Depamide

Patient Information Leaflet

DEPAMIDE 300 mg gastro-resistant tablets

valpromide
This medicine is under additional monitoring. This will allow for 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
Depamide (valpromide) can seriously harm the unborn baby if taken during pregnancy. If you are a woman of childbearing age, you must use an effective method of birth control (contraception) continuously throughout your treatment with Depamide. Your doctor will discuss this with you, but you should also follow the recommendations in section 2 of this leaflet.
If you are planning a pregnancy or think you might be pregnant, contact your doctor urgently.
Do not stop taking Depamide unless your doctor tells you to, as your condition may worsen.
Please read all of this leaflet carefully before you start using this medicine, as 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 their symptoms are the same 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:

1. What Depamide is and what it is used for
2. What you need to know before taking Depamide
3. How to take Depamide
4. Possible side effects
5. How to store Depamide
6. Contents of the pack and other information

1. What Depamide is and what it is used for

Depamide contains the active substance valpromide, which belongs to a group of medicines called
"fatty acid derivative antiepileptics".
Depamide is indicated for:

• Treatment of: generalized and focal epilepsy, absence-type petit mal, myoclonic petit mal, psychomotor epilepsy, behavioural disorders (personality disturbances).
• Treatment of episodes of manic states due to a disorder causing alternating manic and depressive states (bipolar disorder), when lithium is contraindicated or not tolerated. Continuation of therapy after the manic episode may be considered in patients who have responded positively to valproate during acute manic episodes.

2. What you should know before taking Depamide

Do not take Depamide

• if you are allergic to valpromide or any of the other ingredients of this medicine (listed in section 6)
• if you have acute inflammation of the liver (acute hepatitis)
• if you have chronic inflammation of the liver (chronic hepatitis)
• if you or your family members have or have ever had serious liver problems (severe hepatopathy), especially if caused by medicines
• if you have a rare disease called hepatic porphyria
• if you have bleeding (haemorrhage)
• in children under three years of age, Depamide must not be administered (except in exceptional circumstances, as decided by the physician)
• if you suffer from genetic disorders causing disease of specific cellular organelles called mitochondria (e.g., Alpers-Huttenlocher syndrome)
• if you suffer from genetically determined disorders due to deficiency of an enzyme involved in the urea cycle, which manifest with alterations, usually severe, of the nervous system (see "Warnings and precautions")
• if you have carnitine deficiency (a very rare metabolic disorder) that is untreated.

Bipolar disorder

• If you are pregnant, you must not use Depamide for bipolar disorder.
• For bipolar disorder, if you are a woman of childbearing potential, you must not take Depamide unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Depamide. Do not stop taking Depamide 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 notice for women").

Epilepsy

• If you are pregnant, you must not use Depamide for epilepsy, unless nothing else is effective for you.
• For epilepsy, if you are a woman of childbearing potential, you must not take Depamide unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Depamide. Do not stop taking Depamide 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 notice for women").

Warnings and precautions
CONTACT YOUR DOCTOR IMMEDIATELY:

• If you experience liver problems. See the section “LIVER PROBLEMS (HEPATOPATHIES)”. The risk of liver damage increases if Depamide is taken by children under 3 years of age, in individuals taking other antiepileptic medicines simultaneously, or in those with other neurological or metabolic diseases and severe forms of epilepsy. If you or your child taking Depamide develop problems with balance and coordination, feel drowsy or less alert, or vomit, inform your doctor immediately. This may be due to increased ammonia levels in the blood.
• 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. Contact your doctor immediately if you notice any of the symptoms related to these serious skin reactions described in section 4.

Talk to your doctor before taking Depamide:

• Before starting Depamide, because your doctor may require tests to check your liver function, both before starting treatment (see "Do not take Depamide") and at repeated intervals during the first 6 months. If your health condition is similar to those listed under "Do not take Depamide" and "Special warnings", your doctor is more likely to require monitoring tests. Depending on test results and your health status, your doctor may decide to modify the dose of Depamide or to perform further tests.

• If you are a child under 3 years of age, you must not take Depamide with other medicines, and your doctor will evaluate the risk-benefit ratio (liver and pancreas problems) before starting treatment. If you are a child under 3 years of age, do not take Depamide if you are taking medicines containing salicylic acid or its derivatives, as this may increase the risk of liver toxicity (hepatotoxicity).

