DEPAKINE CRONO 300 mg PROLONGED-RELEASE TABLETS

Introduction

Package Leaflet: Information for the User

Depakine Crono 300 mg prolonged-release tablets

sodium valproate/valproic acid

This medicinal product is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. The last section of section 4 will tell you how to report side effects.

Read all of this package leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this package leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.

• This medicine has been prescribed to you only, and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this package leaflet. See section 4.

Contents of the package leaflet

1. What is Depakine Crono 300 mg and what is it used for
2. What you need to know before taking Depakine Crono 300 mg
3. How to take Depakine Crono 300 mg
4. Possible side effects
5. Storage of Depakine Crono 300 mg
6. Package contents and additional information

1. What is Depakine Crono 300 mg and what is it used for

Depakine Crono is a medicine 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 that can make you feel very excited, elated, agitated, enthusiastic, or hyperactive. Mania occurs in a disease called "bipolar disorder". Depakine Crono 300 mg can be taken when lithium cannot be used.

2. What you need to know before taking Depakine Crono 300 mg

Do not take Depakine Crono 300 mg

• If you are allergic (hypersensitive) to the active substance or any of the other ingredients of Depakine Crono, or to any other medicine, you must inform your doctor.

• Bipolar disorder

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

• Epilepsy

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

• If you currently have any liver or pancreatic disease.
• If you have previously had any liver disease.
• If any of your close relatives have a history of severe liver disease (hepatitis), mainly due to medicines.
• If you have a history of a family member dying from liver function disorders during treatment with sodium valproate.
• If you have hepatic porphyria (a very rare metabolic disorder).
• If you have a genetic problem 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 an untreated carnitine deficiency (a very rare metabolic disease).

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

CONSULT YOUR DOCTOR IMMEDIATELY:

The risk of liver damage increases if valproate is given to children under 3 years of age, to people taking other antiepileptic medicines at the same time, or to those with other neurological or metabolic disorders 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 patients at risk.

If you or your child suddenly develops an illness, 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, pain in the upper abdomen, nausea, jaundice (yellowing of the skin or eyes), swelling of the legs, or worsening of epilepsy or a feeling of general malaise. In this case, you must consult your doctor immediately. In a very small number of patients, Depakine Crono can affect the liver or pancreas. The alteration of liver function along with the alteration of the pancreas increases the risk of a fatal outcome.

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

A small number of people who were being treated with antiepileptics such as valproic acid have had thoughts of self-harm or suicide. If at any time you 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 problem caused by a mitochondrial disorder in your family, due to the risk of liver damage. If a metabolic disorder is suspected, particularly inherited enzyme deficiencies such as a "urea cycle disorder" due to the risk of an increase in 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 of age.
• If you have a carnitine deficiency and are taking carnitine.
• If you suffer from impaired kidney function or hypoproteinemia (decreased protein levels in the blood). In this case, your doctor may want to monitor your valproate blood levels or adjust the dose.
• If Depakine Crono is given to children under 3 years of age, the concomitant administration with acetylsalicylic acid (aspirin) should be avoided.
• If you have systemic lupus erythematosus.
• If you have blood disorders (blood clotting or thrombocytopenia). It is recommended to perform a blood test (complete blood count) before starting treatment or before surgery and in cases of spontaneous hematomas or bleeding.
• If you experience weight gain at the start of treatment.
• If you have developed a severe skin rash or peeling, blisters, and/or sores in the mouth after taking valproate.

Use of other medicines

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

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

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

• Products containing estrogens (including some birth control pills).
• Neuroleptics (medicines used to treat psychological disorders).
• Medicines used to treat depression.
• Benzodiazepines (medicines used to help you sleep or treat anxiety).
• Olanzapine and quetiapine (medicines used to treat psychiatric 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 given together), carbamazepine, ethosuximide, felbamate, and topiramate. The concomitant administration of Depakine with topiramate has been associated with encephalopathy and/or hyperammonemia (a condition of the brain and nervous system that occurs as a complication of liver disorders with or without an increase in blood ammonia levels).
• Zidovudine (a medicine used to treat HIV and AIDS).
• Mefloquine (a medicine used to treat or prevent malaria).
• Salicylates (aspirin). See also "Warnings and precautions - Children under 3 years".
• Anticoagulants (medicines used to prevent blood clot formation).
• Cimetidine (a medicine used to treat stomach ulcers).
• Erythromycin and rifampicin (antibiotics).
• Rufinamide.
• Acetazolamide.
• Protease inhibitors, such as lopinavir, ritonavir (used to treat HIV).
• Colestyramine.
• Propofol (an anesthetic).
• Metamizole (a medicine used to treat pain and fever).
• Cannabidiol (used to treat epilepsy and other diseases).
• Methotrexate (used to treat cancer and inflammatory diseases).
• Certain anti-infectives that contain pivalate (e.g., pivampicillin, adefovir dipivoxil).
• Clozapine (for treating mental health disorders).

