Patient Information Leaflet

Valproic Acid Sandoz 300 mg prolonged-release tablets, 500 mg prolonged-release tablets

Equivalent medicine
▼ This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
WARNING
Valproate, if taken during pregnancy, may severely harm the unborn baby. If you are a woman of childbearing age, you must use an effective method of birth control (contraception) continuously throughout the entire duration of treatment with Valproic Acid Sandoz. Your doctor will discuss this with you, but you must also follow the recommendations in section 2 of this leaflet.
If you are planning a pregnancy or think you might be pregnant, urgently consult your doctor.
Do not stop taking Valproic Acid Sandoz unless instructed by your doctor, as your condition could worsen.
Please read this leaflet carefully before taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Valproic Acid Sandoz is and what it is used for
What you need to know before taking Valproic Acid Sandoz
How to take Valproic Acid Sandoz
Possible side effects
How to store Valproic Acid Sandoz
Contents of the pack and other information

1. What Acido Valproico Sandoz is and what it is used for

Acido Valproico Sandoz contains the active substances sodium valproate and valproic acid and belongs to a group of medicines called "antiepileptic fatty acid derivatives". Acido Valproico Sandoz is a medicine used to treat epileptic seizures (caused by disturbed nerve activity leading to discomfort, abnormal behaviours or sensations, or even fits, convulsions and loss of consciousness) and mania.
Acido Valproico Sandoz is used to treat:

epileptic seizures originating in both hemispheres of the brain (generalised epilepsy, e.g. absence seizures, myoclonic seizures and tonic-clonic seizures)
simple epilepsy or epilepsy with mixed symptoms (complex epilepsy), or epilepsy spreading from a localized area of the brain to both hemispheres (secondary generalised epilepsy)
specific syndromes (West, Lennox-Gastaut (childhood epilepsies))
mania, during which you may feel extremely excited, euphoric, agitated, enthusiastic or hyperactive. Mania occurs in a condition called "bipolar disorder". Acido Valproico Sandoz may be used when lithium cannot be used.

2. What you should know before taking Acido Valproico Sandoz

Do not take Acido Valproico Sandoz

if you are allergic to sodium valproate or valproic acid or to any of the other ingredients of this medicine (listed in section 6);
if you suffer from acute or chronic hepatitis (inflammation of the liver);
if you or a member of your family has a history of severe liver disease, especially if related to the use of medicines;
if you suffer from a disease due to a disorder in the formation, at the liver level, of the red pigment of blood (hepatic porphyria);
if you have a tendency to bleeding;
if you have a genetic condition causing a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome);
if you suffer from genetic disorders caused by a deficiency of an enzyme involved in the urea cycle, which manifest with alterations, usually severe, of the nervous system (see section “Warnings and precautions”).

Bipolar disorder

If you are pregnant, you must not use Acido Valproico Sandoz for bipolar disorder.
For bipolar disorder, if you are a woman of childbearing potential, you must not take Acido Valproico Sandoz unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico Sandoz. Do not stop taking Acido Valproico Sandoz or your contraceptive unless you have discussed this with your doctor. Your doctor will advise you further (see below under “Pregnancy, breastfeeding and fertility – Important warning for women”).

Epilepsy

If you are pregnant, you must not use Acido Valproico Sandoz for epilepsy, unless nothing else is effective for you.
For epilepsy, if you are a woman of childbearing potential, you must not take Acido Valproico Sandoz unless you are using an effective method of birth control (contraccettivo) throughout the entire treatment with Acido Valproico Sandoz. Do not stop taking Acido Valproico Sandoz or your contraceptive unless you have discussed this with your doctor. Your doctor will advise you further (see below under “Pregnancy, breastfeeding and fertility – Important warning for women”).

Warnings and precautions
Talk to your doctor or pharmacist before taking Acido Valproico Sandoz.
In children aged 3 years or younger, antiepileptic medicines containing valproic acid are only exceptionally considered as first-line therapy.
Before taking Acido Valproico Sandoz, your doctor may request tests to check your liver function, both before starting treatment (see “Do not take Acido Valproico Sandoz”) and at repeated intervals during the first 6 months. If your health condition is similar to those listed in the section “Do not take Acido Valproico Sandoz” and “Special warnings,” you are more likely to be subjected to monitoring tests. Depending on test results and your health status, your doctor may decide to adjust the dose of Acido Valproico Sandoz or to perform further tests.
In children under 3 years of age, do not use Acido Valproico Sandoz with other medicines, and your doctor will evaluate the risk-benefit ratio (liver and pancreas problems) before starting treatment. In children under 3 years of age, do not use Acido Valproico Sandoz if they are taking medicines containing salicylic acid or its derivatives, as this may increase the risk of liver toxicity (hepatotoxicity).
Inform your doctor before starting to take this medicine in the following cases:

If you have reduced kidney function (renal insufficiency) or reduced levels of protein in the blood (hypoproteinemia), your doctor may decide to adjust treatment based on clinical monitoring (see section “How to take Acido Valproico Sandoz”).
If you have an autoimmune disease affecting skin, bones and joints, lungs, kidneys (“systemic lupus erythematosus”), because your doctor will need to evaluate the risk-benefit ratio during valproate use, due to the possibility of causing immune-mediated diseases.
If you suffer from an enzymatic deficiency of the urea cycle (a rare metabolic disorder) that causes increased levels of ammonia in the blood, because valproate may increase blood ammonium levels (see “Do not take Acido Valproico Sandoz” and “Possible side effects”).
If you have pre-existing bone marrow damage or if you have or have previously had any bone marrow disease, your doctor may decide to perform checks.
If you have blood disorders, because your doctor may perform tests before surgery or dental procedures and in case of spontaneous bruising or sudden bleeding (haemorrhage) (see “Possible side effects”). Your doctor will perform blood tests before starting treatment or before surgery.
If you suffer from a hereditary metabolic disease that reduces the amount of an enzyme called carnitine palmitoyltransferase (CPT) type II, because valproate may increase the risk of developing a muscle cell disease called rhabdomyolysis.
If there are genetic problems in your family causing a disease affecting specific cellular organelles called mitochondria (e.g., Alpers-Huttenlocher syndrome), as valproate may trigger or worsen clinical signs and valproate-induced liver damage (hepatic injury).
If you are a woman of childbearing potential (see “Pregnancy, breastfeeding and fertility”).
If you have ever developed a severe skin rash, skin peeling, blisters and/or mouth ulcers after taking valproate.

In particular, contact your doctor:

If you experience abdominal pain: contact your doctor immediately, as they may discontinue valproate and perform tests to rule out pancreatitis (inflammation of the pancreas).
If you are taking concomitantly medicines that thin the blood, anticoagulants (vitamin K antagonists). In this case, your doctor may prescribe blood coagulation tests.
If you are taking or need to take antibiotics called carbapenems, because concomitant use of valproic acid/sodium valproate is not recommended (see “Other medicines and Acido Valproico Sandoz”).
Before surgery or dental procedures. In this case, your doctor will perform blood tests before surgery.
Serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and angioedema, have been reported with valproate treatment. Seek immediate medical advice if you notice any of the symptoms related to these serious skin reactions described in section 4.

If you notice weight gain, especially at the beginning of treatment (see section “Possible side effects”).

If you develop symptoms during treatment with Acido Valproico Sandoz, such as physical or mental weakness, loss of appetite (anorexia), apathy, drowsiness, repeated vomiting, abdominal pain, recurrence or increased frequency of epileptic seizures/convulsions, or reduced blood pressure. Liver inflammation or increased blood ammonia levels may be the cause (see section 4 “Possible side effects”).

You may experience a reversible worsening in the frequency and severity of seizures (up to status epilepticus), or develop new types of seizures (see “Possible side effects”). In this case, you must inform your doctor immediately.
A small number of patients treated with antiepileptic medicines such as valproate have developed suicidal thoughts or self-harming thoughts. If at any time you have thoughts of this kind, contact your doctor immediately.

LIVER PROBLEMS (HEPATOPATHIES)
How it manifests
Administration of Acido Valproico Sandoz has exceptionally led to severe liver damage (hepatic injury), which has sometimes been fatal.
A newborn or a child under 3 years of age with severe forms of a condition called epilepsy, particularly if they have brain (cerebral) damage, mental (psychic) developmental delay and/or a metabolic or degenerative congenital disease, and are on treatment with multiple medicines, has a higher risk of developing severe liver problems.
If your doctor considers it essential to administer the medicine to a child under 3 years of age for the treatment of a type of epilepsy that improves with valproate, despite the risk of liver damage (hepatopathy), do not take Acido Valproico Sandoz with any other medicine.
If the child is over 3 years old, the risk of these complications is lower, as the probability decreases with increasing age.
In most cases, liver damage (hepatic) occurred during the first 6 months of treatment.
Symptoms
Especially if you are a high-risk patient, clinical symptoms are essential for early diagnosis. In particular, two types of manifestations that may precede yellowing of the skin (jaundice: see “How it manifests”) should be considered:

if you suffer from epilepsy, seizures may reappear
non-specific symptoms not related to epilepsy, which appear rapidly, such as fatigue (asthenia), severe loss of appetite (anorexia), excessive sleepiness (lethargy), excessive tiredness (drowsiness), sometimes associated with repeated vomiting and abdominal pain. If you experience any of the above symptoms during treatment, inform your doctor immediately for evaluation and monitoring. As with most antiepileptic drugs, increases in liver blood tests (liver enzymes) may occur, particularly at the beginning of treatment; in such cases, your doctor will perform frequent checks and may adjust the dose.

Monitoring during treatment
If you take Acido Valproico Sandoz, your doctor will perform liver function tests or other checks before starting treatment and at regular intervals during the first 6 months, and whenever deemed necessary. These checks are particularly important in children.

PANCREATITIS (INFLAMMATION OF THE PANCREAS)
Severe pancreatitis (inflammation of the pancreas), which may even be fatal, is possible, although very rare. These serious pancreatic problems are more frequent in children. The risk decreases with increasing age. If you experience during treatment severe epileptic seizures, neurological disorders, or are taking other anticonvulsant medicines, inform your doctor, as this may increase the risk of pancreatitis. If you have liver disease (hepatic insufficiency) and at the same time pancreatitis, Acido Valproico Sandoz increases the risk of fatal outcome. If you have acute abdominal pain, report it immediately to your doctor, who will examine you and discontinue valproate if pancreatitis is diagnosed.

