Package Leaflet: Information for the User

Valproic Acid and Sodium Valproate ratiopharm 300 mg prolonged-release tablets, 500 mg prolonged-release tablets

Sodium valproate (as Sodium valproate and Valproic acid)
Equivalent medicinal product
▼ 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
Valproic Acid and Sodium Valproate ratiopharm, if taken during pregnancy, can cause severe damage to the fetus.
If you are a woman of childbearing potential, you must use an effective method of birth control (contraception) continuously throughout the entire duration of treatment with Valproic Acid and Sodium Valproate ratiopharm. Your doctor will discuss this with you, but you should also follow the recommendations in section 2 of this leaflet.
If you plan a pregnancy or think you might be pregnant, urgently contact your doctor for an appointment.
Do not stop taking Valproic Acid and Sodium Valproate ratiopharm unless instructed by your doctor, as your condition could worsen.
Please read all of 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 other people, even if they have the same symptoms as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Acido Valproico e Sodio Valproato ratiopharm is and what it is used for

Acido Valproico e Sodio Valproato ratiopharm is a medicine used to treat
seizures (antiepileptic agent) and mania.
Acido Valproico e Sodio Valproato ratiopharm is used in the treatment of:

seizures originating in both cerebral hemispheres (generalized seizures, such as for example absence seizures, myoclonic seizures, and tonic-clonic seizures)
seizures originating in a localized area of the brain (focal seizures), which may subsequently spread to both cerebral hemispheres (secondarily generalized seizures)

Acido Valproico e Sodio Valproato ratiopharm may be used in other forms of seizures,
for example seizures with mixed (complex) symptoms and seizures spreading from a localized area of the
brain to both hemispheres (secondarily generalized seizures), together with other antiepileptic medicines, when these types of seizures do not respond to standard antiepileptic treatment.

Mania, a condition in which you may experience high excitement, euphoria, agitation, enthusiasm, or hyperactivity. Episodes of mania occur as part of a disorder called "bipolar disorder". Acido Valproico e Sodio Valproato ratiopharm may be used when lithium cannot be used.

2. What you should know before taking Acido Valproico e Sodio Valproato ratiopharm

Do not take Acido Valproico e Sodio Valproato ratiopharm

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 have impaired liver or pancreatic function
if you or a family member have previously had serious liver disease
if it is known that there have been cases of liver damage in your family due to use of a medicine containing valproate, sodium valproate or valproic acid as active ingredient;
if you suffer from a disease due to a disorder in the formation of red blood pigment (porphyria)
if you have a tendency to bleeding
if you suffer from enzymatic disorders of the urea cycle (see also Warnings and precautions)
if you have a genetic condition causing a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
if you have carnitine deficiency (a very rare metabolic disease) that is untreated.

Bipolar disorder

If you are pregnant, you must not use Acido Valproico e Sodio Valproato ratiopharm for bipolar disorder.
For bipolar disorder, if you are a woman of childbearing age, you must not take Acido Valproico e Sodio Valproato ratiopharm unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm. Do not stop taking Acido Valproico e Sodio Valproato ratiopharm 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 advice for women").

Epilepsy

If you are pregnant, you must not use Acido Valproico e Sodio Valproato ratiopharm for epilepsy, unless nothing else is effective for you.
For epilepsy, if you are a woman of childbearing age, you must not take Acido Valproico e Sodio Valproato ratiopharm unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm. Do not stop taking Acido Valproico e Sodio Valproato ratiopharm 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 advice for women").

Warnings and precautions
Talk to your doctor before taking Acido Valproico e Sodio Valproato ratiopharm

