EPIVAL CR 300 MG PROLONGED-RELEASE TABLETS - patient leaflet, side effects, dosage

Package leaflet: Information for the patient

Epival ® CR 300 300 mg ■■ Epival ® CR 500 mg prolonged-release tablets Active substance: sodium valproate

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of “ section 4 for how to report side effects.

WARNING

Epival CR (sodium valproate) can seriously harm an unborn child when taken during pregnancy. If you are a female able to have a baby you must use effective method of birth control (contraception) without interruptions during your entire treatment with Epival CR. Your doctor will discuss this with you but you must also follow the advice in section 2 of this leaflet.

Schedule an urgent appointment with your doctor if you want to become pregnant or if you think you are pregnant.

Do not stop taking Epival CR unless your doctor tells you to as your condition may become worse.

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

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor or pharmacist.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

• – If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

• 1. What Epival CR is and what it is used for

• 2. What you need to know before you take Epival CR

• 3. How to take Epival CR

• 4. Possible side effects

• 5. How to store Epival CR

• 6. Contents of the pack and other information

1. what epival cr is and what it is used for

This medicine is an anticonvulsant (medication against epilepsy/ fits). It is also used for the treatment of mania.

Sodium valproate, the active substance in Epival CR, is effective against certain types of convulsions.

From the prolonged-release tablets, sodium valproate is released slowly into your body, thus acting over many hours.

Epival CR is used in the treatment of

• – various forms of epilepsy (fits)

• – mania, where you may feel very excited, elated, agitated, enthusiastic or hyperactive. Mania occurs in an illness called „bipolar disorder“. Epival CR can be used when lithium cannot be used.

2. what you need to know before you take epival cr| do not take epival cr                                ~|- if you are allergic (hypersensitive) to sodium valproate or any of the other ingredients (see section 6.1 “what epival cr contains”).

• – if you have liver problems (e.g. hepatitis).

• – if close family-members have severe liver function disturbances or if there is a history of such disturbances in your family.

• – if you have a severe disturbance of the pancreas function.

• – if you suffer from urea cycle disorders (a metabolic condition).

• – if you suffer from hepatic porphyria (a rare metabolic disease).

• – if you have a genetic problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome).

• – Bipolar disorder

• – For bipolar disorder, you must not use Epival CR if you are pregnant.

• – For bipolar disorder, if you are a woman able to have a baby, you must not take Epival CR, unless you use effective method of birth control (contraception) during your entire treatment with Epival CR. Do not stop taking Epival CR or your contraception, until you have discussed this with your doctor. Your doctor will advise you further (see below under “Pregnancy, breast-feeding and fertility – Important advice for women”).

• – Epilepsy

• – For epilepsy, you must not use Epival CR if you are pregnant, unless nothing else works for you.

• – For epilepsy, if you are a woman able to have a baby, you must not take Epival CR unless you use effective method of birth control (contraception) during your entire treatment with Epival CR. Do not stop taking Epival CR or your contraception, until 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 or pharmacist before taking Epival CR.

Special precautions are necessary

• – if you suffer from “systemic lupus erythematosus” (a rare allergic condition which causes joint pain, skin rashes and fever): You should consult your doctor before you start taking Epival CR

• – if you need to go in for surgery: Inform the treating physician before any type of surgery that you are taking Epival CR, because sodium valproate may prolong the bleeding time. Blood tests may have to be done.

• – if there is a possibility that you suffer from “urea cycle enzymatic deficiency” (a rare metabolic disorder): You may have to undergo tests before starting treatment with Epival CR.

• – if you know that there is a genetic problem caused by a mitochondrial disorder in your family.

• – if you know that you have a carnitine-palmitoyl transferase (CPT-)II deficiency because there is an increased risk of rhabdomyolysis developing with valproate therapy.

A small number of people being treated with anti-epileptics such as sodium valproate have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your doctor

Children and adolescents under 18 years of age:

Epival CR should not be used in children and adolescents under 18 years of age for the treatment of mania.

