Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: G.L. Pharma GmbH, Schlossplatz 1, A-8502 Lannach, Austria
Epival CR prolonged-release tablets is contraindicated in the following situations:
Treatment of epilepsy:
Treatment of bipolar disorder:
Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).
Epival CR is contraindicated in the following situations:
Treatment of epilepsy:
Treatment of bipolar disorder:
The prescriber must ensure that
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of child bearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a health care provider, to rule out unintended use in pregnancy.
Women of childbearing potential who are prescribed valproate must use effective contraception, without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea she must follow all the advice on effective contraception.
Concomitant use with oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (seizure control) when initiating or discontinuing oestrogen-containing products.
The specialist should at least annually review whether valproate is the most suitable treatment for the patient. The specialist should discuss the annual risk acknowledgement form, at initiation and during each annual review and ensure that the patient has understood its content.
For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.6). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.
For the indication bipolar disorder if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative options. The patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
Pharmacist must ensure that:
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings and provide guidance regarding use of valproate in women of childbearing potential and the details of the pregnancy prevention programme. A patient guide and patient card should be provided to all women of childbearing potential using valproate.
An annual risk acknowledgement form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Routine measurement of liver function should be undertaken before therapy and periodically during the first 6 months especially in those who seem most at risk, and those with a prior history of liver disease; such patients should have close clinical supervision. (ee section 4.8)
Liver function tests should include tests reflecting protein synthesis, particularly the prothrombin time, transaminases and/or bilirubin and/or fibrinogen degeneration products. Initially an increase in transaminases may occur, and is usually transient and responds to reduction in dosage.
Patients with biochemical abnormalities should be reassessed clinically and tests of liver function including prothrombin time should be monitored until they return to normal. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of valproate treatment.
The physician should not exclusively rely on blood chemistry, since laboratory results are not necessarily altered. Medical history and clinical condition are essential for clinical evaluation. If necessary, dose adjustments may be considered.
The treating physician should consider that in isolated cases hepatic enzymes may be transiently increased even without any liver function disorder, particularly upon treatment initiation.
Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid or sodium valproate. Patients most at risk are children, particularly those under the age of three suffering from severe seizure disorders. The risk of liver damage is particularly increased with combination therapy with several antiepileptic agents or in the presence of organic brain disease, mental retardation, congenital metabolic and/or degenerative disorders. Monotherapy is to be preferred in this group of patients and particular caution is required.
The majority of cases associated with liver damage occurred during the first 6 months of therapy, predominantly between weeks 2 and 12. Incidence was observed to significantly decrease in children above the age of 3 years.
The outcome of these disorders may be fatal. Concurrent development of hepatitis and pancreatitis increases the risk of fatal outcome.
Clinical symptoms are more helpful than laboratory investigations in the early stages of hepatic failure.
If severe liver function disorder or pancreatic damage are suspected, valproate has to be withdrawn immediately. As a matter of precaution other concomitant medication should also be discontinued, if it may cause similar adverse reactions due to shared metabolic pathways. In isolated cases the clinical condition may worsen despite the above-mentioned precautions.
Awareness of the potential clinical symptoms is essential for early diagnosis. The following symptoms and signs which may precede hepatic damage should be considered especially in case of patients at risk:
These are an indication for immediately stopping administration of the medicinal product.
Patients (or their family, for children) should be instructed to contact a physician immediately if such symptoms or signs occur. In this case clinical examination and assessment of liver function have to be performed immediately.
In patients with hepatic dysfunction any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway and thus increase the risk of hepatic failure (see section 4.5).
Prior to initiation of therapy and also before surgery and in case of haematoma or spontaneous bleeding, clinicians should assure themselves, using appropriate blood tests (full blood cell count including platelet count, bleeding time and coagulation tests), that there is no undue potential for bleeding complications. (see also section 4.8.). Caution should be exercised if clearly prolonged thromboplastin time (reduced Quick’s time) is associated with other altered laboratory results such as decreased fibrinogen level, decreased coagulation factors, increased bilirubin or increased hepatic enzymes.