if you have ever developed a severe skin rash or skin peeling, blisters and/or mouth ulcers after taking valproate.
if you have had previous bone marrow damage; in this case close medical supervision (blood count) is required.
if you suffer from inflammatory disorders of the skin and/or internal organs (SLE; systemic lupus erythematosus); this condition may be worsened or induced by Acido Valproico e Sodio Valproato ratiopharm.
sodium valproate may seriously damage the liver, sometimes with fatal outcomes. Therefore, caution is required in patients who already have liver dysfunction and/or metabolic disorders. Before starting Acido Valproico e Sodio Valproato ratiopharm and during the first six months of treatment, liver function should be monitored (through regular blood tests).
if you experience any symptoms during treatment with Acido Valproico e Sodio Valproato ratiopharm, such as physical or mental weakness, loss of appetite (anorexia), apathy, drowsiness, nausea, repeated vomiting, abdominal pain, aversion to normally consumed foods and/or to valproate/valproic acid, recurrence or worsening of epileptic seizures/convulsions, frequent bruising/nosebleeds and/or prolonged bleeding time, consult your doctor immediately. Liver or pancreas inflammation or increased blood ammonia levels (this can usually be recognized by an ammonia-like odour in the urine) may be the cause. You should not stop taking Acido Valproico e Sodio Valproato ratiopharm on your own without consulting your doctor. Patients with suspected metabolic disorders, especially disorders of the enzyme involved in the urea cycle, should undergo metabolic investigations with the assistance of their doctor before starting treatment (see also “Do not take Acido Valproico e Sodio Valproato ratiopharm”).
very severe liver damage has been reported in children, especially during the first six months of treatment. If Acido Valproico e Sodio Valproato ratiopharm is administered to newborns and children under 3 years of age with a severe form of epilepsy (particularly those with brain abnormalities, mental retardation, liver dysfunction, certain genetic disorders and/or known metabolic disorders), there is a higher risk of hepatic intoxication during the first 6 months of treatment, especially in very young children. The risk of hepatic intoxication is greater especially when combined with other antiepileptic drugs. Symptoms that may indicate liver damage include: general weakness, loss of appetite, lethargy, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain, onset of coagulation disorders (e.g., easy bruising, wounds bleeding longer than normal), jaundice, and recurrence or worsening of seizures. If you recognize these symptoms, you should contact your doctor immediately.
if you have reduced kidney function or protein deficiency in the blood; your doctor may need to reduce the dose to lower the blood level of valproic acid (see section 3).
before undergoing any surgical or dental procedure (e.g., tooth extraction). Since taking Acido Valproico e Sodio Valproato ratiopharm may be associated with an increased tendency to bleed, your doctor must be informed that you are taking Acido Valproico e Sodio Valproato ratiopharm so that blood coagulation can be monitored.
if you are simultaneously taking several medicines that thin the blood (e.g., vitamin K antagonists), as you may be more prone to bleeding. Therefore, blood coagulation (Quick value) should be regularly monitored.
if you notice weight gain, especially at the beginning of treatment. This may be due to increased appetite (see section 4). You should monitor your weight and minimize possible weight gain. Weight gain may be a risk factor for the development of ovarian cysts.
if you or your doctor suspect a genetic condition causing a mitochondrial disorder in your family, due to the risk of liver damage.
if you suffer from the rare disease "carnitine palmitoyltransferase type II deficiency (CPT-II)" because you are at higher risk of muscle disorders (muscle tissue breakdown with muscle cramps), fever and red-brown discoloration of the urine (rhabdomyolysis) when taking this medicine.
if you have a low dietary intake of carnitine, found in meat and dairy products, especially in children under 10 years of age.
if you have carnitine deficiency and are taking carnitine.

In children under three years of age, concomitant use of medicines containing acetylsalicylic acid (a substance present in many medicines for pain relief and fever reduction) and Acido Valproico e Sodio Valproato ratiopharm is not recommended due to an increased risk of liver damage.
Inform your doctor that you are taking Acido Valproico e Sodio Valproato ratiopharm when your urine is tested for ketones (substances released when the body burns fat instead of sugar). If you take this medicine, these tests may give false results.
Contact a doctor immediately:

A small number of patients treated with antiepileptic medicines such as Acido Valproico e Sodio Valproato ratiopharm have experienced suicidal thoughts or intentions. If you experience these feelings at any time, contact your doctor immediately.
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 in association 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 are taking a medicine for epilepsy, in rare cases seizures may worsen or occur more frequently. Contact your doctor immediately if this occurs.

Children and adolescents
Acido Valproico e Sodio Valproato ratiopharm must not be used for the treatment of mania in children and adolescents under 18 years of age.
Other medicines and Acido Valproico e Sodio Valproato ratiopharm
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
The effect and sometimes the side effects of Acido Valproico e Sodio Valproato ratiopharm are increased by:

felbamate (used to treat seizures)
cimetidine (used to treat stomach ulcers)
erythromycin (used to treat bacterial infections)
acetylsalicylic acid (“ASA”, used to reduce pain and fever). Concomitant administration of Acido Valproico e Sodio Valproato ratiopharm and acetylsalicylic acid should be avoided, especially in newborns and children, as it may increase the tendency to bleed.

The effect of Acido Valproico e Sodio Valproato ratiopharm is reduced by:

other medicines for treating seizures such as phenobarbital, primidone, phenytoin and carbamazepine
mefloquine (used to treat malaria), which increases the metabolism of valproic acid and may trigger seizures
methimazole, a medicine used to treat pain and fever
carbapenems (antibiotics used to treat bacterial infections)
estrogen-containing products (including some oral contraceptives). No influence of Acido Valproico e Sodio Valproato ratiopharm on hormonal contraception ("the pill") is expected.
methotrexate (used to treat cancer and inflammatory conditions)
rifampicin (antibiotic used to treat bacterial infections)
protease inhibitors such as lopinavir and ritonavir (used to treat HIV)
cholestyramine (used to reduce elevated blood cholesterol levels).

The effect of Acido Valproico e Sodio Valproato ratiopharm may be increased or reduced by:

fluoxetine (used to treat depression).