Other important things you should know before taking Epival CR:

• - Liver damage

In rare cases severe liver damage resulting in death has been reported. Patients most at risk are children under the age of three years who suffer from severe seizure disorders, particularly in association with mental retardation and/or congenital metabolic disorders. The frequency of such liver diseases generally decreases significantly in patients older than 10 years. Liver damage mostly occurred during the first 6 months of therapy, particularly between weeks 2 and 12 of treatment and usually when other anti-epileptic drugs were given at the same time.

Especially during the first 6 months of treatment, patients at risk should therefore have their liver function checked regularly, and their treatment must be closely monitored.

Signs of severe liver damage may include: increase in seizures, feeling unwell, weakness, loss of appetite, vomiting, pain in the upper abdomen, oedema (swelling of the fingers, legs and toes), lethargy, drowsiness, jaundice (yellowing of the skin or whites of the eyes). If you notice any such symptoms, please consult a doctor immediately.

Similar symptoms may also occur in connection with a disease of the pancreas.

The risk of liver failure may increase if salicylates (e.g. aspirin) are taken at the same time. This risk is particularly high in infants and toddlers. Children under 12 years should not be given Epival CR in combination with acetylsalicylic acid at all. In adolescents, this combination should only be used after careful evaluation of the benefits and risks by their doctor, because it could increase the bleeding tendency and enhance the effects of Epival CR.

• – Patients who suffered from bone marrow damage in the past may need special monitoring by their doctor during treatment.

• – A possible weight gain during therapy was reported. Consult your doctor in order to discuss a suitable strategy against this risk.

• - Urine tests to diagnose diabetes may be false-positive because of Epival CR. Please inform your doctor before such tests that you are taking Epival CR.

• – If you require a blood test to have your thyroid function checked, please inform your doctor about this, because treatment with Epival CR may lead to a false diagnosis of hypothyroidism (insufficient production of thyroid hormone).

• – Occasionally tablet parts may appear in the stools as a visible white residue. However, this does not reduce the effect of the medicine, as the active substance is completely released from the tablet system (matrix) while the drug passes through the intestine.

Other medicines and Epival CR|

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Please read the rest of this leaflet. It includes other important information on the safe and effective use of this medicine that might be especially important for you.

There is a lot of information and it is recommended that you show this leaflet to friends and family to help you discuss and understand your treatment.

Epival CR and other medicines may influence each other in their effects:

• – The effect of certain medicines for depression, medicines used to calm emotional and mental conditions (so-called neuroleptics, MAO-inhibitors, benzodiazepines such as lorazepam, diazepam, or propofol) may be enhanced by Epival CR.

• – The combination with clonazepam (for the treatment of epilepsy) may induce absence seizures: your doctor will adjust the dose of your medication and monitor your treatment carefully.

• – Other medicines used to treat fits/epilepsy (e.g. phenobarbital, primidone, phenytoin, carbamazepine, lamotrigine, felbamate, rufinamide) and Epival CR may increase or reduce each other’s effects.

• – Concomitant use of Epival CR with topiramate and acetazolamide has been associated with encephalopathy and/or hyperammonaemia.

• – The effect of fluoxetine (an antidepressant) may be enhanced by Epival CR, whereas the effect of Epival CR may be reduced.

• – Epival CR may decrease the effect of antipsychotic medicines (e.g. olanzapine).

• – Certain antibiotics (e.g. erythromycin) may increase the effect of Epival CR, others (e.g. meropenem, panipenem, imipenem) may reduce its effect.

• – Cimetidine (used to treat stomach ulcers) may enhance the effect of Epival CR.

• – Cholestyramine (used to treat high blood fat levels) may decrease the effect of Epival CR.

26.2020/216/GB

• – The effect of certain anticoagulants (used to thin the blood, e.g. warfarin) may be increased by Epival CR.

• – The effect of acetylsalicylic acid (e.g. aspirin) may be enhanced by Epival CR and vice versa.

• – Medicines against malaria (mefloquine, chloroquine) may reduce the effect of Epival CR.

• – The effect of zidovudine (used to treat HIV-infections) may be enhanced by Epival CR.