Children and adolescents
Acido Valproico Sandoz must not be used in children and adolescents under 18 years of age for the treatment of mania.

Acido Valproico Sandoz and laboratory tests
Inform your doctor that you are taking this medicine before undergoing certain laboratory tests, as Acido Valproico Sandoz may affect ketone body excretion test results, giving false positives if you are diabetic.

Other medicines and Acido Valproico Sandoz
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription.

Concomitant use of salicylates (e.g., acetylsalicylic acid) should be avoided in children under 3 years of age due to the risk of liver damage.

It is especially important to inform your doctor if you are taking any of the following medicines:

Acido Valproico Sandoz may alter the effect of other medicines:

Neuroleptics (for psychiatric disorders), antidepressants, including monoamine oxidase inhibitors (MAOIs), benzodiazepines (medicines used to induce sleep or treat anxiety). If you take valproate with medicines used for behavioural disorders belonging to classes called neuroleptics, anti-MAO, antidepressants and benzodiazepines, an unintended increase in effect may occur. Therefore, your doctor will monitor you and, when necessary, adjust your treatment.
Olanzapine: if you take valproate with olanzapine-based medicines (used in certain mental illnesses), the blood levels of olanzapine may increase.
Quetiapine (for the treatment of certain mental illnesses)
Clozapine (to treat mental health problems)
Propofol: if you take valproate together with propofol (used for anaesthesia), your doctor may consider reducing the propofol dose, as valproate may increase its blood levels.
other medicines for epilepsy (medicines used for seizures), e.g.:
- Phenobarbital: if you take a medicine called phenobarbital, inform your doctor, as valproate increases phenobarbital blood levels and excessive sedation may occur, especially in children. Your doctor will monitor you during the first 15 days of combined treatment, immediately reducing phenobarbital doses in case of sedation, and possibly checking phenobarbital blood levels.
- Primidone: if you take a medicine called primidone, valproate may increase its blood levels, possibly increasing side effects (such as sedation); this interaction ceases with long-term treatment, so your doctor will perform special checks, especially at the beginning of therapy, adjusting primidone dose when necessary.
- Phenytoin: if you take valproate concomitantly with phenytoin, your doctor will perform checks because valproate alters phenytoin blood levels, possibly causing overdose symptoms.
- Carbamazepine: if you take valproate with carbamazepine, your doctor will perform checks, especially at the beginning of therapy, because valproate increases carbamazepine toxicity.
- Lamotrigine: if you take Acido Valproico Sandoz concomitantly with lamotrigine-based medicines, you may have an increased risk of side effects due to increased lamotrigine toxicity (severe skin disorders). Your doctor will monitor you and reduce lamotrigine dosage if necessary.
- Felbamate: valproic acid may decrease felbamate metabolism (used in epilepsy).
- Ethosuximide: if you take Acido Valproico Sandoz with medicines containing ethosuximide, the blood levels of the latter may increase.
- Rufinamide: if you take Acido Valproico Sandoz with medicines containing rufinamide (used in epilepsy), the blood levels of the latter may increase. The increased rufinamide blood levels depend on the dose of Acido Valproico Sandoz used. This effect is greater in children.
Nimodipine (a medicine used for prevention and treatment of neurological deficits): Acido Valproico Sandoz may enhance the effects of nimodipine.
Zidovudine (a medicine used to treat HIV infections): be cautious when taking valproate with zidovudine-based medicines, as this may increase zidovudine blood levels and related toxic effects.
Metamizole, a medicine used to treat pain and fever.

Your doctor may decide to perform clinical monitoring and adjust doses.

The effect of Acido Valproico Sandoz may be increased or reduced by:

If you take certain antiepileptic medicines (especially phenytoin, phenobarbital and carbamazepine) concomitantly with valproic acid, your doctor may perform checks because valproic acid blood levels may be reduced. Treatment will be adjusted based on results.
If you take Acido Valproico Sandoz with phenytoin or phenobarbital-based medicines, pay particular attention to symptoms of hyperammonaemia (nausea, vomiting, agitation, confusion, seizures, drowsiness, coordination disorders).
The combination of felbamate (a medicine used for seizures) and valproate increases valproic acid blood levels. Therefore, valproate blood levels should be monitored.
Mefloquine (a medicine used to treat malaria) increases valproic acid metabolism and may trigger seizures. Your doctor may monitor you, as you may experience epileptic seizures.
Medicines that thin the blood (vitamin K antagonists). In this case, your doctor may prescribe blood coagulation tests (see section “Warnings and precautions”).
Acetylsalicylic acid.
Concomitant use of valproate and substances that highly bind to proteins (acetylsalicylic acid) may increase valproic acid blood levels. Do not take valproic acid-containing medicines concomitantly with acetylsalicylic acid-containing medicines used to treat fever and pain, especially in newborns and children.
Cimetidine (a medicine used to treat stomach ulcers), erythromycin (a medicine used to treat bacterial infections), fluoxetine (a medicine used to treat depression), rifampicin (an antibiotic): your doctor will perform checks because valproic acid blood levels may be altered.
Carbapenems (antibiotics used to treat bacterial infections). The combination of valproic acid and carbapenems must be avoided because it may reduce the medicine’s effect (see section “Warnings and precautions”).
Lopinavir and ritonavir, protease inhibitors used to treat HIV infections, reduce Acido Valproico Sandoz blood levels.
Cholestyramine: if you take Acido Valproico Sandoz with cholestyramine-based medicines (used to lower blood cholesterol), Acido Valproico Sandoz blood levels may decrease.