Acido Valproico e Sodio Valproato ratiopharm increases the effect and sometimes the side effects of:

other antiepileptic drugs, e.g., carbamazepine, clonazepam, felbamate, lamotrigine, phenobarbital, phenytoin, primidone; rufinamide. After concomitant treatment with valproic acid and clonazepam in patients with a history of absence seizures (a specific type of epileptic seizure), absence status (a prolonged seizure) has occurred; evidence suggests that the combination of valproic acid and lamotrigine may increase the risk of skin reactions, especially in children.
neuroleptic agents (used to treat psychiatric disorders).
benzodiazepines (used to relieve tension and anxiety) such as diazepam and lorazepam.
barbiturates (tranquillisers).
monoamine oxidase inhibitors (MAOIs) (used to treat depression) and other medicines used to treat depression.
codeine (used, among other things, for cough).
zidovudine (used to treat HIV infections).
propofol (used in anaesthesia).
nimodipine (used to prevent changes in brain function).
anticoagulants (e.g., vitamin K antagonists), which may increase the tendency to bleed.

Catatonia (a condition of persistent immobility that cannot be interrupted by external stimuli) occurred in a patient with schizoaffective disorder (a psychological disorder) following concomitant treatment with valproic acid, sertraline (an antidepressant) and risperidone (a neuroleptic agent).
Other interactions:

acetylsalicylic acid (“ASA”, used to reduce pain and fever) may increase the tendency to bleed.
substances that prevent blood coagulation (anticoagulants) may increase the tendency to bleed. Patients monitored by an anticoagulation clinic should report that they are taking Acido Valproico e Sodio Valproato ratiopharm.
in diabetic patients, the test for ketone bodies in urine may give a false positive.
other medicines that stimulate liver metabolism may increase the risk of liver damage.
Concomitant administration of Acido Valproico e Sodio Valproato ratiopharm and topiramate (used to treat epileptic seizures) or acetazolamide (used to treat glaucoma) has been associated with symptoms of brain damage (encephalopathy) and/or increased blood ammonia levels (hyperammonaemia).
concomitant use of valproic acid with a medicine containing the active substance quetiapine may increase the risk of abnormalities in blood count.
concomitant administration of Acido Valproico e Sodio Valproato ratiopharm and certain anti-inflammatory medicines containing pivalate (e.g., pivampicin, adefovir, dipivoxil) should be avoided.
in one study, concomitant use of valproic acid and olanzapine appeared to increase hepatotoxicity. Valproate reduced olanzapine concentrations in adults, which could be associated with a return of psychosis (disturbance of reality perception).
Concomitant administration of Acido Valproico e Sodio Valproato ratiopharm and clozapine (to treat mental health problems) may increase the risk of low neutrophil levels, a type of white blood cell (neutropenia) and inflammation of the heart muscle (myocarditis).

Other medicines that may affect the action of valproic acid or whose action may be influenced by valproic acid include medicines containing one of the following active substances:

cannabidiol (used to treat epilepsy and other conditions).

Acido Valproico e Sodio Valproato ratiopharm with food, drinks and alcohol
Alcohol consumption may affect the activity of Acido Valproico e Sodio Valproato ratiopharm and increase its side effects. You should therefore avoid alcohol during treatment.
You should preferably avoid taking acidic drinks or cold foods at the same time as Acido Valproico e Sodio Valproato ratiopharm.
Pregnancy and breastfeeding
Pregnancy
Important advice for women
Bipolar disorder

If you are pregnant, you must not use Acido Valproico e Sodio Valproato ratiopharm for bipolar disorder.
For bipolar disorder, if you are a woman of childbearing age, you must not take Acido Valproico e Sodio Valproato ratiopharm unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm. Do not stop taking Acido Valproico e Sodio Valproato ratiopharm 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 e Sodio Valproato ratiopharm for epilepsy, unless nothing else is effective for you.
For epilepsy, if you are a woman of childbearing age, you must not take Acido Valproico e Sodio Valproato ratiopharm unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm. Do not stop taking Acido Valproico e Sodio Valproato ratiopharm or your contraceptive before discussing it 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 to your doctor immediately if you are planning to have a baby or are pregnant.
Valproate poses risks if taken during pregnancy. All doses carry a risk, but the risk is higher with higher doses, including the use of valproate in combination with other medicines treating epilepsy.
It may cause serious birth defects and may have consequences on the child's physical and mental development and growth after birth.
The most frequently reported birth defects include spina bifida (incomplete development of some bones of the spine); facial and skull 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 in utero.
Eye malformations associated with other congenital malformations have been reported in children exposed to valproate during pregnancy. These eye malformations may affect vision.
Cases of bleeding problems have been reported in newborns from mothers treated with valproic acid during pregnancy.
If you take valproate during pregnancy, you have a higher risk than other women of having a baby with birth defects requiring medical treatment. Since valproate has been used for many years, we know that approximately 11 out of 100 babies born to women taking valproate have birth defects, compared to 2-3 out of 100 babies born to women not affected by 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. Such children may start walking and talking later, may be intellectually disadvantaged compared to other children, and may 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 children exposed to valproate during pregnancy have an increased risk of developing attention deficit hyperactivity disorder (ADHD).
Before prescribing this medicine, your doctor will explain what could happen to your baby if you become pregnant while taking valproate. If at a later stage you decide you want to have a baby, do not stop taking the medicine or the contraceptive method before discussing it with your doctor.
Some oral contraceptives (contraceptive pills containing oestrogens) may decrease valproate blood levels. Make sure to discuss with your doctor the most suitable contraceptive (birth control) method for you.
If you are a parent or caregiver of a girl treated with valproate, you must contact the doctor as soon as the girl has her first menstrual period.
Consult your doctor about taking folic acid while 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:

I AM STARTING TREATMENT WITH ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM
I AM TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM AND DO NOT PLAN TO HAVE A CHILD
I AM TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM AND PLAN TO HAVE A CHILD
I AM PREGNANT AND TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM

I AM STARTING TREATMENT WITH ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM
If Acido Valproico e Sodio Valproato ratiopharm is prescribed to you for the first time, your doctor will explain the risks to the fetus 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 e Sodio Valproato ratiopharm. Talk to your doctor or visit a family planning clinic if you need advice on contraception.
Key messages:

before starting treatment with Acido Valproico e Sodio Valproato ratiopharm, pregnancy must be ruled out through a pregnancy test confirmed by your doctor;
during the entire treatment with Acido Valproico e Sodio Valproato ratiopharm, you must use an effective method of birth control (contraceptive);
• you must discuss appropriate contraceptive methods with your doctor. Your doctor will explain how to prevent pregnancy and may refer you to a specialist for advice on birth control;
• 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 during pregnancy;
inform your doctor if you wish to have a child;
contact your doctor immediately if you are pregnant or think you might be pregnant

I AM TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM AND DO NOT PLAN TO HAVE A CHILD.
If you are continuing treatment with Acido Valproico e Sodio Valproato ratiopharm but do not plan to have a child, ensure you use an effective contraceptive method continuously throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm. 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) throughout the entire treatment with Acido Valproico e Sodio Valproato ratiopharm;
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 advice on birth control;
you must regularly schedule 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 during pregnancy;
inform your doctor if you wish to have a child;
inform your doctor immediately if you are pregnant or think you might be pregnant.

I AM TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM AND PLAN TO HAVE A CHILD
If you are planning to have a child, make an appointment with your doctor first.
Do not stop taking Acido Valproico e Sodio Valproato ratiopharm or your contraceptive unless you have discussed it 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 the pregnancy course as much as possible and minimize risks for you and your baby.
The specialist may decide to adjust the dose of Acido Valproico e Sodio Valproato ratiopharm or switch to another medicine, or discontinue treatment with Acido Valproico e Sodio Valproato ratiopharm 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 e Sodio Valproato ratiopharm unless your doctor tells you to;
do not stop using birth control (contraceptive) methods before discussing it with your doctor and agreeing on a plan to ensure disease control and minimize risks for the baby;
first make 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 during pregnancy;
your doctor will try to change your medicine or discontinue treatment with Acido Valproico e Sodio Valproato ratiopharm well before pregnancy;
request an urgent appointment with your doctor if you are pregnant or think you might be pregnant.

I AM PREGNANT AND TAKING ACIDO VALPROICO E SODIO VALPROATO RATIOPHARM
Do not stop taking Acido Valproico e Sodio Valproato ratiopharm unless advised by your doctor, because your condition may worsen. Request an urgent appointment with your doctor if you are pregnant or think you might be pregnant. 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 e Sodio Valproato ratiopharm 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 might be pregnant;
do not stop taking Acido Valproico e Sodio Valproato ratiopharm unless your doctor tells you to;
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 on the risks of Acido Valproico e Sodio Valproato ratiopharm during pregnancy, including teratogenicity (birth defects) and physical and mental developmental disorders in children;
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 with you and ask you to sign and keep it. You will also receive the Patient Card from the pharmacist to remind you of the risks of valproate during pregnancy.
If you are pregnant, suspecting or planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Breastfeeding
Do not breastfeed if you are taking valproate and consult your doctor.
Valproate passes into breast milk. Blood disorders have been reported in children/infants breastfed by women taking valproate.
Important advice 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 longer before conception is unknown. The study has limitations and therefore 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 specific types of movement and mental development disorders 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 therapy
The need to consult the specialist if you are planning to conceive a child 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 have questions, contact your doctor. Do not stop treatment without discussing it with your doctor. If you stop treatment, your symptoms may worsen.
You should 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 the Patient Card from the pharmacist to remind you of the potential risks of valproate.
Driving and using machines
Do not drive and do not use tools or machinery without consulting your doctor or pharmacist.
At the beginning of treatment, if you have taken higher doses or are taking other medicines that also act on the central nervous system, drowsiness or confusion may occur. This may alter your reaction ability to the extent that your ability to drive a vehicle or use tools and machinery may be impaired, regardless of the underlying disease. This effect is more pronounced with concomitant alcohol consumption.
The use of multiple antiepileptic medicines or medicines with sedative, hypnotic and/or muscle-relaxant properties (benzodiazepines) may increase this effect.
Acido Valproico e Sodio Valproato ratiopharm 300 mg prolonged-release tablets contain sodium.
This medicine contains 27.7 mg of sodium (main component of table salt) in each prolonged-release tablet. This is equivalent to 1.4% of the maximum recommended daily dietary intake of sodium for an adult.
Acido Valproico e Sodio Valproato ratiopharm 500 mg prolonged-release tablets contain sodium.
This medicine contains 46.2 mg of sodium (main component of table salt) in each prolonged-release tablet. This is equivalent to 2.3% of the maximum recommended daily dietary intake of sodium for an adult.