• – Concomitant use of Epival CR with protease inhibitors such as lopinavir and ritonavir (used in the treatment of HIV-infections) may decrease the levels of valproic acid metabolites.

• – The effect of temozolomide (for tumour treatment) may be increased by Epival CR.

• – Rifampicin may decrease valproic acid blood levels, resulting in decreased therapeutic effect. Therefore your doctor may adjust the Epival CR dosage if co-administered with rifampicin.

• – If quetiapine and Epival CR are used at the same time it may increase the risk of so-called “neutropenia/le­ukopenia” (a decrease in certain blood cells).

In particular, tell your doctor or nurse if you are taking any of the following medicines:

Carbapenem agents (antibiotic used to treat bacterial infections). The combination of valproic acid and carbapenems should be avoided because it may decrease the effect of sodium valproate.

The potential liver-damaging effect of Epival CR may be increased if you ingest alcohol or use other treatments that could have a negative effect on the liver.

Epival CR does not appear to influence the effect of oral contraceptives.

| Taking Epival CR with food, drink and alcohol ~|

You can take Epival CR with or after food. During treatment with Epival CR you should not drink alcoholic beverages, as sodium valproate may potentiate the effects of alcohol.

| Pregnancy, breast-feeding and fertility ~|

Important advice for women

Bipolar disorder

• – For bipolar disorder, you must not use Epival CR if you are pregnant.

• – For bipolar disorder, if you are a woman able to have a baby, you must not take Epival CR, unless you use effective method of birth control (contraception) during your entire treatment with Epival CR. Do not stop taking Epival CR or your contraception, until you have discussed this with your — doctor. Your doctor will advise you further.

Epilepsy

• – For epilepsy, you must not use Epival CR if you are pregnant, unless nothing else works for you.

• – For epilepsy, if you are a woman able to have a baby, you must not take Epival CR unless you use effective method of birth control (contraception) during your entire treatment with Epival CR. Do not stop taking Epival CR or your contraception, until you have discussed this with your doctor. Your doctor will advise you further.

The risks of valproate when taken during pregnancy (irrespective of the disease for which valproate is used)

• – Talk to your doctor immediately if you are planning to have a baby or are pregnant.

• – Valproate carries a risk if taken during pregnancy. The higher the dose, the higher the risks but all doses carry a risk.

• – It can cause serious birth defects and can affect the way in which the child develops as it grows. Birth defects which have been reported include spina bifida (where the bones of the spine are not properly developed); facial and skull malformations; heart, kidney, urinary tract and sexual organ malformations; limb defects.

• – If you take valproate during pregnancy you have a higher risk than other women of having a child with birth defects that require medical treatment. Because valproate has been used for many years we know that in women who take valproate around 10 babies in every 100 will have birth defects. This compares to 2 to 3 babies in every 100 born to women who don’t have epilepsy.

• – It is estimated that up to 30–40% of preschool children whose mothers took valproate during pregnancy may have problems with early childhood development. Children affected can be slow to walk and talk, intellectually less able than other children, and have difficulty with language and memory.

• – Autistic spectrum disorders are more often diagnosed in children exposed to valproate and there is some evidence children may be more likely to develop symptoms of Attention Deficit Hyperactivity Disorder (ADHD).

• – Before prescribing this medicine to you, your doctor will have explained what might happen to your baby if you become pregnant whilst taking valproate. If you decide later you want to have a baby you must not stop taking your medicine or your method of contraception until you have discussed this with your doctor.

• – If you are a parent or a caregiver of a female child treated with valproate, you should contact the doctor once your child using valproate experiences menarche.

• – Ask your doctor about taking folic acid when trying for a baby. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate use.

Please choose and read the situations which apply to you from the situations described below:

o I AM STARTING TREATMENT WITH Epival CR

o I AM TAKING Epival CR AND NOT PLANNING TO HAVE A BABY

o I AM TAKING Epival CR AND PLANNING TO HAVE A BABY o I AM PREGNANT AND I AM TAKING Epival CR

I AM STARTING TREATMENT WITH Epival CR

If this is the first time you have been prescribed Epival CR your doctor will have explained the risks to an unborn child if you become pregnant. Once you are able to have a baby, you will need to make sure you use an effective method of contraception without interruption throughout your treatment with Epival CR. Talk to your doctor or family planning clinic if you need advice on contraception.