Your doctor may perform checks because valproic acid levels may be altered.

Other interactions
If you take valproic acid-containing medicines concomitantly with anticonvulsant medicines containing topiramate or with acetazolamide (a diuretic medicine), your doctor will monitor you, as there is an increased risk of elevated blood ammonia levels and/or brain inflammation (hyperammonaemic encephalopathy).
Products containing oestrogens (including some birth control pills) may reduce valproate blood levels. Discuss with your doctor the most appropriate method of contraception (birth control) for you (see section “Warnings and precautions”).
Valproate generally does not have an enzyme-inducing effect; therefore, it does not reduce the effectiveness of combined hormonal contraceptives.
If you take medicines acting on the nervous system, belonging to the benzodiazepine class (diazepam, lorazepam, clonazepam), concomitantly with valproate, your doctor may monitor you, as benzodiazepine blood levels may be altered.
Be cautious if you take valproic acid concomitantly with sertraline (an antidepressant) and risperidone (a medicine acting on the psyche), as catatonia (a condition reducing motor and intellectual activity) may develop.
If you take valproate concomitantly with an antipsychotic medicine called quetiapine, there may be an increased risk of reduced levels of certain blood cells (neutropenia/leucopenia).

Acido Valproico Sandoz with food and drinks
Alcohol consumption is not recommended during treatment with Acido Valproico Sandoz.

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant or are planning to become pregnant, or if you are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.

Important warning for women
Bipolar disorder

If you are pregnant, you must not use Acido Valproico Sandoz for bipolar disorder.
For bipolar disorder, if you are a woman of childbearing potential, you must not take Acido Valproico Sandoz unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico Sandoz. Do not stop taking Acido Valproico Sandoz or your contraceptive unless you have discussed this with your doctor. Your doctor will advise you further.

Epilepsy

If you are pregnant, you must not use Acido Valproico Sandoz for epilepsy, unless nothing else is effective for you.
For epilepsy, if you are a woman of childbearing potential, you must not take Acido Valproico Sandoz unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico Sandoz. Do not stop taking Acido Valproico Sandoz or your contraceptive unless you have discussed this with your doctor. Your doctor will advise you further.

Risks of taking valproate during pregnancy (regardless of the condition for which it is used)

Talk immediately with your doctor if you are planning to have a child or are pregnant.
Valproate poses risks if taken during pregnancy. The risk is higher with higher doses, but all doses carry a risk, including valproate use in combination with other epilepsy medicines.
It may cause serious birth defects and may affect the child’s physical and mental development and growth after birth. The most frequently reported birth defects include: spina bifida (incomplete development of certain vertebrae); facial and cranial malformations; heart, kidney, urinary tract and genital organ malformations; limb defects and multiple associated malformations affecting various organs and body parts. Birth defects may lead to disabilities that can be severe.
Hearing problems or deafness have been reported in children exposed to valproate during pregnancy.
Eye malformations associated with other congenital malformations have been reported in children exposed to valproate during pregnancy. These eye malformations may affect vision.
Women who take valproate during pregnancy have a higher risk, compared to other women, of having a child with birth defects requiring medical treatment. As valproate has been used for many years, we know that about 11 out of 100 children born to women taking valproate have birth defects, compared to 2-3 out of 100 children born to women without epilepsy.
It is estimated that up to 30-40% of preschool-aged children whose mothers took valproate during pregnancy may experience developmental problems in early childhood. These children may start walking and talking later, be intellectually disadvantaged compared to other children, and have language and memory difficulties.
Autism spectrum disorders are more frequently diagnosed in children exposed to valproate during pregnancy, and there is some evidence that these children have a higher risk of developing symptoms of attention deficit hyperactivity disorder (ADHD).
Before prescribing this medicine, your doctor will explain what could happen to your child if you become pregnant while taking valproate. If later you decide you want to have a child, do not stop taking the medicine or the contraceptive method before discussing it with your doctor.
If you are the parent or caregiver of a girl treated with valproate, contact the doctor as soon as the girl has her first menstrual period.
Some contraceptive pills (oestrogen-containing contraceptive pills) may reduce valproate blood levels. Make sure to discuss with your doctor the most appropriate method of contraception (birth control) for you.
Consult your doctor about taking folic acid when trying to become pregnant. Folic acid may reduce the general risk of spina bifida and miscarriage, possible in all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Read and select the situations applicable to you from those described below:
o I AM STARTING TREATMENT WITH ACIDO VALPROICO SANDOZ
o I AM TAKING ACIDO VALPROICO SANDOZ AND DO NOT PLAN TO HAVE A CHILD
o I AM TAKING ACIDO VALPROICO SANDOZ AND PLAN TO HAVE A CHILD
o I AM PREGNANT AND TAKING ACIDO VALPROICO SANDOZ

I AM STARTING TREATMENT WITH ACIDO VALPROICO SANDOZ
If Acido Valproico Sandoz is prescribed to you for the first time, your doctor will explain the risks to the foetus in case of pregnancy. If you are of childbearing age, you must ensure you use an effective contraceptive method continuously throughout the entire treatment with Acido Valproico Sandoz. Talk to your doctor or visit a family planning clinic if you need advice on contraception.