• If there is a family history of genetic disorders causing disease of specific cellular organelles called mitochondria, due to a possible risk of liver damage.

• If you have high levels of ammonia in the blood (hyperammonaemia), because valproate can increase ammonia levels in the blood (see "Do not take Depamide" and "Possible side effects").

• If it is suspected that you suffer from metabolic disorders, particularly inherited enzyme deficiencies such as "urea cycle disorder", due to a possible risk of increased blood ammonia levels.

• If you suffer from a disease that reduces the amount of an enzyme called carnitine palmitoyltransferase (CPT) type II, because valproate may increase the risk of a muscle cell disease called rhabdomyolysis.

• 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 supplements.

• If you have reduced kidney function (renal insufficiency) or reduced levels of protein in the blood (hypoproteinaemia), your doctor may decide to modify therapy based on clinical monitoring.

• If you suffer from a skin and tissue disease called "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 have ever developed a severe skin rash, skin peeling, blisters and/or mouth ulcers after taking valproate.

• If you experience sudden abdominal pain, because your doctor may discontinue treatment and perform tests to rule out pancreatitis (inflammation of the pancreas).

• If you are on special diets, because Depamide may cause weight gain at the beginning of treatment (see "Possible side effects").

• If you are taking antibiotics belonging to a class called carbapenems, because concomitant use of valpromide is not recommended (see "Other medicines and Depamide").

• If you are a woman of childbearing potential (see "Pregnancy, breastfeeding and fertility").

• 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, before surgery, and in case of spontaneous bruising or bleeding.

If you take this medicine for epilepsy, as with other antiepileptic drugs, you may experience a reversible worsening in the frequency and severity of seizures (up to status epilepticus) or may develop new types of seizures (see "Possible side effects"). In this case, you must inform your doctor immediately.
If during treatment with Depamide you have thoughts that lead you to want to harm yourself or commit suicide, inform your doctor immediately, as such disorders have been observed with a class of medicines called "antiepileptics", such as valpromide.
Alcohol consumption is strongly discouraged during treatment with valpromide because it may increase the effects of alcohol.
If you suffer from diabetes, because if you undergo tests for ketone bodies, Depamide may alter the results.
Elderly patients and patients with serious diseases may have poor tolerance to valpromide. Therefore, in these conditions, your doctor will perform adequate monitoring, particularly when valpromide is administered at relatively high doses or in combination with high doses of other medicines used to treat mental disorders or epilepsy (psychotropics or antiepileptics).
LIVER PROBLEMS (HEPATOPATHIES)

• How it manifests
  Administration of Depamide has exceptionally led to severe liver damage (hepatic damage), which has sometimes been fatal. If you are a newborn or a child under 3 years of age with severe forms of a disease called epilepsy, especially if you have brain damage (cerebral), mental developmental delay (psychic), and/or a congenital metabolic or degenerative disease, and are on treatment with multiple medicines, you have a higher risk of developing severe liver problems.

If the child is over 3 years of age, the risk of these complications is lower, as the probability decreases with increasing age.
In most cases, liver damage occurred during the first 6 months of treatment.

• Symptoms
  In particular, if you are a high-risk patient, clinical symptoms are essential for early diagnosis. Two types of symptoms 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, who will perform tests.
• Monitoring during treatment
  If you are taking Depamide, your doctor will perform liver tests, including bilirubin and transaminases (liver function), before starting treatment and at regular intervals during the first 6 months, and other blood tests called prothrombin time and fibrinogen to monitor blood coagulation. An increase in some of these tests may require discontinuation of valproate treatment, and as a precaution, salicylates taken concomitantly should also be discontinued.