3. How to take Valproic Acid and Sodium Valproate ratiopharm

Girls and women of childbearing age
Treatment with Valproic Acid and Sodium Valproate ratiopharm must be initiated and supervised by a physician specialized in the treatment of epilepsy or bipolar disorder.
Male patients
It is recommended that treatment with Valproic Acid and Sodium Valproate ratiopharm be initiated and supervised by a specialist experienced in managing epilepsy or bipolar disorder – see section 2 Important information for male patients.
Epileptic seizures
Dosage
Always take Valproic Acid and Sodium Valproate ratiopharm exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist. In long-term treatment, the usual average daily dose is as follows:
Valproic Acid and Sodium Valproate ratiopharm 300 mg prolonged-release tablets:
Age Body weight Average daily dose Prolonged-release
(kg) (mg/day) tablets/day
Children
3-6 years about 15-25 kg 450-600 1½ - 2
7-14 years about 25-40 kg 750-1200 2½ - 4
Adolescents from 14 years about 40-60 kg 1000-1500 3-5
Adults from about 60 kg 1200-2100 4-7
Valproic Acid and Sodium Valproate ratiopharm 500 mg prolonged-release tablets:
Age Body weight Average daily dose Prolonged-release
(kg) (mg/day) tablets/day
Children
3-6 years about 15-25 kg 450-600
7-14 years about 25-40 kg 750-1200 1½ - 2
Adolescents from 14 years about 40-60 kg 1000-1500 2-3
Adults from about 60 kg 1200-2100 2-4

In children up to 3 years of age, dosage forms with a lower active ingredient content should preferably be used (e.g. solution). For treatment in children ≥ 3 years of age, Valproic Acid and Sodium Valproate ratiopharm 300 mg prolonged-release tablets may be used, divided into two equal doses.

Dose increases (gradual) are recommended until the optimal effective dose is reached. In some cases, the full therapeutic effect may not be observed until after 4–6 weeks. Therefore, the daily dose should not be increased too rapidly compared to average quantities.

If Valproic Acid and Sodium Valproate ratiopharm is taken in combination with other antiepileptic medicines or to replace a previously used medicine, the dose of the previously administered antiepileptic should be immediately reduced. If the previously used medicine needs to be discontinued, it should be gradually tapered off.

Other medicines used in the treatment of epileptic seizures accelerate the metabolism of valproic acid. If administration of these medicines is stopped, the blood concentration of valproic acid increases slowly; therefore, valproic acid concentrations should be monitored for a period of 4–6 weeks. The daily dose of Valproic Acid and Sodium Valproate ratiopharm should be reduced as necessary.

Previous treatment with immediate-release valproic acid medicines should be gradually replaced by Valproic Acid and Sodium Valproate ratiopharm until treatment can be continued with single doses of Valproic Acid and Sodium Valproate ratiopharm.

Your doctor will determine the exact required dose on an individual basis.

Follow your doctor’s instructions; otherwise, you will not achieve the full benefit from the medicine.

Mania

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

Initial dose

The recommended initial daily dose is 750 mg.

Recommended daily maintenance dose

Valproic Acid and Sodium Valproate ratiopharm 300 mg prolonged-release tablets
The recommended daily doses usually range from 1000 mg to 2000 mg.

Valproic Acid and Sodium Valproate ratiopharm 500 mg prolonged-release tablets
The recommended daily doses usually range from 1000 mg to 2000 mg.

Route of administration

For oral use. The prolonged-release tablets must be swallowed whole or divided in half, must not be chewed, and should be taken with a sufficient amount of liquid (e.g. a glass of water).

Occasionally, components of the prolonged-release tablets may be visible as white residues in the faeces. This does not in any way compromise the efficacy of the medicine, as the active substance completely dissolves from the tablet structure (matrix) during passage through the intestine.

Frequency of administration

The daily dose is divided into 1–2 doses.

The prolonged-release tablets should preferably be taken 1 hour before meals (in the morning on an empty stomach). If gastrointestinal adverse effects occur due to treatment, the prolonged-release tablets should be taken during or after meals.

Duration of treatment

The treatment of epileptic seizures is primarily a long-term therapy.

The specialist doctor (neurologist, paediatric neurologist) must decide individually, based on the course of the disease in the individual patient, on the dose concentration, duration of treatment, dosing regimen, and discontinuation of Valproic Acid and Sodium Valproate ratiopharm.

Generally, in the treatment of epileptic seizures, the dose should not be reduced or the medicine discontinued until the patient has been seizure-free for at least two to three years.