Cases of severe pancreatitis, sometimes associated with fatalities, have been very rarely reported The risk of fatal outcome is highest in infants and decreases with increasing age. Severe seizures or severe neurological impairment with concomitant anticonvulsant therapy may be risk factors for severe pancreatitis. Hepatic failure with pancreatitis increases the risk of fatal outcome. Patients should be advised to consult their doctor immediately if they develop symptoms of pancreatitis (e.g. abdominal pain, nausea and vomiting). Medical evaluation (including measurement of serum amylase) should be undertaken in patients presenting with symptoms suggestive of pancreatitis, and sodium valproate should be discontinued if pancreatitis is diagnosed. Patients with prior history of pancreatitis should have close clinical supervision (see section 4.8).
During long-term therapy in combination with other antiepileptics, particularly phenytoin, symptoms and signs of brain damage (encephalopathy) may develop (increased seizure frequency, lack of drive, stupor, muscle weakness, motor disturbances [choreatiform dyskinesias], severe EEG alterations).
Valproate very commonly causes weight gain, which may be marked and progressive. All patients should be warned of this risk at the initiation of therapy and appropriate strategies adopted to minimise weight gain.
In rare cases valproate may induce systemic lupus erythematosus or aggravate preexisting lupus erythematosus. In patients with systemic lupus erythematosus valproate should be used only after rigorous benefit-risk assessment.
Treatment with valproate may cause hyperammonaemia. Therefore ammonia and valproate serum levels should be determined upon manifestation of symptoms such as apathy, somnolence, vomiting, hypotension or increase in seizure frequency; valproate doses may need to be reduced.
When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia induced by valproate.
Patients with a history of bone marrow damage have to be closely monitored.
In patients with renal insufficiency dose reduction may be necessary. Doses should be adjusted according to the clinical response, since monitoring of plasma concentrations may be misleading.
Patients with preexisting carnitine-palmitoyl transferase (CPT-)II deficiency should be warned of an increased risk of rhabdomyolysis developing with valproate therapy.
In infants younger than 3 years monotherapy with valproate is recommended. Prior to therapy start the benefit of antiepileptic treatment has to be weighed against the risk of liver damage or pancreatitis. Concomitant use of salicylates has to be avoided in these patients due to the risk of hepatotoxicity.
Dependent on its plasma concentration valproate may displace thyroid hormones from plasma protein binding sites and increase their metabolism which may lead to the false presumption diagnosis of hypothyroidism.
Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positive results in the urine testing of possible diabetics.
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
The concomitant use of valproic acid/sodium valproate and carbapenem agents is not recommended (see section 4.5).
As with other antiepileptics, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions, with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).
This medicinal product contains 42 mg sodium per prolonged-release tablet, equivalent to 2.1 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Valproate may potentiate the effect of other psychotropics such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and dosage should be adjusted when appropriate. The combination with clonazepam may induce absences.
Valproate does not affect serum concentrations of lithium.
Valproate may potentiate the effects of alcohol. Therefore the consumption of alcohol should be avoided during valproate therapy.
Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate decreases phenytoin total plasma concentration. Moreover valproate increases phenytoin free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate may reduce lamotrigine metabolism and increase its mean half-life, dosages should be adjusted (lamotrigine dosage decreased) when appropriate. The combination of lamotrigine and valproate may increase the risk of (severe) skin reactions, especially in children. Therefore clinical monitoring and dose reduction of lamotrigine (as necessary) are recommended.
Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
The anticoagulant effect of warfarin, other coumarin anticoagulants and the anti-platelet effect of acetylsalicylic acid may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored during oral anticoagulation.
Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Valproic acid may increase the serum level of felbamate by approximately 50% by reducing the average clearance of felbamate by up to 16 %. Dosage has to be adjusted according to clinical monitoring.
In healthy test persons valproate displaced diazepam from the plasma albumin bond and inhibited its metabolism. In combination treatment the concentration of unbound diazepam may be increased and the plasma clearance and distribution volume of the free diazepam fraction lowered (by 25%; 20%). However, the half life remains unchanged.