Key messages:

• – Pregnancy must be excluded before start of treatment with Epival CR with the result of a pregnancy test, confirmed by your doctor.

• – You must use an effective method of birth control (contraception) during your entire treatment with Epival CR.

• – You must discuss the appropriate methods of birth control (contraception) with your doctor. Your doctor will give you information on preventing pregnancy, and may refer you to a specialist for advice on birth control.

• – You must get regular (at least annual) appointments with a specialist experienced in the management of bipolar H disorder or epilepsy. During this visit your doctor will make sure you are well aware and have understood all the risks and advices related to the use of valproate during pregnancy.

• – Tell your doctor if you want to have a baby.

• – Tell your doctor immediately if you are pregnant or think you might be pregnant.

I AM TAKING Epival CR AND NOT PLANNING TO HAVE A BABY

If you are continuing treatment with Epival CR but you are not planning to have a baby make sure you are using an effective method of contraception without interruption during your entire treatment with Epival CR. Talk to your doctor or family planning clinic if you need advice on contraception.

Key messages:

• – You must use an effective method of birth control (contraception) during your entire treatment with Epival CR.

• – You must discuss contraception (birth control) with your doctor. Your doctor will give you information on preventing pregnancy, and may refer you to a specialist for advice on birth control.

• – You must get regular (at least annual) appointments with a specialist experienced in the management of bipolar disorder or epilepsy.

During this visit your doctor will make sure you are well aware and have understood all the risks and advices related to the use of valproate during pregnancy.

• – Tell your doctor if you want to have a baby.

• – Tell your doctor immediately if you are pregnant or think you might be pregnant.

I AM TAKING Epival CR AND PLANNING TO HAVE A BABY

If you are planning to have a baby, first schedule an appointment with your doctor.

Do not stop taking Epival CR or your contraception, until you have discussed this with your doctor. Your doctor will advise you further.

Babies born to mothers who have been on valproate are at serious risk of birth defects and problems with development which can be seriously debilitating. Your doctor will refer you to a specialist experienced in the management of bipolar disorder or epilepsy, so that alternative treatment options can be evaluated early on. Your specialist can put several actions in place so that your pregnancy goes as smoothly as possible and any risks to you and your unborn child are reduced as much as possible.

Your specialist may decide to change the dose of Epival CR or switch you to another medicine, or stop treatment with Epival CR, a long time before you become pregnant – this is to make sure your illness is stable.

Ask your doctor about taking folic acid when planning to have a baby. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate use.

Key messages:

• – Do not stop taking Epival CR unless your doctor tells you to.

• – Do not stop using your methods of birth control (contraception) before you have talked to your doctor and worked together on a plan to ensure your condition is controlled and the risks to your baby are reduced.

• – First schedule an appointment with your doctor. During this visit your doctor will make sure you are well aware and have understood all the risks and advices related to the use of valproate during pregnancy.

• – Your doctor will try to switch you to another medicine, or stop treatment with Epival CR a long time before you become pregnant.

• – Schedule an urgent appointment with your doctor if you are pregnant or think you might be pregnant.

I AM PREGNANT AND I AM USING Epival CR

Do not stop taking Epival CR, unless your doctor tells you to as your condition may become worse. Schedule an urgent appointment with your doctor if you are pregnant or think you might be pregnant. Your doctor will advise you further.

Babies born to mothers who have been on valproate are at serious risk of birth defects and problems with development which can be seriously debilitating.

You will be referred to a specialist experienced in the management of bipolar disorder, or epilepsy, so that alternative treatment options can be evaluated.

In the exceptional circumstances when Epival CR is the only available treatment option during pregnancy, you will be monitored very closely both for the management of your underlying condition and to check how your unborn child is developing. You and your partner could receive counselling and support regarding the valproate exposed pregnancy.