Special patient groups

Patients with kidney problems

Your doctor may decide to adjust the dose.

In patients with reduced renal function and low blood protein levels, the effect of valproic acid may be increased. Your doctor must adjust or reduce the daily dose as appropriate.

If you take more Valproic Acid and Sodium Valproate ratiopharm than you should

If you have taken too much Valproic Acid and Sodium Valproate ratiopharm, contact your doctor immediately.

Symptoms of overdose may include: coma with increased muscle tone, reduced reflexes, pupil constriction, confusion, drowsiness, metabolic acidosis, increased sodium levels in the blood, impaired respiratory or cardiac function.

In addition, high doses have caused unusual neurological disturbances, such as an increased tendency to epileptic seizures and behavioural changes.

Isolated cases of acute and chronic overdose resulting in fatal outcomes have been reported in the scientific literature. Therefore, always adhere strictly to the dose prescribed by your doctor.

If you forget to take Valproic Acid and Sodium Valproate ratiopharm

Do not take a double dose to make up for a forgotten tablet.

If you forget to take a dose, you may take it later, unless it is almost time for your next dose. In that case, follow your regular dosing schedule.

If you stop taking Valproic Acid and Sodium Valproate ratiopharm

Under no circumstances should you stop or discontinue treatment with Valproic Acid and Sodium Valproate ratiopharm on your own initiative, as this may jeopardize the success of your treatment and may trigger a recurrence of epileptic seizures. Consult your doctor first if you notice any intolerance to the medicine or any change in your condition.

If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following frequency categories have been used to assess the side effects:

Very common	≥1/10
Common	≥1/100, <1/10
Uncommon	≥1/1,000, <1/100
Rare	≥1/10,000, <1/1,000
Very rare	≤10,000
Not known	Frequency cannot be estimated from the available data

Contact your doctor immediately if you experience any of the following serious side effects, as you may
require urgent medical treatment:
Very common (may affect more than 1 in 10 people)

Problems with balance and coordination, feeling lethargic or less alert, associated with vomiting. This may be due to excess ammonia in the blood.

Common (may affect up to 1 in 10 people)

Severe liver damage (sometimes fatal), not dose-dependent. This can be very serious, especially in children, and usually occurs within the first six months of treatment. In children, particularly those taking other anticonvulsant medicines at the same time, the risk of liver damage is significantly increased. Early recognition is important. Sometimes these symptoms are accompanied by drowsiness and high levels of ammonia in the blood. This may be detected by an ammonia-like odour in the urine. For further information, see section 2 “Warnings and precautions”.
Bruising or spontaneous bleeding due to a decrease in platelet count (thrombocytopenia). This is more common in women and elderly people.
Numbness with immobility of the body (stupor), severe drowsiness and sleepiness after which you may become temporarily unconscious. This is sometimes accompanied by increased seizures. These side effects usually occur if a higher dose is taken suddenly or if multiple antiepileptic medicines (especially phenobarbital or topiramate) are taken simultaneously. These side effects resolve by reducing the dose of valproic acid or discontinuing treatment.
Abnormal movements and muscle rigidity (extrapyramidal disorders).
Deficiency of white blood cells leading to increased susceptibility to infections (leucopenia).

Uncommon (may affect up to 1 in 100 people)

Inflammation of the pancreas (pancreatitis). This inflammation is accompanied by nausea, vomiting and severe pain in the upper abdomen radiating to the back. This side effect can be serious. Rare cases of pancreatic damage, sometimes fatal, have been reported.
Swelling with painful, itchy hives affecting mainly the eyes, lips, throat and sometimes hands and feet (angioedema).
Syndrome involving excessive fluid retention due to excessive release of antidiuretic hormone; this causes a marked drop in blood sodium levels and may lead to confusion.
Kidney disease (renal failure, tubulo-interstitial nephritis) which may present as reduced urine production.
Increase in frequency and severity of seizures.
Breathing difficulties and pain due to leakage of lung fluid. Breathing difficulties, chest pain or pressure (especially during inspiration), shortness of breath and dry cough due to fluid accumulation around the lungs (pleural effusion).
Excessive production of saliva.

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

Fever, red spots on the skin, joint pain, eye inflammation or blisters on the skin/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, sometimes accompanied by flu-like symptoms such as fever, chills or muscle pain
- these symptoms may indicate serious allergic reactions called Stevens-Johnson syndrome, toxic epidermal necrolysis, Lyell’s syndrome)
Syndrome with drug rash, fever, swollen lymph nodes and possible involvement of other organs (DRESS).
Valproic acid may also cause a severe decrease in white blood cells, reduced platelet or red blood cell count (bone marrow failure) or an abnormal increase in red blood cells or other bone marrow disorders (shown in blood tests). This may sometimes present with fever and breathing difficulties.
Reduced production of thyroid hormones (hypothyroidism).
Autoimmune disease with rash, joint inflammation, joint pain, fever, fatigue, rash. These may be signs of systemic or generalised lupus erythematosus.
Breakdown of muscle tissue with symptoms of muscle cramps, fever and reddish-brown discoloration of urine (rhabdomyolysis).