PANCREATIC INFLAMMATION (PANCREATITIS)
Severe inflammation of the pancreas (pancreatitis), which may be fatal, is possible, although very rare.
Other medicines and Depamide
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription. Some medicines may affect the action of valproate and vice versa.
A portion of the valpromide taken is converted into a substance called valproic acid, which has a therapeutic effect (active metabolite). For this reason, valpromide may have the same interactions as valproic acid or valproates.
Effects of valproate on other medicines
Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines
If you take valpromide with medicines used for behavioural disorders belonging to classes called neuroleptics, MAO inhibitors, antidepressants and benzodiazepines, an increased effect may occur. Therefore, your doctor will monitor you and, when necessary, adjust your therapy.
Phenobarbital
If you take a medicine called phenobarbital, inform your doctor because valproate increases the amount of phenobarbital in the blood and excessive sedation may occur, especially in children. Your doctor will monitor you during the first 15 days of combined treatment and may reduce the dose of phenobarbital if sedation occurs, and may monitor the amount of phenobarbital in the blood.
Primidone
If you take a medicine called primidone, valproate may increase its amount in the blood, with a possible increase in side effects (such as sedation); this interaction ceases with long-term treatment, so your doctor will monitor you especially at the beginning of therapy, adjusting the dose of primidone when necessary.
Phenytoin
If you take valproate concomitantly with a phenytoin-based medicine, your doctor will perform tests because valproate alters the amount of phenytoin in the blood, with possible overdose symptoms.
Carbamazepine
If you take valproate with a carbamazepine-based medicine, your doctor will perform tests, especially at the beginning of therapy. These tests are performed because valpromide increases the toxicity of carbamazepine.
Lamotrigine
If you take Depamide 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 the dose of lamotrigine if necessary.
Ethosuximide
If you take valpromide with a medicine containing ethosuximide, the amount of the latter in the blood may increase.
Zidovudine
Be cautious when taking valproate with zidovudine-based medicines because the combination may lead to increased blood levels of the latter and related toxicity.
Felbamate
Valproic acid may decrease the metabolism of felbamate.
Olanzapine
If you take Depamide with olanzapine-based medicines (used in certain mental disorders), the amount of the latter in the blood may increase.
Rufinamide
If you take Depamide with medicines containing rufinamide (used in epilepsy), the amount of the latter in the blood may increase. The increased amount of rufinamide in the blood depends on the dose of Depamide used. This effect is greater in children.
Propofol
If you take valproate together with propofol (used for anaesthesia), your doctor will consider reducing the dose of propofol because valproate may increase its blood levels.
Nimodipine
Depamide may increase the effects of nimodipine.
Clozapine (for treating mental health problems).
Effects of other medicines on valpromide
If you take medicines for epilepsy (particularly phenytoin, phenobarbital and carbamazepine) concomitantly with valproic acid, your doctor may monitor you because the amount of valproic acid in the blood may be reduced. Therapy will be adjusted based on results.
The combination of felbamate and valproate increases the amount of valproic acid in the blood. Therefore, blood levels of valproate should be monitored.
If you take Depamide with phenytoin or phenobarbital-based medicines, pay particular attention to symptoms of hyperammonaemia (nausea, vomiting, agitation, confusion, seizures, drowsiness, muscle coordination problems).
If you take an antimalarial medicine called mefloquine concomitantly with valproic acid, your doctor may monitor you because you may have epileptic seizures.
In case of concomitant use of valpromide and substances that bind highly to proteins (acetylsalicylic acid), blood levels of valproic acid may increase.
Your doctor will perform blood coagulation tests if you are taking Depamide with medicines to make the blood thinner belonging to the class of "vitamin K dependent" agents.
If you take Depamide with cimetidine, erythromycin or rifampicin-based medicines, your doctor will perform tests because blood levels of valproic acid may be altered.
Do not take Depamide concomitantly with antibiotics belonging to the class of carbapenems (used to treat bacterial infections) (see "Warnings and precautions").
Protease inhibitors
If you take Depamide with medicines such as lopinavir and ritonavir (medicines used in severe viral diseases), blood levels of Depamide may decrease.
Colestyramine
If you take Depamide with colestyramine-based medicines (used to lower blood cholesterol), blood levels of Depamide may decrease.
Metamizole
If you take Depamide with metamizole, used to treat pain and fever, blood levels of Depamide may decrease.
Methotrexate (used to treat tumours and inflammatory diseases).
Other interactions
Some anti-infective agents containing pivalate (e.g., pivampicillin, adefovir dipivoxil).
If you take valproic acid-containing medicines concomitantly with anticonvulsant medicines containing topiramate or with acetazolamide (used for high blood pressure), your doctor will monitor you because there is an increased risk of elevated blood ammonia levels and/or brain inflammation (hyperammonaemic encephalopathy).
Estrogen-containing products
Estrogen-containing products (including some birth control pills) may decrease valproate blood levels. Discuss with your doctor the most appropriate method of contraception (birth control) for you.
Valproate generally does not have an enzyme-inducing effect; therefore, it does not reduce the effectiveness of combined oral contraceptives.
Quetiapine
If you take valproate in association with an antipsychotic medicine called quetiapine, there may be an increased risk of reduced levels of certain blood cells (neutropenia/leucopenia).
Cannabidiol (used to treat epilepsy and other conditions).
Depamide with food, drinks and alcohol
Alcohol consumption is strongly discouraged during treatment with valpromide because it may increase the effects of alcohol.
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 notice for women
Bipolar disorder