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

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

Taking Depakine Crono 300 mg with food and drinks

Do not drink alcoholic beverages.

Children and adolescents

Children and adolescents under 18 years of age.

Depakine Crono must not be used in children and adolescents under 18 years of age 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, you should not use Depakine Crono if you are pregnant.

• For bipolar disorder, if you are a woman of childbearing potential, you should not take Depakine Crono unless you use an effective method of birth control (contraception) throughout your treatment with Depakine Crono. Do not stop taking Depakine Crono or your contraceptive until you have discussed this with your doctor. Your doctor will advise you.

Epilepsy

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

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. With the highest dose, the risk is greater, but all doses have a risk, even when valproate is used in combination with other medications to treat epilepsy.
• It can cause serious birth defects and may affect the physical and mental development of the child and how they grow after birth. The most frequently reported birth defects include spina bifida(where the bones of the spine do not develop properly); malformations of the skull and face, heart, kidney, urinary tract, genital organs, and limb defects, as well as multiple malformations that affect several organs and parts of the body. Birth defects can result in disabilities that can be severe.
• Hearing problems or deafness have been reported in children exposed to valproate during pregnancy.
• Ocular malformations have been reported in children exposed to valproate during pregnancy in association with other congenital malformations. These ocular malformations can 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 who take valproate, around 11 babies out of 100 will have birth defects. In comparison, 2 to 3 babies out of 100 born to women who do not have 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. The affected children may speak and walk slowly, be less intellectually capable than other children, and have language and memory difficulties.
• In children exposed to valproate, autism spectrum disorders are more frequently diagnosed, 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 what can happen to your baby if you become pregnant while taking valproate. If you later decide that you want to have a baby, do not stop taking your medication or your contraceptive until you have discussed this with your doctor.
• If you are a father or caregiver of a girl being treated with valproate, you should contact your doctor when your daughter being treated with valproate has her menarche (first menstruation).
• Some oral contraceptives (birth control pills that contain estrogen) may decrease valproate levels in the blood. Make sure to talk to your doctor about the most suitable birth control method (contraception) for you.
• Consult your doctor about taking folic acid when trying to have a baby. Folic acid may decrease the overall risk of spina bifidaand early abortion that exists during all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with the use of valproate.

Choose and read the situations that apply to 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 the fetus if you become pregnant. Once you are of childbearing age, you will need to ensure that you use an effective contraceptive method without interruption throughout your treatment with Depakine Crono. Consult your doctor or family planning clinic if you need advice on contraception.

Important messages:

• Pregnancy should be excluded before starting treatment with Depakine Crono, through 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 Crono.
• You should talk to your doctor about suitable methods of birth control (contraception). Your doctor will give you information on how to prevent pregnancy and may refer you to a specialist for birth control advice.
• You should have regular check-ups (at least annual) with a specialist experienced in the treatment of bipolar disorder or epilepsy. During this visit, your doctor will ensure that you know and have understood all the risks and warnings related to the use of valproate during pregnancy.
• Tell 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 contraceptive method 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 an effective method of birth control (contraception) throughout your treatment with Depakine Crono.
• You should 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 birth control advice.
• You should have regular check-ups (at least annual) with a specialist experienced in the treatment of bipolar disorder or epilepsy. During this visit, your doctor will ensure that you know and have understood all the risks and warnings related to the use of valproate during pregnancy.
• Tell 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 discussed this with 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 with experience in the treatment of bipolar disorder or epilepsy, so that alternative treatment options can be evaluated from the start. Your specialist may take several actions to ensure that your pregnancy develops as well as possible and the risks to you and the fetus are reduced as much as possible.