Key messages:

Before starting treatment with Acido Valproico Sandoz, pregnancy must be ruled out by a pregnancy test confirmed by your doctor; during the entire treatment with Acido Valproico Sandoz, you must use an effective method of birth control (contraceptive);
You must discuss appropriate methods of birth control (contraceptives) with your doctor. Your doctor will explain how to prevent pregnancy and may refer you to a specialist for contraception advice;
You must schedule regular appointments (at least once a year) with a specialist experienced in managing bipolar disorder or epilepsy. During this visit, your doctor will ensure you are fully aware and understand all risks and advice related to valproate use in pregnancy;
Inform your doctor if you wish to have a child;
Inform your doctor immediately if you are pregnant or think you may be.

I AM TAKING ACIDO VALPROICO SANDOZ AND DO NOT PLAN TO HAVE A CHILD
If you are continuing treatment with Acido Valproico Sandoz but do not plan to have a child, ensure you use an effective contraceptive method continuously throughout the entire treatment with Acido Valproico Sandoz. Talk to your doctor or a family planning clinic if you need advice on contraception.

Key messages:

You must use an effective method of birth control (contraceptive) during the entire treatment with Acido Valproico Sandoz;
You must discuss contraception (birth control) with your doctor. Your doctor will explain how to prevent pregnancy and may refer you to a specialist for contraception advice;
You must schedule regular appointments (at least once a year) with a specialist experienced in managing bipolar disorder or epilepsy. During this visit, your doctor will ensure you are fully aware and understand all risks and advice related to valproate use in pregnancy;
Inform your doctor if you wish to have a child;
Inform your doctor immediately if you are pregnant or think you may be.

I AM TAKING ACIDO VALPROICO SANDOZ AND PLAN TO HAVE A CHILD
If you are planning to have a child, schedule an appointment with your doctor first.
Do not stop taking Acido Valproico Sandoz or your contraceptive unless you have discussed this with your doctor. Your doctor will advise you further.
Children born to mothers treated with valproate have a high risk of birth defects and developmental problems that may be severely disabling. Your doctor will refer you to a specialist experienced in managing bipolar disorder or epilepsy to evaluate alternative therapeutic options as soon as possible. The specialist may take various measures to facilitate pregnancy as much as possible and minimise risks for you and your child.
The specialist may decide to adjust the dose of Acido Valproico Sandoz, switch to another medicine, or discontinue treatment with Acido Valproico Sandoz well before pregnancy to ensure the disease is stable.
Ask your doctor about taking folic acid when planning to have a child. Folic acid may reduce the general risk of spina bifida and miscarriage, possible in all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Key messages:

Do not stop taking Acido Valproico Sandoz unless instructed by your doctor;
Do not stop using birth control methods (contraceptives) before discussing it with your doctor and agreeing on a plan to ensure disease control and reduce risks for the child;
First, schedule an appointment with your doctor. During this visit, the doctor will ensure you are fully aware and understand all risks and advice related to valproate use in pregnancy;
Your doctor will try to change your medicine or discontinue Acido Valproico Sandoz well before pregnancy;
Request an urgent appointment with your doctor if you are pregnant or think you may be.

I AM PREGNANT AND TAKING ACIDO VALPROICO SANDOZ
Do not stop taking Acido Valproico Sandoz unless instructed by your doctor, as your condition may worsen. Request an urgent appointment with your doctor if you are pregnant or think you may be. Your doctor will advise you further.
Children born to mothers treated with valproate have a high risk of birth defects and developmental problems that may be severely disabling.
You will be referred to a specialist experienced in managing bipolar disorder or epilepsy to evaluate alternative therapeutic options.
In exceptional circumstances, if Acido Valproico Sandoz is the only available treatment option during pregnancy, you will be closely monitored for both management of your underlying condition and fetal development. You and your partner may receive counselling and support regarding valproate exposure during pregnancy.
Ask your doctor for advice on taking folic acid. Folic acid may reduce the general risk of spina bifida and miscarriage, possible in all pregnancies. However, it is unlikely to reduce the risk of birth defects associated with valproate use.

Key messages:

Request an urgent appointment with your doctor if you are pregnant or think you may be;
Do not stop taking Acido Valproico Sandoz unless instructed by your doctor;
Ensure you are referred to a specialist experienced in treating epilepsy or bipolar disorder to evaluate the need for alternative treatment options;
You must receive detailed counselling regarding the risks of Acido Valproico Sandoz in pregnancy, including teratogenicity and effects on child development;
Ensure you are referred to a specialist in prenatal monitoring to identify possible cases of malformation.

Make sure to read the patient guide you will receive from your doctor. Your doctor will discuss the Annual Risk Acknowledgement Form and ask you to sign and keep it. You will also receive from the pharmacist the Patient Alert Card to remind you of the risks of valproate in pregnancy.