• If you are pregnant, you must not use Depamide for bipolar disorder.
• For bipolar disorder, if you are a woman of childbearing potential, you must not take Depamide unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Depamide. Do not stop taking Depamide 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 Depamide for epilepsy, unless nothing else is effective for you.
• For epilepsy, if you are a woman of childbearing potential, you must not take Depamide unless you are using an effective method of birth control (contraceptive) throughout the entire treatment with Depamide. Do not stop taking Depamide 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 disease for which it is used)

• Talk to your doctor immediately 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 the use of valproate in combination with other medicines used to treat epilepsy.
• It may cause serious birth defects and may affect the physical and mental development and growth of the child 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 malformations affecting various organs and body parts. Birth defects may lead to disabilities that may 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. Because 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 who do not have 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, 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 a higher risk of developing attention deficit hyperactivity disorder (ADHD).
• If you take valproate during pregnancy, your baby may have a lower birth weight than expected for gestational age. In women taking valproate, about 11-15 out of 100 babies may have lower weight than expected for gestational age. This corresponds to 5-10 out of 100 babies born to women in the general population.
• Before prescribing this medicine, your doctor will explain what could happen to your baby if you become pregnant while taking valproate. If later you decide you want to have a child, do not stop taking the medicine or your 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 birth control pills (estrogen-containing birth control pills) may decrease 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 DEPAMIDE
O I AM TAKING DEPAMIDE AND DO NOT PLAN TO HAVE A CHILD
O I AM TAKING DEPAMIDE AND PLAN TO HAVE A CHILD
O I AM PREGNANT AND TAKING DEPAMIDE
I AM STARTING TREATMENT WITH DEPAMIDE
If Depamide 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 Depamide. Talk to your doctor or visit a family planning clinic if you need advice on contraception.
Key messages:

• before starting treatment with Depamide, pregnancy must be ruled out through a pregnancy test confirmed by your doctor;
• during the entire treatment with Depamide, you must use an effective method of birth control (contraceptive);
• you must discuss appropriate methods of birth control (contraceptives) with your doctor. The 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 the 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 may be.

I AM TAKING DEPAMIDE AND DO NOT PLAN TO HAVE A CHILD.
If you are continuing treatment with Depamide but do not plan to have a child, ensure you use an effective contraceptive method continuously throughout the entire treatment with Depamide. 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 Depamide;
• you must discuss contraception (birth control) with your doctor. The 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 the 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 may be.

I AM TAKING DEPAMIDE 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 Depamide 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 immediately. The specialist may take various measures to facilitate the pregnancy as much as possible and minimise risks for you and the child.
The specialist may decide to modify the dose of Depamide or switch to another medicine, or discontinue Depamide treatment 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 Depamide unless your doctor tells you to;
• do not stop using birth control methods (contraceptives) before discussing it with your doctor and agreeing on a plan to ensure control of your disease 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 the risks and advice related to valproate use during pregnancy;
• your doctor will try to change your medicine or discontinue Depamide treatment well before pregnancy;
• request an urgent appointment with your doctor if you are pregnant or think you may be.

I AM PREGNANT AND TAKING DEPAMIDE
Do not stop taking Depamide unless your doctor tells you to, because 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 Depamide is the only available treatment option during pregnancy, you will be closely monitored for management of your underlying disease and for monitoring 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 Depamide 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 Depamide 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 and ask you to sign and keep it. You will also be given the Patient Card by the pharmacist to remind you of the risks of valproate during pregnancy.
Additional risks for the newborn

• If you take valproate during pregnancy, the newborn may rarely have severe bleeding (haemorrhagic syndrome) due to reduced levels of several coagulation factors. These reductions in coagulation factors may sometimes be fatal, which is why your doctor will perform several tests.
• If you take valproate during the third trimester of pregnancy, the newborn may have reduced blood sugar (hypoglycaemia).
• If you take valproate during pregnancy, the newborn may have disorders due to 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., agitation, irritability, hyperexcitability, nervousness, increased movements (hyperkinesia), muscle activity disorders (tonicity), tremor, seizures and feeding disorders).

