developmental problems in childhood. Affected children may speak and walk slowly, be intellectually less capable than other children, and have language and memory difficulties.
• Children exposed to valproate have been diagnosed with autism spectrum disorders more frequently, and there is some evidence that these children have a higher risk of developing Attention Deficit Hyperactivity Disorder (ADHD).
• Before prescribing this medication, 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 medication or your contraceptive until you have spoken to your doctor.
• If you are a father or caregiver of a girl being treated with valproate, you should 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 levels in the blood. 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 become pregnant. 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 fertile, you will need to ensure that you use an effective method of birth control (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 excluded before starting treatment with Depakine, by the result of a pregnancy test, confirmed by your doctor.
• You must use an effective method of birth control (contraception) throughout your treatment with Depakine.
• You must talk to your doctor about the most suitable method of birth control (contraception). Your doctor will give you information on how to prevent pregnancy and may refer you to a specialist for advice on birth control.
• 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 birth control (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 birth control (contraception) throughout your treatment with Depakine.
• You must talk to your doctor about birth control (contraception). Your doctor will give you information on how to prevent pregnancy and may refer you to a specialist for advice on birth control.
• 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 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 perform several actions to ensure that your pregnancy develops as well as possible and that the risks to you and the fetus are reduced as much as possible.

Your specialist may decide to change the dose of Depakine or switch to another medication, or stop your treatment with Depakine well before you become pregnant - to ensure that your underlying disease is stable.

Consult your doctor about taking folic acid when trying to become pregnant. 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.

Important messages:

• Do not stop taking Depakine unless your doctor tells you to.
• Do not stop using your contraceptives (contraception) until you have spoken to your doctor and worked together on a plan to ensure that your disease 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 medication 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 TAKING DEPAKINE

Do not stop taking Depakine unless your doctor tells you to, as your disease 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 disease and to check how the fetus is developing. You and your partner may receive counseling and support regarding pregnancy exposure to valproate.

Consult your doctor about taking folic acid. 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.

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 experienced in treating epilepsy to evaluate the need for alternative treatment options.
• You must receive counseling about the risks of Depakine during pregnancy, including teratogenicity (birth defects) and developmental disorders in children.
• Make sure you are referred to a prenatal monitoring specialist to detect possible malformations.

Make sure to read the Patient Guide that your doctor will provide you. 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 also 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 may be fatal, so in the newborn, specific blood tests and coagulation tests should be performed.

• Low blood sugar in newborns of mothers who took Depakine during pregnancy.

• There have been reports of hypothyroidism in newborns of mothers who took valproate during pregnancy.

• A withdrawal syndrome (such as agitation, irritability, hyperexcitability, nervousness, hyperkinesia, muscle tone disorders, tremors, seizures, and feeding disorders) may occur in newborns whose mothers took valproate during the last trimester of pregnancy.

Breastfeeding

Consult your doctor or pharmacist before taking any medication.

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 the lactation period generally does not pose a risk to the infant, and it is usually not necessary to stop 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 adverse 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 100 children had these disorders when born to fathers treated with valproate, compared to 3 out of 100 children born to fathers treated with lamotrigine or levetiracetam (other medications that may be used to treat your disease). 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 the precautions associated with the use of valproate and the possibility of other treatments that may be used to treat your disease, depending on your individual situation.

Make sure to read the patient guide that your doctor will provide you. 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 decrease your reaction time. These effects, as well as the underlying disease, may impair your ability to drive vehicles or operate machinery. Therefore, do not drive, operate machinery, or engage in other activities that require special attention until your doctor assesses your response to this medication.

Important information about some components of Depakine 200 mgmg

This medication contains 27.68 mg of sodium in each tablet. This is equivalent to 1.4% of the maximum daily sodium intake recommended for an adult.

This medication contains cornstarch without gluten.

Follow exactly the administration instructions for Depakine as indicated by your doctor. Consult your doctor or pharmacist if you have any doubts.

Remember to take your medication.

Girls and women of childbearing age

Depakine treatment should be initiated and supervised by a doctor specializing in epilepsy treatment.

Male patients

It is recommended that Depakine be initiated and supervised by an experienced specialist in epilepsy treatment - see section 2 Important information for male patients.

Your doctor will inform you of the duration of your Depakine treatment. Do not stop treatment prematurely. Make sure to perform regular check-ups with your doctor. This is very important, as the dose you are taking may need adjustments over time.

Depakine is prescribed individually and for a specific situation. You must follow the treatment strictly, never stop it without consulting your doctor. The doses recommended in this prospectus are orientative. Depakine doses 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 30 mg/kg of body weight.
• Adolescents (≥12 years) and adults (≥18 years): The recommended dose is 20-30 mg/kg of body weight.
• Older adults (≥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: Your doctor may have recommended lower doses than those indicated in this prospectus. This is because people with kidney disease may need to reduce the Depakine dose.

Depakine is for oral administration. Depakine tablets should be swallowed whole, without breaking, crushing, or chewing them with a little water, preferably during meals.

Make sure to take the tablets every day at the same time.

The possible doses are adjusted individually, established according to the patient's body weight. Depakine 200 mg tablets may vary between 1 to 3 tablets (200 mg-600 mg of valproate) per day. For patients who need higher daily doses, due to a higher body weight, other presentations are available.

Patients with kidney 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.

If you estimate that the action of Depakine 200 mg is too strong or too weak, inform your doctor or pharmacist.

If you take more Depakine 200 mg than you should

If you have taken more Depakine than you should, consult your doctor or pharmacist immediately or call the Toxicological Information Service, phone: 91 562 04 20 indicating the medication and the amount taken.