Ask your doctor about taking folic acid. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate use.

Key messages:

• – Schedule an urgent appointment with your doctor if you are pregnant or think you might be pregnant.

• – Do not stop taking Epival CR unless your doctor tells you to.

• – Make sure you are referred to a specialist experienced in the treatment of epilepsy, or bipolar disorder to evaluate the need for alternative treatment options.

• – You must get thorough counselling on the risks of Epival CR during pregnancy, including teratogenicity and developmental effects in children.

GI25420GB, Epival CR 300/500 mg Tab.

• – Make sure you are referred to a specialist for prenatal monitoring in order to detect possible occurrences of malformations.

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

BREASTFEEDING

Very little Epival CR gets into the breast milk. However, talk to your doctor about whether you should breast-feed your baby.

| Driving and using machines ~|

Use of this drug may affect reactivity and the patient's ability to drive, particularly if other medicines against epilepsy/fits or medicines with a calming effect are taken and in combination with alcohol.

Successful seizure control over a period of several months may enable patients to actively participate in road traffic. Your treating physician will inform you whether you may drive a vehicle.

3. how to take epival cr

Epival CR treatment must be started and supervised by a doctor specialised in the treatment of epilepsy or bipolar disorders. Always take Epival CR exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

DOSAGE AND DURATION OF TREATMENT

Dosage and duration of treatment are individually adjusted by your doctor.

In general, treatment is started with a lower dose, which is then gradually increased by your doctor until your optimal dose is reached.

The daily dose may be taken either once daily or in two divided doses.

If you have the feeling that the effect of Epival CR is too weak or too strong, please consult your doctor or pharmacist.

The duration of treatment and the dose may vary from one person to another; they will therefore be decided by your doctor depending on the course of your illness.

Epilepsy:

In general, the treatment of epilepsy is a long-term treatment.

Monotherapy (epilepsy treatment with sodium valproate only)

Adults

The recommended dose is between 1000 and 2000 mg daily; if necessary, a higher daily dose (up to 2500 mg per day) may be prescribed by your doctor.

Use in children and adolescents

Children over 20 kg body weight:

The dose is based on the child’s weight. In general, 20 to 30 mg sodium valproate per kg body weight per day are administered (for example in case of 30 kg body weight and an average dose of 25 mg/kg: 2% tablets of 300 mg per day, or 1% tablets of 500 mg per day).

If necessary, the doctor may prescribe daily doses higher than 30 mg per kg body weight.

For children under 20 kg body weight, other presentations of Epival CR (for example an oral solution or a syrup) are available and may be prescribed instead of tablets.

The following table serves as a general dosage guideline for orientation:

Age	Body Weight	Average Dose
3 – 6 months	approx. 5.5 – 7.5 kg	150 mg per day
6 – 12 months	approx. 7.5 – 10 kg	150 – 300 mg per day
1 – 3 years	approx. 10 – 15 kg	300 – 450 mg per day
3 – 6 years	approx. 15 – 20 kg	450 – 600 mg per day
7 – 11 years	approx. 20 – 40 kg	600 – 1200 mg per day
12 – 17 years	approx. 40 – 60 kg	1000 – 1500 mg per day
Adults (including elderly patients)	approx. 60 kg and higher	1200 – 2100 mg per day

Patients with disturbed kidney and/or liver function:

Your doctor may prescribe a lower dose.

Combination therapy

If you are also taking other medicinal products to treat your illness, your doctor will adjust the dose accordingly.

Mania:

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

Initial dose

The recommended initial daily dose is 750 mg.

Average recommended maintenance daily dose

The recommended daily doses usually range between 1000 mg and 2000 mg.

Use in children and adolescents

Epival CR is not recommended for the use in children and adolescents for the treatment of mania.

