Prospect: information for the user

Depakine Crono 500 mg prolonged-release tablets

valproate sodium/sodium valproate

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 not listed in this prospect. See section 4.

Depakine Crono is a medication for the treatment of epilepsy and mania.

Depakine Crono is used in the treatment of:

• Different types of epilepsy in adults and children.

-Mania, which is a disorder by which you may feel very excited, euphoric, agitated, enthusiastic or hyperactive. Mania appears in a disease called “bipolar disorder”. Depakine Crono 500 mg can be taken when lithium cannot be used.

Do not take Depakine Crono 500 mg

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

• Bipolar disorder

• For bipolar disorder, do not use Depakine Crono if you are pregnant.
• For bipolar disorder, if you are a woman of childbearing potential, do not take Depakine Crono, unless you use an effective method of contraception (birth control) throughout the treatment with Depakine Crono. Do not stop taking Depakine Crono or your contraceptive, until you have spoken to your doctor. Your doctor will advise you (see below in “Pregnancy, breastfeeding and fertility - Important warning for women”).

• Epilepsy

• For epilepsy, do not use Depakine Crono if you are pregnant, unless no other treatment works.
• For epilepsy, if you are a woman of childbearing potential, do not take Depakine Crono, unless you use an effective method of contraception (birth control) throughout the treatment with Depakine Crono.Do not stop taking Depakine Crono or your contraceptive, until you have spoken to your doctor. Your doctor will advise you(see below in “Pregnancy, breastfeeding and fertility - Important warning for women”).

• 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 family history of liver function disorder during treatment with valproate sodium.
• 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 if you have any doubts, consult your doctor before taking Depakine Crono.

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 must 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 must see your doctor immediately. In a very small number of patients, Depakine Crono can affect the liver or pancreas. Liver function disorder combined with pancreatic disorder 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 small number of people who have been treated with antiepileptic medications like valproate 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 that you have any metabolic disorder, particularly inherited 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 a carnitine deficiency and are taking carnitine.
• If you have kidney dysfunction 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 Crono 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 peeling, blisters, or mouth sores after taking valproate.

Use of 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, and other health-related products, as it may be necessary to interrupt treatment or adjust the dose of one or more of them.

Some medications may alter the effect of Depakine Crono 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 psychological disorders).
• Medications used to treat depression.
• Benzodiazepines (medications used to sleep or treat anxiety).
• Olanzapine and quetiapine (medications used to treat psychiatric disorders).
• Other medications used to treat epilepsy, including phenobarbital, phenytoin, primidone, lamotrigine (the risk of severe skin rash may increase when lamotrigine and valproate 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
• Inhibitors of protease, 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 diseases).
• Methotrexate (used to treat cancer and inflammatory diseases).
• Some anti-infectives containing pivalate (e.g., pivampicillin, adefovir dipivoxil).
• Clozapine (for treating mental health 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 Crono, or they may directly affect the activity of Depakine Crono. You may need different doses of medication or take different medications. Your doctor or pharmacist will advise you.

Taking Depakine Crono 500 mg with food and drinks

Do not consume alcoholic beverages.

Children and adolescents

Children and adolescents under 18 years.

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

Pregnancy, breastfeeding and fertility

Pregnancy

Consult your doctor or pharmacist before using any medication.

Important warning for women

Bipolar disorder

• For bipolar disorder, do not use Depakine Crono if you are pregnant.

• For bipolar disorder, if you are a woman of childbearing potential, do not take Depakine Crono, unless you use an effective method of contraception (birth control) throughout the treatment with Depakine Crono.Do not stop taking Depakine Crono or your contraceptive, until you have spoken to your doctor. Your doctor will advise you(see below in “Pregnancy, breastfeeding and fertility - Important warning for women”).

Epilepsy

• For epilepsy, do not use Depakine Crono if you are pregnant, unless no other treatment works.
• For epilepsy, if you are a woman of childbearing potential, do not take Depakine Crono, unless you use an effective method of contraception (birth control) throughout the treatment with Depakine Crono.Do not stop taking Depakine Crono or your contraceptive, until you have spoken to your doctor. Your doctor will advise you(see below in “Pregnancy, breastfeeding and fertility - Important warning for women”).