Important notice for male patients
Potential risk associated with valproate use in the 3 months before conception
A 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 not known. 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 be given the Patient Card by the pharmacist to remind you of the potential risks of valproate.
Breastfeeding
If you are taking valproate during breastfeeding, your doctor will evaluate whether to discontinue or continue treatment because the medicine is excreted in breast milk and may cause blood disorders (haematological) (see "Possible side effects").
Your doctor will carefully evaluate whether to stop breastfeeding or discontinue treatment or abstain from Depamide therapy, 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 levels of testosterone (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.
Driving and using machines
If you take Depamide with a class of medicines called "barbiturates" or other medicines that reduce central nervous system activity, some individuals may experience fatigue (asthenia) and drowsiness.
The same symptoms may occur after consuming alcoholic beverages. Your doctor will explain the problems you may have when driving or performing tasks requiring normal attention.
Depamide contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per gastro-resistant tablet, i.e. essentially 'sodium-free'.

3. How to take Depamide

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 Depamide must be initiated and supervised by a specialist
experienced in the treatment of epilepsy or bipolar disorders.
Male patients
It is recommended that treatment with Depamide be initiated and supervised by a specialist
experienced in managing epilepsy or bipolar disorder – see section 2. Important warning
for male patients.

• Epilepsy and behavioural disorders

The recommended dose is:
2 to 6 tablets daily, according to medical prescription.
Before starting treatment with Depamide, please note the following:

• If you are a patient not previously treated with other antiepileptic medicines, your doctor will increase the dose at intervals of 2–3 days, reaching the prescribed dose within about one week.
• If you are taking psychotropic medicines for mental disorders, your doctor will gradually increase the dose of Depamide, reaching the optimal dose in about two weeks, while reducing, if necessary, the dose of other treatments.

Depamide, in its 300 mg coated tablet formulation, is primarily indicated for the treatment of adolescents and adults. It is not recommended for use in children.

• Manic episodes associated with bipolar disorder

Adults
The recommended dose is:
the dose considered appropriate by your doctor for each individual patient.
The recommended initial daily dose is 750 mg.
The dose should be increased as rapidly as possible to reach the lowest therapeutic dose that provides the desired clinical effect. The daily dose should be adjusted according to clinical response to establish the minimum effective dose for the individual patient.
The usual average daily dose ranges between 1000 and 2000 mg of valproate. Patients receiving a daily dose exceeding 45 mg/kg body weight should be closely monitored.
If you suffer from a condition causing severe mood disturbances (manic episodes associated with bipolar disorder), your doctor will determine the minimum effective dose.
Patients with kidney problems
Your doctor may decide to adjust the dose.
Use in children and adolescents
Children and adolescents under 18 years of age:
Depamide must not be used in children and adolescents under 18 years of age for the treatment of mania.
If you take more Depamide than you should
If you take or ingest too much Depamide, contact your doctor immediately or go to the nearest hospital.
Signs and symptoms of overdose
Signs of severe acute overdose generally include: coma, reduced muscle tone (hypotonia), reduced reflexes (hyporeflexia), decreased pupil size (miosis), impaired respiratory function, changes in blood acidity (metabolic acidosis), low blood pressure (hypotension), heart disturbances, circulatory collapse/shock, and increased sodium levels in the blood (hypernatremia).
Death has occurred following severe overdose, although the outcome of intoxications is generally favourable.
However, symptoms may vary, and epileptic seizures have been reported with very high blood levels of valpromide.
Cases of increased pressure in the head (intracranial hypertension) have also been reported.
If you forget to take Depamide
Do not take a double dose to make up for a forgotten dose.
If you have any doubts about how to use Depamide, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, DEPAMIDE may cause side effects, although not everybody gets them.
If you experience any side effect, including those not listed in this leaflet, please contact your doctor or pharmacist.
Contact your doctor immediately if you notice any of the following serious side effects.
You may need urgent medical treatment:

• Problems with balance and coordination, feeling lethargic or less alert, associated with vomiting. This may be due to increased levels of ammonia in the blood.
• Kidney disorders (renal failure, tubulointerstitial nephritis), which may present as reduced urine output.
• Uncommon: difficulty breathing, pain or pressure in the chest (especially during inspiration), shortness of breath, and dry cough due to fluid accumulation around the lungs (pleural effusion).