ADMINISTRATION

Take the tablets whole with sufficient amounts of fluid. If gastrointestinal side-effects (e.g. nausea) occur at the beginning of treatment, you should take the tablets during or after meals. The tablets may be divided into halves, but must not be chewed or crushed.

| If you take more Epival CR ~|

Symptoms of an acute overdose may include nausea, vomiting, dizziness, sometimes also serious, or even fatal, side-effects affecting the central nervous system and breathing. If you take more tablets than you should or if a child has taken the medicine by accident, consult your doctor or go to the nearest accident and emergency department immediately. Take this leaflet and any remaining tablets with you so the doctor will know what you have taken.

Information for doctors: Advice for management of overdose is at the end of this leaflet.

| If you forget to take Epival CR ~|

If you forgot to take a dose at the right time, take it as soon as you remember. However, if you are already nearing the time for your next scheduled dose, you should skip the forgotten dose and then continue treatment as prescribed. Do not take a double dose to make up for a forgotten dose.

| If you stop taking Epival CR ~|

Do not interrupt or stop the treatment with Epival CR without consulting your doctor. This could have a negative effect on your treatment and might induce more seizures. Please discuss any signs of intolerance or changes in the course of your illness with your treating physician.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor straight away, if you notice any of the following serious side effects – you may need urgent medical treatment:

– Signs including rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. In a very small number of patients, serious skin reactions may occur and may sometimes even be life-threatening and may include blistering or bleeding of the skin around the lips, nose, eyes and genitals, or skin lesions affecting also the palms or the soles of your feet. These skin reactions may be accompanied by a feeling of being generally unwell, flu-like symptoms, fever and aching muscles.

• – Vomiting, problems with balance and coordination and feeling lethargic or less alert may be signs of an increased amount of ammonia in the blood.

• – Deep loss of consciousness (coma) may occur in very few patients.

• – A sudden illness with signs including feeling sick, being sick repeatedly, being very tired and weak, stomach pain, jaundice (yellowing of the skin or whites of the eyes), loss of appetite, or a general feeling of being unwell may be signs of liver problems and problems of the pancreas.

• – Increased tendency to bleed, or if you seem to get bruises or infections more easily.

Tell your doctor as soon as possible, if you have any of the following side effects:

• – Changes in mood (depression), confusion (occasionally followed by disturbed consciousness or associated with hallucinations or convulsions (fits)), lethargy, feeling less responsive than normal, twitching of the eyes, or loss of brain function (usually temporary)

• – Disturbance or lack of coordination affecting balance and manner of walking, limb or eye movements and/or speech; dizziness/spinning sensation

• – Drowsiness: this is often experienced when other medication used to treat epilepsy is given at the same time.

• – Dementia and memory loss (usually reversible)

• – Trembling, particularly at higher dosages

• – Pins and needles (tingling or numbness of the hands and feet)

• – Parkinson-like symptoms (such as reduced capacity of movement, trembling, increased muscular tension), or involuntary movements

• – Increased alertness, hyperactivity, aggression and inappropriate behaviour

• – Porphyria (a rare metabolic disease which may be associated with red coloration of the urine, abdominal spasms and pain as well as vomiting).

• – Double vision (rare).

Tell your doctor or pharmacist, if any of the following side effects get serious or last longer than a few days, or if you notice any side effects not listed in this leaflet:

• – Vasculitis (inflammation of the blood vessels), which may present as pain, reddening or itching

• – Menstruation disorders, e.g. irregular periods or missed periods, cysts on the ovaries, breast enlargement in men, increased growth of face or body hair, acne

• – Oedema (swelling of the hands, ankles and feet)

• – Nystagmus (rapid, uncontrollable movements of the eyes)

• – Tinnitus (buzzing, hissing, whistling, ringing or other persistent noise in the ears), hearing loss

• – Headache

• – Increased appetite leading to weight gain

• – Lack of appetite, weight loss, constipation, increased saliva

• – Feeling sick, stomach ache or diarrhoea, especially at the beginning of treatment; this can usually be helped by taking the tablets with or after food (see under 3: “Administration”).

• – Temporary hair loss has been noted in some patients. Regrowth normally begins within six months, although the hair may become curlier than before.

• – Kidney problems leading to sugar/glucose in the urine and other abnormalities, bedwetting in children, or increased need to pass urine

• – Skin changes, e.g. rash.