Risks of valproate when taken during pregnancy (regardless of the disease for which it is used)

• 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 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 includespina bifida(where the spinal bones do not develop properly); skull and facial malformations, heart malformations, kidney malformations, genital 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, in association 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 baby 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 babies in every 100 will have birth defects. In comparison, 2 to 3 babies in every 100 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 have a higher risk of being diagnosed with autism spectrum disorder 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 girl 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 have a baby. 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.

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

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

I AM STARTING TREATMENT WITH DEPAKINE CRONO

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

Important messages:

• You must exclude pregnancy before starting treatment withDepakine Crono, by the result of a pregnancy test, confirmed by your doctor.
• You must use a method for effective birth control (contraception) throughout the treatment withDepakine Crono.
• 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 bipolar disorder or 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 CRONO AND DO NOT INTEND TO HAVE A BABY

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

Important messages:

• You must use a method for effective birth control (contraception) throughout the treatment withDepakine Crono.
• 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 bipolar disorder or 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 CRONO 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 Crono 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 bipolar disorder or epilepsy, to evaluate alternative treatment options from the start. Your specialist may decide to change your Depakine Crono dose or switch to another medication, or stop your treatment with Depakine Crono well before you become pregnant – to ensure that your underlying condition is stable.

Consult your doctor about taking folic acid when trying to have a baby. 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 Crono unless your doctor tells you to.
• Do not stop using your contraceptives (birth control) 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 medication or stop your treatment with Depakine Crono 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 CRONO

Do not stop taking Depakine Crono 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 bipolar disorder or epilepsy, to evaluate alternative treatment options.

In exceptional cases, when Depakine Crono 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 exposure to valproate.

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 Crono unless your doctor tells you to.
• Make sure you are referred to a specialist experienced in treating epilepsy or bipolar disorder to evaluate the need for alternative treatment options.
• You must have counseling about the risks of Depakine Crono 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 Crono during pregnancy, the following may also occur:

• Problems with blood clotting due to partial or complete lack of some substances necessary for blood clotting. In the latter case, the problem can be fatal, so a blood test and specific coagulation tests should be performed in the newborn.

• Low blood sugar in newborns of mothers who have taken Depakine Crono during pregnancy.

• There have been reports of hypothyroidism in newborns of mothers who have taken 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 have taken 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 Crono during the breastfeeding period 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, taking into account the safety profile of Depakine Crono, 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 medications 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 movement and developmental disorders 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 must 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 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. You will also receive a Patient Card from your pharmacist to remind you of the potential risks of valproate.

Driving and operating machinery

Depakine Crono 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 medication.

Important information about some components of Depakine Crono 500 mg

This medication contains 46.08 mg of sodium in each tablet. This is equivalent to 2.3% of the maximum daily sodium intake recommended for an adult.

Follow exactly the administration instructions for Depakine Crono 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

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

Male patients

It is recommended that Depakine Crono be initiated and supervised by a specialist with experience in the treatment of epilepsy or bipolar disorder - see section 2 Important information for male patients.

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

Depakine Crono is prescribed on an individual basis and for a specific situation. You must follow the treatment strictly, never stop it without consulting your doctor. The doses recommended in this leaflet are indicative. The doses of Depakine Crono are established according to body weight, your specific situation, and the doctor's prescription.

Indicative recommended doses for the treatment of epilepsy

• Infants 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 patients (≥65 years): 15-20 mg/kg of body weight.
• Patients with liver insufficiency: Depakine Crono 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 leaflet. This is because people with kidney disease may need to reduce the dose of Depakine Crono.

The possible doses are always adjusted individually, established according to the patient's body weight. The doses with Depakine Crono 500 mg may vary between 2-6 tablets (1000 mg-3000 mg of valproate) per day.

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

Mania

The daily dose should be established and controlled individually by your doctor.

Initial dose

The recommended initial daily dose is 750 mg.

Medium daily dose

The recommended daily dose is usually between 1,000 mg and 2,000 mg.

Depakine Crono is for oral administration. Depakine Crono 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.

Patients with kidney problems

Your doctor may decide to adjust your dose.

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

If you take more Depakine Crono 500 mg than you should

If you have taken more Depakine Crono than you should, consult your doctor or pharmacist immediately or call the Toxicological Information Service, phone: 91 5620420 indicating the medication and the amount taken.