Additional risks for the newborn

If you take valproate during pregnancy, the newborn may rarely experience severe bleeding (haemorrhagic syndrome) due to reduced levels of several coagulation factors. These reductions in coagulation factors can sometimes be fatal, which is why your doctor will perform several checks.
If you take valproate in the third trimester of pregnancy, the newborn may have low blood sugar (hypoglycaemia).
If you take valproate during pregnancy, the newborn may have disorders caused by reduced levels of hormones produced by the thyroid gland (hypothyroidism).
If you take valproate during the last trimester of pregnancy, the newborn may have disorders due to “withdrawal syndrome” (e.g., particularly agitation, irritability, hyper-excitability, nervousness, increased movements (hyperkinesia), muscle activity disorders (tonicity), tremor, seizures and feeding disorders). If you are pregnant, do not interrupt treatment with valproic acid or reduce intake without consulting your doctor, as this could cause epileptic seizures that may seriously harm you and the unborn child.

Breastfeeding
If you are breastfeeding, do not take this medicine unless specifically prescribed by your doctor, as the medicine is released into breast milk and may cause blood disorders (haematological) (see “Possible side effects”).
Your doctor will carefully evaluate whether to discontinue breastfeeding or discontinue/abstain from treatment with Acido Valproico Sandoz, considering the benefit of breastfeeding for the child and the benefit of treatment for the woman.

Fertility
If you are a woman of childbearing age, the medicine may increase the likelihood of menstrual cessation (amenorrhoea), presence of multiple ovarian cysts (polycystic ovaries), and increased blood testosterone levels (see “Possible side effects”). If you are a man, valproate administration may impair your fertility (see “Possible side effects”). These fertility disorders are reversible after discontinuation of treatment.

Important warning for male patients
Potential risk associated with valproate use in the 3 months before conception
One study suggests a possible risk of movement and mental development disorders (problems affecting early childhood development) in children born to fathers treated with valproate in the 3 months before conception. In this study, about 5 out of 100 children had such disorders when born to fathers treated with valproate, compared to about 3 out of 100 children born to fathers treated with lamotrigine or levetiracetam (other medicines that may be used to treat your condition). The risk for children born to fathers who discontinued valproate treatment 3 months (the time required to form new sperm) or more before conception is unknown. The study has limitations, so it is not entirely clear whether the increased risk of movement and mental development disorders suggested by this study is caused by valproate. The study was not large enough to show which particular type of movement and mental development disorder the children may be at risk of developing.
As a precautionary measure, your doctor will discuss with you:

The potential risk for children born to fathers taking valproate
The need to consider effective contraception (birth control) for you and your partner during treatment and for 3 months after stopping treatment
The need to consult a specialist if you are planning to conceive and before stopping contraception (birth control)
The possibility of other treatments that may be used to treat your condition, depending on your individual situation

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 partner becomes pregnant while you have taken valproate in the 3 months before conception and you have questions, contact your doctor. Do not stop treatment without discussing it with your doctor. If you stop treatment, your symptoms may worsen.
You must plan regular appointments with your prescribing doctor. During this visit, your doctor will discuss with you the precautions associated with valproate use and the possibility of other treatments that may be used to treat your condition, depending on your individual situation.
Make sure to read the patient guide you will receive from your doctor. You will also receive from the pharmacist the Patient Alert Card to remind you of the potential risks of valproate.

Driving and using machines
If you take Acido Valproico Sandoz with barbiturates or other medicines with central nervous system depressant activity, you may experience asthenia, drowsiness or confusion, which may impair your ability to drive a vehicle, operate machinery or perform activities involving risk of falls or accidents.
The same symptoms may occur after consuming alcoholic beverages.
Your doctor will inform you about possible problems you may have when driving or performing tasks requiring normal attention.

Acido Valproico Sandoz contains sodium
Acido Valproico Sandoz 300 mg prolonged-release tablets contain 28.3 mg of sodium per tablet. This should be considered in patients with impaired renal function or those on a low-sodium diet.
Acido Valproico Sandoz 500 mg prolonged-release tablets contain 47.2 mg of sodium per tablet. This should be considered in patients with impaired renal function or those on a low-sodium diet.

3. How to take Acido Valproico Sandoz

Take this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.

Girls and women of childbearing age
Treatment with Acido Valproico Sandoz must be initiated and supervised by a specialist doctor experienced in the treatment of epilepsy or bipolar disorder.

Male patients
It is recommended that treatment with Acido Valproico Sandoz be initiated and supervised by a specialist experienced in managing epilepsy, bipolar disorder, or migraine – see section 2 Important information for male patients.

Epilepsy treatment
The daily dose must be determined and monitored individually by your doctor. Before starting treatment with Acido Valproico Sandoz, please consider the following:

If you are a patient not previously treated with other antiepileptic medicines, your doctor may gradually increase the dose every 2–3 days, reaching the recommended dose within about one week.
If you are currently taking other antiepileptic medicines, your doctor will gradually replace them with valproate, reaching the optimal dose over approximately two weeks, while reducing and then stopping the other treatments.
If your doctor decides to add another antiepileptic medicine, it will be introduced gradually (see “Other medicines and Acido Valproico Sandoz”).

Oral administration of Acido Valproico Sandoz: practical considerations
The recommended dose is generally determined by your doctor based on your age, body weight, therapeutic response, and clinical condition. If the desired therapeutic response is not achieved, your doctor may decide to monitor the blood levels of valproic acid.