The following side effects have been reported:

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

• – uncontrolled trembling or shaking movements in one or more parts of your body (tremor)

• – nausea

Common (may affect up to 1 in 10 people):

• – isolated, moderate hyperammonaemia (increased levels of ammonia in the blood without abnormal liver test values)

• – especially in case of excessively high doses, treatment with valproate may cause transitory anomalies of the blood count or blood clotting disturbances

26.2020/216/GB

• – lack of enough red blood cells (anaemia)

• – increased appetite

• – weight gain

• – decreased sodium levels in the blood (hyponatraemia)

• – loss of appetite (anorexia)

• – irritability

• – seeing or sensing things that aren’t there while a person is awake and conscious (such as hearing voices)

• – confusional state

• – aggression

• – agitation

• – disturbance in attention

• – tickling/tingling sensation or numbness, trembling

• – movement disorders due to impaired regulation of muscle coordination in the brain (so-called extrapyramidal symptoms; stupor)

• – dizziness

• – sleepiness, the state of feeling drowsy, ready to fall asleep

• – trouble with memory

• – convulsions (fits)

• – headache

• – twitching of the eyes (nystagmus)

• – partly reversible tinnitus and partly reversible impairment of hearing

• – increased bleeding

• – vomiting, diarrhoea, lack of appetite or constipation may occur at the beginning of treatment

• – gingival disorder, especially gingival hyperplasia

• – upper abdominal pain

• – hypersensitivity reactions

• – nail and nail bed disorders

• – transient hair loss

• – severe abdominal cramps during a women's period

Uncommon (may affect up to 1 in 100 people):

• – reduced number of blood platelets (especially in children), transitorily severely reduced number of white blood cells (leucopenia)

• – local reactions at the injection site; nausea and drowsiness may occur a few minutes after administration, but usually resolve within a few minutes

• – severe reduction in all blood cells which can cause weakness, bruising or make infections more likely (pancytopenia)

• – increased formation of “antidiuretic” hormone (leading to increased build-up of fluid in tissue) (Syndrome of inappropriate antidiuretic hormone secretion (SIADH))

• – excessive levels of androgens in the female body (hyper-androgenaemia)

• – acne and excessive growth of facial or body hair

• – hair disorder (e.g. altered hair texture, change of hair colour, abnormal hair growth), transient hair loss

• – unconscious state

• – continual tightening and contraction of certain muscles resulting in problems walking and talking

• – loss of muscle coordination; awkward, uncoordinated walking unsteadiness when walking

• – abnormal brain function

• – lethargy (occasionally followed by disturbed consciousness and sometimes associated with hallucinations or convulsions)

• – reversible parkinsonism (tremor, stiffness and shuffling)

• – aggravated convulsions

• – pain, reddening or itching of the skin, which may be signs of an inflammation of the blood vessels (vasculitis)

• – collection of fluid around the lungs in the chest cavity, which can cause shortness of breath and may require treatment

• – increased formation of saliva (hypersalivation)

• – inflammation of the pancreas, which may take a lifethreatening course (see section 2 under “Other things you should know before taking Epival CR”)

• – severe liver damage, sometimes taking a fatal course (see section 2 “Other things you should know before taking Epival CR”)

• – rash

• – bone disorders including osteopenia and osteoporosis (thinning of the bone) and fractures. Check with your doctor or pharmacist if you are on long-term anti-epileptic medication, have a history of osteoporosis, or take steroids.

• – kidney disorder (renal insufficiency)

• – absence of menstrual period in women

• – low body temperature

• – peripheral oedema (accumulation of fluid in tissue)

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

• – tissue damage when valproate was inadvertently injected into an artery or in the area around a vein; inflammation at the injection site, pain

• – decreased production of blood cells by the bone marrow (including pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis)

• – allergic reactions (ranging from rash to hypersensitivity reactions)

• – abnormally low level of thyroid gland hormone

• – elevation of testosterone levels

• – vomiting, disturbed coordination of movements and progressive clouding of consciousness may be signs of increased ammonia levels in the blood. If such symptoms occur, consult a doctor immediately.