A Depakine Crono overdose can be dangerous. 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 undergo cardio-respiratory monitoring. In some cases, hypotension, miosis, cardiovascular and respiratory alterations, circulatory collapse/shock, metabolic acidosis, hypocalcemia, and hypernatremia have also been observed. There have been cases of death after massive overdose; however, a favorable outcome is usually the case.

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 the leaflet of the medication to the healthcare professional.

If you forgot to take Depakine Crono 500 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 Crono 500 mg

The abrupt suspension of treatment with Depakine Crono without your doctor's explicit indication may be harmful to you, as it may trigger seizures with severe consequences. Do not stop or alter the dose of Depakine Crono without consulting your doctor beforehand.

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

Like all medications, Depakine Crono may cause side effects, although not everyone will experience them.

Inform your doctor immediately if any of the following severe 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 (medications used to treat seizures) at the same time or if the Depakine Crono 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 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.
• Allergic reactions 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, 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.
• 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 (tremor), 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), difficulty breathing, and 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.

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

• Blood disorders: anemia (reduced red blood cells) and thrombocytopenia (reduced platelets).
• Nervous system disorders: involuntary movements (extrapyramidal disorders), stupor, drowsiness, seizures, memory loss, headache, rapid and uncontrolled 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), mouth pain and swelling, ulcers, and burning sensation in the mouth (stomatitis), abdominal pain, 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 components) and leukopenia (reduced white blood cells).
• 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: angioedema (inflammation of the face, hands, throat, lips, and respiratory tract) 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 (SIADH), (fluid retention and decreased levels of certain electrolytes in the blood), hyperandrogenism (increased hair growth, virilization, acne, alopecia of male pattern, and/or increased androgens).
• Vascular disorders: small blood vessel inflammation (vasculitis).
• General disorders: peripheral edema (non-severe swelling of the legs, feet, and ankles), hypothermia.
• Reproductive system disorders: irregular or absent menstruation (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 cells), and macrocytic anemia (reduced red blood cells with increased size).
• Complementary examinations: decreased coagulation factors, biotin/biotinidase deficiency (low levels of vitamin B8).
• Nervous system disorders: reversible dementia, cognitive disorder, double vision.
• Renal disorders: involuntary urination (enuresis), tubulointerstitial nephritis, and frequent urination and thirst (Fanconi syndrome).
• Skin and subcutaneous tissue disorders: skin lesions with red patches, blisters, and peeling that can be severe (Stevens-Johnson syndrome), DRESS syndrome (severe skin lesions, 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 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 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, familial, 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 valproate side effects 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 experienceany type of side effect, consult your doctor or pharmacist, even if it is apossibleside effect that does not appear in this prospectus.You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

This medication does not require special conservation conditions.

Keep the tablets in the original packaging until they are used. Depakine Chrono tablets, in contact with ambient humidity, may become soft, but the medication remains effective.

Keep Depakine Chrono out of sight and reach of children.

Do not use Depakine Chrono after the expiration date that appears on the packaging. The expiration date is the last day of the month indicated.

Medicines should not be thrown down the drains or in the trash. Dispose of the packaging and unused medicines at the SIGRE collection point of the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and unused medicines. By doing so, you will help protect the environment.

Composition of Depakine Crono 500 mg

Each Depakine Crono 500 mg prolonged-release tablet contains 333 mg of sodium valproate and 145 mg of valproic acid, equivalent to 500 mg of sodium valproate.

The other components (excipients) are: cellulose ether, acrylic and methacrylic ester copolymer, hydrated colloidal silica, hypromellose, macrogol 6000, talc, titanium dioxide, and polyacrylate.

Appearance of the product and contents of the packaging

Depakine Crono 500 mg is presented in the form of prolonged-release tablets. The tablets are white, oblong in shape.Each package contains 100 tablets for 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 Winthrop Industrie

1, rue de la Vierge, Ambarès et Lagrave,

F-33565 Carbon Blanc cedex, France

or

sanofi-aventis, S.A.

Ctra.C-35 (La Batllòria-Hostalric) Km. 63,09

17404 Riells i Viabrea (Gerona)

Spain

This leaflet was approved in January 2025

You can access detailed and updated information about this medication 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/60350.

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