Specifically, the recommended dose is:
The usual initial daily dose is 10–15 mg/kg; doses are then progressively increased until reaching the optimal dosage, which generally ranges from 20 to 30 mg/kg. However, if seizure control is not adequate at this dosage, doses may be further increased. In such cases, your doctor will monitor you closely (see “Warnings and precautions”).

In adults, the usual dosage is 20–30 mg/kg per day.
In elderly patients, the dosage should be determined based on monitoring of treatment response.
In patients with kidney problems (renal impairment) or low blood protein levels (hypoproteinemia), your doctor may adjust the dose if necessary.

The use of the prolonged-release formulation – Acido Valproico Sandoz – allows for a reduced number of daily administrations (1–2 times per day). Additionally, the possibility of dividing the tablets (fractionation) provides greater dosing flexibility (posology).

Acido Valproico Sandoz may also be used in children, provided they are able to swallow tablets, which can be divided.

Mania
The daily dosage must be individually determined and monitored by your doctor.

Initial dose
The recommended initial dose is 750 mg. Prolonged-release formulations may be administered once or twice daily. The dose is usually increased until reaching the lowest therapeutic dose that produces the desired clinical effect. Your doctor will adjust the daily dose according to your clinical response to establish the minimum effective dose.

Average daily dose
The recommended daily dose usually ranges between 1000 and 2000 mg. If you receive a daily dose exceeding 45 mg/kg body weight, your doctor will monitor you closely.

Use in children and adolescents
In children, the usual dosage for epilepsy treatment is approximately 30 mg/kg/day.
This medicine must not be used for the treatment of mania in children and adolescents under 18 years of age.

If you take more Acido Valproico Sandoz than you should
In case of accidental overdose of Acido Valproico Sandoz, contact your doctor immediately or go to the nearest hospital.

Signs and symptoms of overdose
At normal doses, blood levels of valproic acid have relatively low toxicity, and acute valproic acid intoxication is very rare.
Toxicity is more likely at higher doses.

Signs of severe acute overdose generally include coma, reduced muscle tone (hypotonia), diminished reflexes (hyporeflexia), constricted pupils (miosis), impaired respiratory function, changes in blood acidity (metabolic acidosis), low blood pressure (hypotension), cardiovascular disturbances, circulatory collapse/shock, and increased blood sodium levels (hypernatremia).

In adults or children, elevated blood levels of valproic acid may cause neurological disturbances, such as increased tendency to epileptic seizures and behavioral changes.

Fatal outcomes have occurred following severe overdose, although the prognosis in cases of intoxication is generally favorable.

Symptoms may vary, and epileptic seizures have been reported with very high blood levels of valproic acid.

Cases of increased pressure in the head (intracranial hypertension) associated with cerebral edema have also been reported.

If you forget to take Acido Valproico Sandoz
Do not take a double dose to make up for the missed tablet.
If you forget to take a dose, take it as soon as possible, unless it is almost time for your next dose. In that case, continue with your regular dosing schedule.

If you stop taking Acido Valproico Sandoz
If you wish to discontinue treatment with this medicine, inform your doctor first. Do not stop taking this medicine even if you feel better.

If you have any questions about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
It is very important that you contact your doctor immediately if you experience any of the following
symptoms, as urgent medical measures may be required (see section “Warnings and precautions”):

if you experience abdominal pain, as this could be a symptom of pancreatitis (inflammation of the pancreas);
if you have symptoms such as physical or mental weakness, loss of appetite (anorexia), apathy, drowsiness, repeated episodes of vomiting, abdominal pain, or recurrence of epileptic seizures, as these could be symptoms of hepatitis (liver inflammation);
if symptoms such as apathy, drowsiness, vomiting, hypotension, and increased frequency of seizures occur (these could be symptoms of elevated ammonia levels in the blood);
breathing difficulties, pain or pressure in the chest (especially during inspiration), shortness of breath, and dry cough due to fluid accumulation around the lungs (pleural effusion) (Uncommon)

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

darkened areas of the skin and mucous membranes (hyperpigmentation) (Not known)

Very common (may affect more than 1 in 10 people)

nausea
tremor

Common (may affect up to 1 in 10 people)

anaemia
thrombocytopenia (reduced number of platelets in the blood)
vomiting
severe liver damage
gingival disorders
stomatitis
upper abdominal pain
diarrhoea
hyponatraemia (low levels of sodium in the blood)
weight gain or weight loss. Weight gain may be a sign of polycystic ovary and should be carefully monitored.
increased or decreased appetite
paraesthesia (sensory disturbances), dose-dependent
extrapyramidal disorders (inability to stay still, rigidity, tremors, slow movements, involuntary movements, muscle contractions)
stupor (confusion)
postural tremor
drowsiness
seizures
impaired memory
headache
confusion
hallucinations
aggression
agitation
attention disorders
deafness
tinnitus (ringing in the ears)
hypersensitivity
transient and/or dose-related alopecia (hair loss)
dysmenorrhoea (painful menstruation)
haemorrhage
nystagmus (rapid involuntary eye movements)
dizziness occurring a few minutes after intravenous administration (into a vein), resolving spontaneously within a few minutes
nail and nail bed disorders
involuntary loss of urine (urinary incontinence)