• – obesity

• – hyperactivity

• – abnormal behavior

• – learning disorder

• – chronic abnormal brain function

• – reversible dementia

• – loss of neurons and the connections between them

• – cognitive impairment

• – double vision

• – potentially life-threatening condition affecting less than 10% of the skin in which cell death causes the epidermis (outer layer) to separate from the dermis (middle layer; Stevens-Johnson syndrome)

• – life-threatening condition affecting greater than 30% of the skin in which cell death causes the epidermis (outer layer) to separate from the dermis (middle layer; Toxic Epidermal Necrolysis)

• – severe reaction of the skin and gut lining that may include rash and shedding or death of tissue (erythema multiforme)

• – Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)

• – systemic lupus erythematosus (a rare immune disorder)

• – allergic painful swelling of skin and mucous membranes, particularly in the face

• – breakdown of damaged skeletal muscle (rhabdomyolysis)

• – enuresis (involuntary discharge of urine)

• – inflammation of the spaces between renal tubules (tubulointerstitial nephritis)

• – reversible failure of the tubules in the kidney to reabsorb small molecules (Fanconi syndrome)

• – male infertility

• – changes on the ovaries and menstrual irregularities in women (polycystic ovarian syndrome)

• – abnormal blood clotting

• – abnormal coagulation tests

• – biotin deficiency/bi­otinidase deficiency (a rare nutritional disorder)

• – porphyria (a rare metabolic disease)

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

• – increased breast growth in men

• – transient brain affection or loss of consciousness. If you notice any of these or similar symptoms, contact a doctor as quickly as possible.

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

• – depressed states

• – increase in alertness

There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the bone) and fractures. Check with your doctor or pharmacist if you are on long-term antiepileptic medication, have a history of osteoporosis, or take steroids.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system:

Yellow Card Scheme

Website:

By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store epival cr

Keep out of the sight and reach of children.

Tightly close the container after each use.

Do not use Epival CR after the expiry date which is stated on the container. The expiry date refers to the last day of that month.

Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. contents of the pack and other information

What Epival CR contains

• – The active substance is sodium valproate. 1 prolonged-release tablet contains 300/500 mg sodium valproate.

• – The other ingredients are:

What Epival CR looks like and contents of the pack

White, oval-shaped prolonged-release tablets, with score line and engraving “CC3” / “CC5” on one side. The tablets can be divided into equal halves.

Epival CR is available in tablet container of 30, 50 or 100 tablets.

Marketing Authorisation Holder and Manufacturer G.L. Pharma GmbH, Schlossplatz 1, A-8502 Lannach

This leaflet was last updated on 18.05.2020.

Reg.no.: PL 21597/0005 (300 mg)

PL 21597/0006 (500 mg)

The following information is intended for healthcare professionals only:

Overdose

Symptoms

Symptoms and signs of massive overdose usually include coma, muscular weakness, hyporeflexia/a­reflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. However, symptoms may vary considerably. Very high plasma levels of valproic acid lead to neurological disorders, e.g. increased risk of seizures. Cerebral oedema and intracranial hypertension have been reported. Single cases of massive overdose with a fatal outcome have been published.

Management

No specific antidote is known.

Management of overdose should be symptomatic, including activities to eliminate the active substance and support of vital functions: induced vomiting, gastric lavage (up to 10 to 12 hours following ingestion) with aspiration protection and monitoring within the scope of intensive care, assisted ventilation if necessary.

Haemodialysis, haemoperfusion and forced diuresis have been used successfully, however, only the free portion of valproic acid (approx. 10%) is eliminated. Peritoneal dialysis shows little effect. Insufficient experience is available regarding the effect of charcoal haemoperfusion, total plasma replacement and plasma transfusion. Therefore intensive internistic treatment without any particular method of detoxification, especially in children, but with drug level monitoring, is recommended.

Intravenous naloxone has also been used, sometimes in association with activated charcoal given orally, for improving the patient’s state of consciousness.

GI25420GB, Epival CR 300/500 mg Tab.

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