Tell your doctor if any of the following side effects become severe or last longer than a few days:
Very common (may affect more than 1 in 10 people)

Tremors (trembling).
Particularly at the beginning of therapy, non-common reports of mild gastrointestinal disturbances (nausea, stomach ache), which usually disappeared after a few days, even if treatment continued. Nausea may be prevented by taking the medicine with food.

Common (may affect up to 1 in 10 people)

Uncontrolled muscle contractions, unsteadiness when walking (parkinsonism, extrapyramidal disorders, ataxia).
Low red blood cell count (anaemia), low blood pressure, rapid heartbeat, general fatigue and muscle cramps due to abnormally low sodium levels in the blood (hyponatraemia).
Hypersensitivity.
Hallucinations, confusion.
Aggression, agitation, attention disorder. These side effects are particularly common in children.
Dizziness, changes in consciousness (including coma), seizures, drowsiness, lethargy or abnormal behaviour and memory, with or without more frequent or severe seizures, especially if phenobarbital and topiramate are taken simultaneously or if the dose of valproic acid is suddenly increased; headache, involuntary eye movements (nystagmus).
Hearing problems and deafness.
Ringing in the ears (tinnitus).
Bleeding.
Pain in the upper abdomen, diarrhoea, vomiting. These symptoms often occur at the beginning of treatment and usually resolve spontaneously within a few days.
Repeated vomiting, extreme tiredness, abdominal pain, dizziness, feeling of weakness, loss of appetite, severe pain in the upper abdomen, nausea, jaundice (yellowing of the skin or whites of the eyes), leg swelling or worsening of epilepsy or a general feeling of being unwell may be signs of serious liver or pancreatic disorders.
Gum disease (especially excessive gum growth), inflammation of the oral mucosa (stomatitis).
Hair loss, nail bed and nail disorders.
Menstruation with severe back or lower abdominal pain and headache, irregular menstruation.
Weight gain or weight loss (dose-dependent), increased or decreased appetite.
Involuntary loss of urine (urinary incontinence).
Altered sensations such as tingling or numbness of the skin.

Uncommon (may affect up to 1 in 100 people)

Abnormally low count of all types of blood cells (pancytopenia).
Drowsiness, coma, reversible parkinsonism (syndrome with features of Parkinson’s disease), coordination problems (ataxia), disturbance in sensory perception.
Particularly at high doses or in combination therapy with other anticonvulsant medicines, chronic brain diseases (encephalopathy) with disturbances in brain function, including mental performance, have been reported. The mechanism of development has not been sufficiently clarified.
Excessive hair growth, especially in women (hirsutism), masculine appearance in women (virilism), acne, male-pattern baldness.
Inflammation of a blood vessel (vasculitis)
Rash
Hair disorders such as changes in hair texture or colour, or abnormal hair growth
Bone abnormalities have been reported, including thinning of the bones (osteopenia, osteoporosis) and bone fractures. If you are receiving long-term treatment with an antiepileptic medicine, have previously had osteoporosis, or are taking steroids, you should consult your doctor.
Absence of menstruation (amenorrhoea)
Fluid accumulation in the limbs (peripheral oedema)
Reduced body temperature (hypothermia)
Irritability
Hyperactivity

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

Reduced levels of blood clotting factors (including factor VIII deficiency), which may cause prolonged bleeding time from wounds. Abnormal blood clotting (shown in blood tests). Valproic acid may inhibit blood coagulation (blood platelet function), causing prolonged bleeding time. Valproate may reduce fibrinogen levels and inhibit platelet aggregation, leading to prolonged bleeding time.
Inability to break down chemicals called porphyrins (porphyria)
Obesity
Abnormal behaviour, restlessness, learning disorders. These side effects occur mainly in children.
Reversible dementia, cognitive impairment
Rash or skin lesions with a pink/red ring and pale centre, which may be itchy, scaly or fluid-filled. The rash may appear especially on the palms of the hands or soles of the feet. These may be signs of a condition called erythema multiforme.
Nocturnal enuresis, kidney problems, impaired kidney function (Fanconi syndrome), excretion of phosphate, sugar-like components and proteins, hyperacidity (metabolic acidosis), kidney inflammation
Enlarged ovaries with cysts
Double vision (diplopia)
Male infertility, usually reversible after discontinuation of treatment and may be reversible after dose reduction. Do not stop treatment without first consulting your doctor.
Increased levels of male hormones.

Very rare (may affect up to 1 in 10,000 people)

Breast development in men (gynaecomastia)
Brain function disorder, accompanied by reduction in brain tissue, which resolved after discontinuation of Valproic Acid and Sodium Valproate ratiopharm
In long-term therapy with Valproic Acid and Sodium Valproate ratiopharm, together with other seizure-treatment medicines, particularly phenytoin, signs of brain damage (encephalopathy) may occur, accompanied by increased seizure frequency, lack of energy, episodes of physical rigidity while conscious (stupor), muscle weakness (muscular hypotonia), movement disorders (choreiform dyskinesias) and severe general changes in the electroencephalogram (EEG).