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

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

Important messages:

• Do not stop taking Depakine Crono unless your doctor tells you to.
• Do not stop using your contraceptives (contraception) before discussing with your doctor and working 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 have understood 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 treatment with Depakine Crono long 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 CRONO

Do not stop taking Depakine Crono 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 with experience in the treatment of bipolar disorder or epilepsy, so that alternative treatment options can be evaluated.

In exceptional circumstances, when Depakine Crono 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 related to pregnancy with valproate exposure.

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

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 with experience in the treatment of epilepsy or bipolar disorder to evaluate the need for alternative treatment options.
• You should be counseled about the risks of Depakine Crono during pregnancy, including teratogenicity (birth defects) and physical and mental 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. Your doctor will discuss the Annual Risk Acknowledgement Form 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 newborn babies of mothers who have taken Depakine Crono during pregnancy, the following may also occur:

• Coagulation problems may occur due to partial or total lack of some of the substances necessary for blood coagulation. In the latter case, the problem can be fatal, so specific analytics and coagulation tests should be performed on the newborn.
• Hypoglycemia may occur in newborns of mothers who have taken Depakine Crono during pregnancy.

• Cases of hypothyroidism have been reported in neonates of mothers who have taken valproate during pregnancy.

• A withdrawal syndrome (such as agitation, irritability, hyperexcitability, nervousness, hyperkinesia, tonicity disorders, tremors, convulsions, 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 does not generally pose a risk to the infant, and it is not usually necessary to stop breastfeeding. Nevertheless, you should consult your doctor about the convenience of maintaining or not maintaining breastfeeding, taking into account the safety profile of Depakine Crono, especially blood disorders (see section “Possible adverse effects”).

Important information for male patients

Potential risks associated with the use of valproate in the 3 months prior to conception of a child

A study suggests a possible risk of movement and mental development disorders (problems with childhood development) in children born to fathers treated with valproate in the 3 months prior to conception. In this study, around 5 out of 100 children presented with these disorders when born to fathers treated with valproate, compared to 3 out of 100 children when born to fathers treated with lamotrigine or levetiracetam (other medications that can be used to treat your disease). The risk to children born to fathers who stopped treatment with valproate 3 months (the time necessary to form new sperm) or more before conception is unknown. The study has limitations, and therefore, it is not clear whether the higher risk of movement and mental development disorders suggested by this study is caused by valproate. The study was not extensive enough to demonstrate what specific type of movement and mental development disorder children may develop.

As a precautionary measure, your doctor will talk to you about:

• The potential risk in children born to fathers treated with valproate.
• The need to consider effective birth control methods (contraception) for you and your female partner during treatment and during the 3 months following treatment interruption.
• The need to consult your doctor when planning to conceive a child and before stopping contraception (birth control).
• The possibility of using other treatments to treat your disease, depending on your individual situation.

Do not donate sperm when 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 prior to 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 maintain regular appointments with your doctor. During this visit, your doctor will talk to you about the precautions associated with the use of valproate and the possibility of other treatments that can be used to treat your disease, depending on your individual situation.

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

Driving and using machines

Depakine Crono may cause symptoms such as drowsiness, dizziness, or vision changes, and may reduce your reaction ability. These effects, as well as your underlying disease, may impair your ability to drive vehicles or operate machines. Therefore, do not drive, operate machines, or engage in other activities that require special attention until your doctor assesses your response to this medication.

Important information about some of the components of Depakine Crono 300 mg

This medication contains 27.65 mg of sodium in each tablet. This is equivalent to 1.4% of the maximum daily sodium intake recommended for an adult.

3. How to take Depakine Crono 300 mg

Follow the administration instructions for Depakine Crono exactly 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

Treatment with Depakine Crono should be initiated and supervised by a doctor specializing 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 have regular check-ups with your doctor. This is very important, as the dose you are taking may need to be modified over time.

Depakine Crono is prescribed individually and for a specific situation. You should strictly follow the treatment, never stopping it without consulting your doctor. The recommended doses in this prospectus are indicative. The doses of Depakine Crono are established according to body weight, your specific situation, and the prescriber's criteria.

Recommended dosage guidelines 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 adults (≥65 years): 15-20 mg/kg of body weight. Patients with liver failure: Depakine Crono should not be administered to patients with severe liver disease.
• Patients with renal failure: 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 dose of Depakine Crono.

The possible doses are always adjusted individually, based on the patient's body weight. The doses with Depakine Crono 300 mg can range from 1 to 3 tablets (300 mg - 900 mg of sodium valproate) per day. For those patients who need higher daily doses, since body weight is greater, other presentations are available.