Inform your doctor or pharmacist if any of the following side effects worsen or
persist for more than a few days; you may require medical treatment:
Rare: frequent urination and thirst (Fanconi syndrome).
Frequency not known: darkened areas of the skin and mucous membranes (hyperpigmentation).
Very common side effects (may affect more than 1 in 10 people):

• Nausea.
• Tremor.

Common side effects (may affect from 1 to 10 in 100 people):

• Liver dysfunction: mild increases in liver blood tests (liver enzymes), especially at the beginning of treatment; this increase is temporary (transient) and asymptomatic (without clinical signs). Cases of liver inflammation (hepatitis) have been reported (see “Warnings and precautions”).
• Vomiting, gum disorders, mainly gum swelling (gingival hyperplasia), inflammation of the mouth lining (stomatitis), upper abdominal pain, diarrhoea; these effects frequently occur in some patients at the beginning of treatment but usually disappear after a few days without discontinuing therapy.
• Disorders affecting a part of the nervous system called extrapyramidal (inability to stay still, rigidity, tremors, slow movements, involuntary movements, muscle contractions), stupor, tremor when attempting to maintain a fixed posture (postural tremor), somnolence, seizures, poor memory, headache, involuntary eye movements (nystagmus), dizziness occurring a few minutes after intravenous injection, resolving spontaneously within a few minutes.
• Confusion, hallucinations, aggression*, agitation*, attention disorders* (*These side effects have been observed mainly in children).
• Decreased haemoglobin in the blood (anaemia), reduced platelet count (thrombocytopenia).
• Dose-dependent weight gain or weight loss, increased or decreased appetite. Since weight gain is a risk factor for a condition affecting the ovary called “polycystic ovary syndrome”, it should be carefully monitored (see “What you need to know before taking Depamide”).
• Hypersensitivity, transient hair loss (transient alopecia), and/or dose-related hair loss.
• Painful menstrual cycle (dysmenorrhoea).
• Bleeding (see “What you need to know before taking Depamide” and “Warnings and precautions”).
• Deafness.
• Reduced sodium levels in the blood (hyponatraemia).
• Nail disorders.
• Involuntary loss of urine (urinary incontinence).

Uncommon side effects (may affect from 1 to 10 in 1,000 people):

• Inflammation of the pancreas (pancreatitis), sometimes fatal (see “Warnings and precautions” and “What you need to know before taking Depamide”).
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH), increased production of male hormones (hyperandrogenism) characterised by excessive hair growth (hirsutism), development of male characteristics in women (virilism), acne, male-pattern hair loss and/or increased male hormones (androgens).
• Difficulty performing voluntary movements (ataxia), confusion (encephalopathy), coma, increased sleepiness (lethargy), Parkinson-like symptoms that may be reversible (reversible parkinsonism), altered sensation in limbs or other body parts (paraesthesia). Worsening of seizures (see “Warnings and precautions”).
• Irritability (occasionally aggression, hyperactivity, and behavioural disorders).
• Changes in number or shape of blood cells (leucopenia or pancytopenia, red blood cell hypoplasia).
• Swelling of the face, hands and feet, lips, tongue or throat (angioedema), skin redness (rash), hair abnormalities (such as abnormal hair structure, changes in hair colour, abnormal hair growth).
• Absence of menstruation (amenorrhoea) and irregular menstrual periods.
• Inflammation of blood vessels (vasculitis).
• Reduced body temperature (hypothermia).
• Reduced kidney function (renal failure).
• Mild peripheral fluid accumulation (mild peripheral oedema).