Uncommon (may affect up to 1 in 100 people)

neutropenia (deficiency of neutrophils)
leucopenia (deficiency of white blood cells) or pancytopenia (reduction in the number of all blood cells)
hypoplasia (reduced volume) of red blood cells
peripheral oedema
bleeding
hypersalivation (excessive salivation)
pancreatitis, sometimes fatal (see also section “Warnings and precautions”)
irritability, hyperactivity and confusion, particularly at the beginning of treatment (occasionally aggression, behavioural disturbances)
spasticity (spasms)
ataxia (loss of muscular coordination), particularly at the beginning of treatment
coma
encephalopathy
lethargy (pathological deep sleep)
reversible parkinsonism (Parkinson's disease-like symptoms)
angioedema (rapid swelling (oedema) of the skin, mucosa and submucosal tissues)
skin rash
hair changes (such as abnormal hair structure, changes in hair colour, abnormal hair growth)
amenorrhoea (absence of menstruation)
vasculitis (inflammation of blood vessels)
renal failure
syndrome of inappropriate secretion of ADH (SIADH)
hyperandrogenism (increased levels of male sex hormones causing hirsutism, virilization, acne, male-pattern alopecia)
reduced body temperature (hypothermia)
worsening of seizures (see section “Warnings and precautions”)
double vision

Rare (may affect up to 1 in 1,000 people)

myelodysplastic syndrome (failure to produce normal blood cells)
bone marrow failure including aplastic anaemia (anaemia due to insufficient production of blood cells in the bone marrow)
agranulocytosis (reduction in granulocytes)
macrocytic anaemia (anaemia with larger red blood cells)
macrocytosis (larger red blood cells)
hypothyroidism (underactive thyroid)
hyperammonaemia (excess ammonia in the blood)
abnormal behaviour
psychomotor hyperactivity
learning disorders
hallucinations
reversible dementia associated with reversible cerebral atrophy
cognitive disorders
confusional states
severe skin allergic reaction (Stevens-Johnson syndrome), toxic epidermal necrolysis (a severe skin disease in which the epidermis detaches in sheets, leaving large denuded areas), erythema multiforme (skin irritation)
allergic reactions
reports of severe hypersensitivity reactions with severe skin rash, which may be accompanied by fever, fatigue, swelling of the face or lymph glands, increased eosinophils (a type of white blood cell), effects on liver, kidney or lung (a reaction called DRESS)
male infertility
enuresis (involuntary loss of urine)
inflammation of the kidneys (tubulointerstitial nephritis)
reversible Fanconi syndrome (kidney disorder)
systemic lupus erythematosus (chronic autoimmune disease)
rhabdomyolysis (damage to skeletal muscles) (see also section “Warnings and precautions”)
obesity
double vision

Frequency not known (frequency cannot be estimated from the available data)

Congenital malformations and developmental disorders
Elevated levels of testosterone hormone. Cases of a disease affecting the ovaries called "polycystic ovary" have been reported in patients who experienced significant weight gain.
Reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Valproic Acid Sandoz

Laboratory values
Elevated testosterone levels have been reported.
Rare: reduction in coagulation factors, factor VIII deficiency (von Willebrand factor), abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, prolonged INR).
Isolated cases of reduced fibrinogen and biotin/biotinidase deficiency have been reported.

Additional side effects in children
Some side effects of valproate occur more frequently or are more severe in children than in adults.
These include liver damage, pancreatic infection (pancreatitis), aggression, agitation, attention disorders, abnormal behaviour, hyperactivity, and learning disorders.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Acido Valproico Sandoz

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.". The expiry date refers to the last day of that month.
Store below 25°C.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Acido Valproico Sandoz 300 mg prolonged-release tablets contains
The active substance is sodium valproate. One prolonged-release tablet contains 199.8 mg of sodium valproate and 87 mg of valproic acid (equivalent to 300 mg of sodium valproate).
The other components are: hydrated colloidal silica, anhydrous colloidal silica, hypromellose (high viscosity), hypromellose (low viscosity), ethylcellulose, sodium saccharin, macrogol 6000, titanium dioxide (E171), methacrylic acid-ethyl acrylate copolymer, talc.

What Acido Valproico Sandoz 500 mg prolonged-release tablets contains
The active substance is sodium valproate. One 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 are: hydrated colloidal silica, anhydrous colloidal silica, hypromellose (high viscosity), hypromellose (low viscosity), ethylcellulose, sodium saccharin, macrogol 6000, titanium dioxide (E171), methacrylic acid-ethyl acrylate copolymer, talc.

Description of the appearance of Acido Valproico Sandoz and the contents of the pack
Acido Valproico Sandoz 300 mg prolonged-release tablets
Aluminium/aluminium blister pack containing 30 tablets.

Acido Valproico Sandoz 500 mg prolonged-release tablets
Aluminium/aluminium blister pack containing 30 tablets.

Marketing Authorization Holder
Sandoz S.p.A.
Viale Luigi Sturzo, 43
20154 Milan
Italy

Manufacturer
Salutas Pharma GmbH,
Otto-von-Guericke-Allee 1,
39179 Barleben - Germany
Lek Pharmaceuticals d.d.,
Verovškova Ulica 57,
Ljubljana, 1526,
Slovenia

Valproic acid Sandoz

Patient Information Leaflet