In children under 11 years of age, the administration of Depakine 200 mg/ml oral solution is considered more appropriate.

Mania

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

Initial dose

The recommended initial daily dose is 750 mg.

Average daily dose

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

Depakine Crono is for oral administration. The tablets of Depakine Crono should be swallowed whole, without splitting, chewing, or crushing, with a little water, preferably during meals.

Try to take the tablets every day at the same time.

Patients with kidney problems

Your doctor may decide to adjust your dose.

If you think the effect of Depakine Crono is too strong or too weak, tell your doctor or pharmacist.

If you take more Depakine Crono 300 mg than you should

If you have taken more Depakine Crono than you should, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562.04.20, indicating the medication and the amount taken.

An overdose of Depakine Crono can be dangerous. Among the symptoms of poisoning 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 the 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. There have been cases of death after massive overdose; however, the usual outcome is favorable.

However, the symptoms can 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 valproate presentations can lead to hypernatremia when there is an overdose.

It is recommended to take the package and the prospectus of the medication to the healthcare professional.

If you forget to take Depakine Crono 300 mg

In case of forgetting a dose, wait for the next one. Do not take a double dose to make up 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 treatment with Depakine Crono 300 mg

Sudden discontinuation of treatment with Depakine Crono without your doctor's explicit indication can be harmful to you, as it may trigger episodes with seizures with serious consequences. Do not stop or change the dose of Depakine without consulting your doctor first.

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

4. Possible side effects

Like all medications, Depakine Crono can cause side effects, although not all people experience them.

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

• Somnolence, change in level of consciousness (including coma), confusion, slow or abnormal behavior, and memory loss associated or not with 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 dose of Depakine Crono has been suddenly increased.
• Confusion that can be caused by a decrease in sodium levels in the blood or by a condition called Syndrome of Inadequate Secretion of the Antidiuretic Hormone (SIADH).
• Problems with balance and coordination, feeling of lethargy or being less alert, associated with vomiting. This can be due to an increase in blood ammonia levels.
• Increased number and severity of seizures.
• Repeated vomiting, extreme fatigue, abdominal pain, somnolence, weakness, loss of appetite, severe pain in the upper abdomen, nausea, jaundice (yellowing of the skin or the whites of the eyes), swelling of the legs or worsening of epilepsy or general feeling of discomfort. These can be symptoms of serious liver and pancreas disorders.
• Allergic reactions that can 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 those of the flu, such as fever, chills, or muscle pain - these can be signs of conditions called 'toxic epidermal necrolysis' or 'Stevens-Johnson syndrome'.
• Allergic inflammation with painful hives that cause itching (frequently around the eyes, lips, throat, and sometimes on hands and feet) – these can be symptoms of “angioedema”.
• Syndrome that involves skin rash, fever, lymph node enlargement, and possible failure of other organs – these can be signs of a condition called “DRESS” or drug rash with eosinophilia and systemic symptoms.

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

Tell 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 can affect more than 1 in 10 patients are:

• Nervous system disorders: tremor.
• Gastrointestinal disorders: nausea.

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

• Blood disorders: reduction in the number of red blood cells (anemia) and reduction in the number of platelets (thrombocytopenia).
• Nervous system disorders: involuntary movement disorders (extrapyramidal disorders), stupor, somnolence, seizures, memory failure, headache, rapid and uncontrolled eye movements (nistagmus), dizziness. In isolated cases or associated with an increase in seizures during treatment, cases of confusion that decrease after treatment discontinuation and dose reduction have been described.
• Renal and urinary disorders: urinary incontinence.
• Ear 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 appear in some patients at the beginning of treatment and usually disappear within a few days without interrupting treatment.
• Skin and subcutaneous tissue disorders: alteration of the nail and the skin under the nail, hypersensitivity, hair loss (transient and/or related to the dose).
• Metabolic and nutritional disorders: decrease in blood sodium levels (hyponatremia), weight gain.
• Vascular disorders: bleeding.
• 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 can affect up to 1 in 100 patients are:

• Blood disorders: scarcity of blood components (pancytopenia) and decrease in the number of white blood cells in the blood (leukopenia).
• Nervous system disorders: coma, encephalopathy, lethargy, disorder characterized by tremor, difficulty walking, movement, and coordination (reversible parkinsonism), lack of coordination (ataxia), numbness or tingling in the feet or hands (paresthesia), worsening of seizures.
• Renal and urinary disorders: renal failure.
• Gastrointestinal disorders: pancreatitis that can be fatal.
• Skin and subcutaneous tissue disorders: inflammation of the feet, hands, throat, lips, and respiratory tract (angioedema) and rash, growth, and abnormal texture of the hair, and changes in hair color.
• Musculoskeletal and connective tissue disorders: alterations in bones, including osteopenia and osteoporosis (decalcification of bones) and fractures. Consult your doctor or pharmacist if you are on long-term treatment with antiepileptics, have a history of osteoporosis, or take steroids.
• Endocrine disorders: Syndrome of Inadequate Secretion of the Antidiuretic Hormone (retention of fluids and decrease in certain electrolyte levels in the blood), hyperandrogenism (excessive hair growth, virilization, acne, male-pattern baldness, and/or increased androgens).
• Vascular disorders: inflammation of small blood vessels (vasculitis).
• General disorders: swelling of the ankles, feet, and legs due to fluid accumulation (non-severe peripheral edema), decrease in body temperature.
• Reproductive system disorders: irregular or absent menstruation (amenorrhea).

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

• Blood disorders: bone marrow failure, including pure red cell aplasia (stop or decrease in the production of red blood cells, which causes severe anemia, whose symptoms include unusual fatigue and lack of energy), agranulocytosis (decrease in the number of white blood cells), decrease in the number of red blood cells with a larger than normal size (macrocytic anemia, macrocytosis).
• Complementary tests: decrease in coagulation factors, biotin/biotinidase deficiency (low levels of vitamin B8).
• Nervous system disorders: reversible dementia, mental disorder, double vision.
• Kidney disorders: involuntary urination (enuresis), tubulointerstitial nephritis, frequent urination, and thirst (Fanconi syndrome).
• Skin and subcutaneous tissue disorders: skin lesions with red spots, blisters, and peeling that can be severe (Stevens-Johnson syndrome), DRESS syndrome (severe skin lesion characterized by generalized rash, fever, lymph node inflammation, blood alterations, and involvement of internal organs).
• Musculoskeletal and connective tissue disorders: systemic lupus erythematosus, rhabdomyolysis (muscle pain and weakness).
• Endocrine disorders: hypothyroidism.
• Metabolic and nutritional disorders: obesity, increased ammonia levels in the blood (hyperammonemia).
• Neoplasms: 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 first), polycystic ovaries.
• Psychiatric disorders: abnormal behavior*, hyperactivity*, learning disorders* (* mainly observed in children).

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

• Congenital, familial, and genetic disorders: autism spectrum disorders, congenital malformations, and developmental disorders.
• Complementary tests: false positives may appear in the urine ketone elimination test in diabetic patients.
• Decrease in carnitine levels (detected in blood or muscle tests).
• Skin and subcutaneous tissue disorders: darker skin 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 prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medications: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Conservation of Depakine Crono 300 mg

This medication does not require special storage conditions.

Keep the tablets in their original packaging until use. Depakine Crono tablets, in contact with ambient humidity, may soften, but the medication remains effective.

Keep out of sight and reach of children.

Do not use Depakine Crono after the expiration date shown on the packaging. The expiration date is the last day of the month indicated.

Medications should not be thrown away through the sewers or in the trash. Deposit the packaging and medications you no longer need in the SIGRE Point of the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medications you no longer need. This way, you will help protect the environment.

6. Packaging Content and Additional Information

Composition of Depakine Crono 300 mg

Each Depakine Crono 300 mg prolonged-release tablet contains 200 mg of sodium valproate and 87 mg of valproic acid, equivalent to 300 mg of sodium valproate. The other components are: acrylic and methacrylic acid ester copolymer, ethylcellulose, hydrated colloidal silica, hypromellose, macrogol 6000, talc, titanium dioxide, and polyacrylate.

Appearance of the Product and Packaging Content

Depakine Crono 300 mg is presented in the form of prolonged-release tablets. The tablets are white, oblong-shaped. Each package contains 100 tablets for oral administration.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

sanofi-aventis, S.A.

C/ Rosselló i Porcel, 21

08016 Barcelona

Spain

Manufacturer:

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 (Girona)

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 mobile phone (smartphone). You can also access this information at the following internet address:https://cima.aemps.es/info/60351.

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