Rare side effects (may affect from 1 to 10 in 10,000 people):

• Reduced production of thyroid hormones (hypothyroidism) (see “Warnings and precautions”).
• Increased ammonia levels in the blood (hyperammonaemia). A mild and isolated increase in blood ammonia (isolated hyperammonaemia) may occur without changes in liver function tests (liver function) and should not lead to discontinuation of treatment. However, during monotherapy or combination therapy with other drugs (e.g. phenobarbital, carbamazepine, phenytoin, topiramate), altered consciousness due to increased blood ammonia (hyperammonaemic encephalopathy) may occur, despite normal liver function and absence of liver cell damage (cytolysis). The syndrome of altered consciousness due to increased blood ammonia (valproate-induced hyperammonaemic encephalopathy) presents acutely and is characterised by loss of consciousness and neurological disturbances with increased frequency of epileptic seizures. It may appear a few days or weeks after starting therapy and resolves upon discontinuation of valproate. The state of confusion (encephalopathy) is not dose-dependent.
• Blood disorder due to bone marrow problems (myelodysplastic syndrome).
• Reversible dementia associated with reversible brain changes (cerebral atrophy), learning difficulties (cognitive disorders), confusion, a specific state of unconsciousness called “stupor”, and increased sleepiness (“lethargy”), sometimes leading to transient coma (encephalopathy): these effects are rare or associated with an increase in seizure frequency during therapy and resolve upon treatment discontinuation or dose reduction. These cases have been reported mainly during combination therapy with other drugs (particularly phenobarbital) or after a sudden increase in valproate dose. Decreased muscle tone (hypotonia) and sedation have also been reported.
• Abnormal behaviour*, psychomotor hyperactivity*, learning difficulties* (*These side effects have been observed mainly in children).
• Impaired bone marrow function (bone marrow failure, including pure red cell aplasia). Changes in number or shape of blood cells (agranulocytosis, macrocytic anaemia, macrocytosis).
• Decreased coagulation factors, abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, prolonged INR) (see also “Pregnancy, breastfeeding and fertility”). Isolated cases of reduced fibrinogen have been reported. Deficiency of vitamin H (biotin) and of the enzyme called biotinidase.
• Severe skin disorders (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme). Allergic reactions, particularly drug reaction with eosinophilia and systemic symptoms (DRESS), with increased levels of certain white blood cells (eosinophilia) and systemic disturbances.
• Male infertility, which is generally reversible after treatment discontinuation and may be reversible after dose reduction. Do not stop treatment without first consulting your doctor. Polycystic ovary.
• Night-time urine loss (enuresis), kidney disorders (tubulointerstitial nephritis, reversible Fanconi syndrome).
• Skin and tissue disorders, such as systemic lupus erythematosus, muscle disorders (rhabdomyolysis); (see “What you need to know before taking Depamide”).
• Obesity.
• Double vision.

Side effects with unknown frequency (frequency cannot be estimated from the available data):

• Congenital malformations and developmental disorders (see “Warnings and precautions – Pregnancy, breastfeeding and fertility”).
• Decreased bone mineral density (osteopenia and osteoporosis) and fractures in patients on long-term Depamide therapy.
• Allergic reactions.

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, inflammation of the pancreas (pancreatitis), aggression, agitation, attention disorders, abnormal behaviour, hyperactivity, and learning difficulties.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please contact 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 Depamide

Do not store above 30°C.
Keep in the original container.
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.
Keep this medicine out of the sight and reach of children.
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 Depamide contains
The active substance is: valpromide. One gastro-resistant tablet contains 300 mg of valpromide.
The other components are: sodium docusate, sodium carboxymethylstarch (type A), colloidal anhydrous silica, talc, magnesium stearate, methacrylic acid/ethyl acrylate copolymer (1:1), sodium hydroxide, triethyl citrate, titanium dioxide, yellow iron oxide.
Description of the appearance of Depamide and package contents
Depamide is available as gastro-resistant tablets.
One box contains 30 gastro-resistant 300 mg tablets.
Marketing Authorization Holder
Sanofi S.r.l. – Viale L. Bodio, 37/B - Milan
Manufacturer
SANOFI WINTHROP INDUSTRIES - 1, rue de la Vierge - 33440 Ambares (F)
SANOFI-AVENTIS S.A. - Carretera de la Batlloria a Hostalric - Riells - (E)
Detailed and up-to-date information on this medicinal product is available by scanning with a smartphone the QR code present on this package leaflet and on the outer packaging. The same information is also available at the following URL:
https://qr.Ioevalproato.it/it-IT/depamide