Not known (frequency cannot be estimated from the available data)

Birth defects and developmental disorders if taken during pregnancy (see also section 2. “Important advice for women”)
Increase in number of lymphocytes (a particular type of white blood cells) in the blood (lymphocytosis)
Apathy and drowsiness (sedation)
Gastrointestinal disturbances; these occur mainly at the beginning of treatment and normally resolve spontaneously; constipation
Reduction in carnitine levels (indicated by blood or muscle tests)
Reduced activity of biotinidase, biotin deficiency
Prolonged bleeding time
Darker areas of skin and mucous membranes (hyperpigmentation).

Additional adverse effects in children
Some adverse effects of valproate occur more frequently or are more severe in children than in adults.
These include liver damage, pancreatic infections (pancreatitis), aggression, agitation, attention
disorder, abnormal behaviour, hyperactivity and learning disorders.
If other dose-independent adverse effects occur, the medicine must be discontinued by the
attending physician. If severe impairment of liver function or pancreatic damage is suspected,
treatment with Valproic Acid and Sodium Valproate ratiopharm must be immediately discontinued.
Other medicines with the same metabolic elimination pathway that may cause similar adverse
effects should temporarily be discontinued. In isolated cases, clinical progression may still occur.
Reporting of adverse effects
If you experience any adverse effect, including those not listed in this leaflet, consult your doctor or
pharmacist. You can also report adverse effects directly via the national reporting system at:
www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting adverse effects, you can help provide more information on the safety of this medicine.
5. How to store Valproic Acid and Sodium Valproate ratiopharm
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister and packaging after “EXP”. The
expiry date refers to the last day of that month.
Store in the original packaging and keep in a dry place to protect the medicine from moisture. This
medicine is hygroscopic. The prolonged-release tablets must not be removed from their foil until
immediately before administration. The blister must not be cut.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.
6. Contents of the pack and other information
What Valproic Acid and Sodium Valproate ratiopharm 300 mg contains:

The active substances are sodium valproate and valproic acid. One prolonged-release tablet contains 200 mg of sodium valproate and 87 mg of valproic acid (equivalent to a total of 300 mg of sodium valproate).
The excipients are hypromellose 4000 mPa∙s, hypromellose 15000 mPa∙s, potassium acesulfame, hydrated colloidal silica, sodium lauryl sulphate, dibutyl sebacate, basic butyl methacrylate copolymer, magnesium stearate, titanium dioxide.

Description of the appearance of Valproic Acid and Sodium Valproate ratiopharm 300 mg and
contents of the pack
Valproic Acid and Sodium Valproate ratiopharm 300 mg are white, prolonged-release, film-coated,
oblong tablets with a break line on both sides.
The tablet can be divided into two equal halves.
Pack sizes:
20, 30, 50, 60, 90, 100, 200, 200 (200x1 multipack), 500 (hospital pack)
prolonged-release tablets.
What Valproic Acid and Sodium Valproate ratiopharm 500 mg contains:

The active substances are sodium valproate and valproic acid. One prolonged-release tablet contains 333 mg of sodium valproate and 145 mg of valproic acid (equivalent to a total of 500 mg of sodium valproate).
The excipients are hypromellose 4000 mPa∙s, hypromellose 15000 mPa∙s, potassium acesulfame, hydrated colloidal silica, sodium lauryl sulphate, dibutyl sebacate, basic butyl methacrylate copolymer, magnesium stearate, titanium dioxide.

Description of the appearance of Valproic Acid and Sodium Valproate ratiopharm 500 mg and
contents of the pack
Valproic Acid and Sodium Valproate ratiopharm 500 mg are white, prolonged-release, film-coated,
oblong tablets with a break line on both sides.
The tablet can be divided into two equal halves.
Pack sizes:
20, 28, 30, 50, 56, 60, 90, 100, 120, 200, 200 (200x1 multipack), 500 (hospital pack)
prolonged-release tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder and Manufacturer
ratiopharm GmbH – Graf-Arco Strasse, 3 – 89079 Ulm (Germany)
Manufacturer
Merckle GmbH – Ludwig-Merckle Strasse, 3 – 89143 Blaubeuren (Germany)
This medicine is authorised in the Member States of the European Economic Area under the
following names:
Czech Republic Valproat-ratiopharm Chrono 300/500 mg
Germany Valproat-ratiopharm chrono 300/500 mg Retardtabletten
Italy Valproic Acid and Sodium Valproate ratiopharm 300 mg/500 mg
prolonged-release tablets
Portugal Ácido Valpróico Ratiopharm 300/500 mg prolonged-release
tablets
Netherlands Natriumvalproaat chrono 300/500 mg Teva, tablets with
prolonged release
Slovakia Valpro-ratiopharm Chrono 500mg
This leaflet was last updated on:

Valproic acid and sodium valproate ratiopharm

Package Leaflet: Information for the User