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, although a favorable outcome is usually expected.

However, symptoms may vary 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 the prospectus of the medication to the healthcare professional.

If you forget to take Depakine 200 mg

In case of forgetting a dose, wait for the next one. Do not take a double dose to compensate for the missed doses. Continue taking the treatment according to your doctor's instructions. If you have forgotten several doses, contact your doctor immediately.

If you interrupt the treatment with Depakine 200 mg

Stopping treatment abruptly without your doctor's explicit indication may be harmful to you, as it may trigger seizures with severe consequences. Do not suspend or alter the Depakine dose without consulting your doctor beforehand.

If you have any other doubts about the use of this product, ask your doctor or pharmacist.

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

Inform your doctor immediately if you experience any of the following severe side effects. You may need urgent medical attention:

• Drowsiness, change in level of consciousness (including coma), confusion, slow or abnormal 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 drowsy or less alert, associated with vomiting. This may be due to an increase in your blood ammonia levels.
• Increased frequency and severity of seizures.
• Vomiting repeatedly, extreme fatigue, abdominal pain, drowsiness, weakness, loss of appetite, severe upper stomach pain, nausea, jaundice (yellowing of the skin or eyes), swelling of the legs or worsening of epilepsy or general feeling of discomfort. These may be symptoms of severe liver and pancreas disorders.
• Allergic reactions that may manifest as:
• Ampoules 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'.
• Inflammatory reaction of allergic origin with painful itchy rashes (often around the eyes, lips, throat, and sometimes on hands and feet) - these may be symptoms of 'angioedema'.
• Syndrome involving skin rash, fever, lymph node enlargement, 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.
• Decrease in white blood cell count 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.
• Tremors, 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: tremors.

-Gastrointestinal disorders: nausea.

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

-Blood disorders: anemia (reduced red blood cell count) and thrombocytopenia (reduced platelet count).

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

-Renal and urinary disorders: urinary incontinence.

-Auditory disorders: hearing problems or deafness.

-Gastrointestinal disorders: vomiting, gum problems (mainly hypertrophy), pain and swelling in the mouth, ulcers, and burning sensation in the mouth (stomatitis), pain in the upper abdomen, and diarrhea, which frequently occur 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: decreased blood sodium levels (hyponatremia), weight gain.

-Vascular disorders: hemorrhage.

-Hepatobiliary disorders: liver damage.

-Reproductive system 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 disorders: pancytopenia (reduced blood cell count) and leukopenia (reduced white blood cell count).

-Nervous system disorders: coma, encephalopathy, lethargy, disorder characterized by tremors, 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 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 decreased levels of certain electrolytes 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), hypothermia.

-Reproductive system disorders: irregular menstruation or amenorrhea.

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

• Blood disorders: bone marrow insufficiency including pure red cell aplasia (cessation or reduction of red blood cell production. This causes severe anemia, with symptoms including unusual fatigue and lack of energy), agranulocytosis (reduced white blood cell count), reduced red blood cell count with larger-than-normal size (macrocyclic anemia, macrocytosis).
• Complementary examinations: decreased coagulation factors, biotin/biotinidase deficiency (low levels of vitamin B8).
• Nervous system disorders:reversible cognitive impairment causing confusion and changes in intellect or reasoning (reversible dementia), disorder of knowledge, double vision.

-Renal disorders: involuntary urination (enuresis), tubulointerstitial nephritis, urinating more frequently and with increased thirst (Fanconi syndrome).

• Skin and subcutaneous tissue disorders: skin lesions with red patches, blisters, and peeling that can be severe (Stevens-Johnson syndrome),Síndrome DRESS (severe skin lesion characterized by generalized rash, fever, lymph node inflammation, blood abnormalities, and internal organ damage).
• Musculoskeletal and connective tissue disorders: systemic lupus erythematosus, rhabdomyolysis (muscle pain and weakness).
• Endocrine disorders: hypothyroidism.
• Metabolism and nutrition disorders: obesity and increased blood ammonia levels (hyperammonemia).

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

-Reproductive system disorders: male infertility (usually reversible after treatment discontinuation and may be reversible after dose reduction. Do not stop treatment without consulting your doctor), 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, congenital, and familial disorders: autism spectrum disorders, congenital malformations, and developmental disorders.

-Complementary examinations: false positives in urine ketone elimination tests 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.

Keep the container perfectly closed to protect it from moisture. Depakine tablets, in contact with the ambient humidity, may become softened, but the medication remains effective.

Store below 25°C.

Keep out of sight and reach of children.

Do not use Depakine after the expiration date appearing on the container. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through drains or in the trash. Dispose of the containers and medicines you no longer need at the SIGRE collection point of the pharmacy. If in doubt, ask your pharmacist how to dispose of the containers and medicines you no longer need. In this way, you will help protect the environment.

Composition of Depakine 200 mg gastro-resistant tablets

The active ingredient is valproate sodium. Each gastro-resistant tablet contains 200 mg of valproate sodium.

The other components are: povidone, calcium silicate, magnesium stearate, talc, macrogol 400, cornstarch without gluten, titanium dioxide, diethyl phthalate, and cellulose acetophthalate.

Appearance of the product and contents of the packaging

Depakine 200 mg is presentedin the form of gastro-resistant tablets. The tablets are round and white.Each package contains 40 and 100 tabletsfor oral administration.

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-aventis, S.A.

Ctra.La Batlloria a Hostalrich, Km.63,09

17404 – Riells i Viabrea (GERONA), Spain

This leaflet has been approved inJanuary 2025

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

https://cima.aemps.es/info/48827

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/