In healthy individuals, simultaneous treatment with valproate and lorazepam led to a reduction in the plasma clearance of lorazepam by up to 40%.
Concomitant administration of valproate with topiramate and acetazolamide has been associated with encephalopathy and/or hyperammonaemia. Patients should therefore be monitored as appropriate.
Valproate may reduce plasma levels of olanzapine.
Valproate may cause plasma levels of rufinamide to increase. This effect depends on valproate plasma levels. Caution should be exercised, especially in children, because this patient group is more likely to be affected by this interaction.
Valproate may cause propofol blood concentrations to increase. In case of concomitant use with valproate the dose of propofol has to be reduced.
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%.
Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, primidone, carbamazepine) may decrease valproic acid plasma concentrations. Dosages should be adjusted according to blood levels in case of combined therapy.
Upon concomitant use of valproate with phenytoin or phenobarbital the plasma levels of valproic acid metabolites may increase. Therefore patients under combined treatment with these substances should be closely monitored for signs or symptoms of hyperammonaemia.
Combined use of felbamate and valproate decreases valproate clearance by 22 – 50% and may thus increase valproate serum levels. Valproate dosage should be adjusted on the basis of monitoring.
Caution should be exercised since both mefloquine and chloroquine may lower the seizure threshold. In addition, mefloquine may decrease valproate levels and thus possibly precipitate epileptic seizures during combined therapy. The dosage of valproate may need to be adjusted.
Highly protein-bound agents like acetylsalicylic acid may displace valproic acid from its binding sites and increase the level of free valproic acid in plasma. Concomitant use of medicinal products containing valproate with those containing acetylsalicylic acid should be avoided in children under the age of 12 years and may be considered in adolescents only after careful benefit-risk assessment.
In case of concomitant use of valproate with cimetidine or erythromycin, plasma levels of valproic acid may be increased as a result of reduced hepatic metabolism.
Decreases in blood levels of valproic acid have been reported when carbapenem agents were co-administered, resulting in a decrease in valproic acid levels by 60-100% within about two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproate is not considered to be manageable and should therefore be avoided (see 4.4). If treatment with this group of antibiotics is essential, close monitoring of valproic acid blood levels should be performed.
Rifampicin may decrease valproic acid blood levels, resulting in decreased therapeutic effect. Therefore valproate dosage adjustment may be necessary if co-administered with rifampicin.
Cholestyramine may decrease the absorption of valproate.
Caution is recommended since concomitant use of fluoxetine may alter (increase or decrease) serum levels of valproic acid. Therefore serum level monitoring of valproic acid is recommended.
Concomitant use of valproate with protease inhibitors such as lopinavir and ritonavir may cause the levels of valproic acid metabolites to decrease.
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives
Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
Co-administration of valproate with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of valproate with potential decrease in clinical efficacy.
Therefore, caution is advised when metamizole and valproate are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.
Caution is advised when using sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Pharmaceuticals with a potential hepatotoxic effect as well as alcohol may increase the liver toxicity of valproic acid.
As valproate is predominantly excreted renally in the form of ketone bodies, the possibility of false positive results of a test for ketone body excretion in diabetic patients tested for ketoacidosis should be considered.
Concomitant use of valproate and quetiapine may increase the risk of neutropenia/leukopenia.
Valproic acid may cause displacement of thyroid hormones from protein binding sites, enhancing their metabolisation. This may lead to a false presumption diagnosis of hypothyroidism.
Valproate is contraindicated as treatment for bipolar disorder during pregnancy. Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy. Valproate is contraindicated for use in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.4).
Valproate therapy must not be discontinued without the approval of a physician. Sudden withdrawal of therapy or uncontrolled dose reduction may precipitate epileptic seizures causing harm to the pregnant woman and/or the unborn child.
Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.
Valproate was shown to cross the placental barrier both in animal species and in humans (see section 5.2).
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).
Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16 – 13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube effects, facial dysmorphia, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple malformations anomalities involving various body systems.
In utero exposure to valproate may also result in hearing impairment or deafness due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases did not recover.
In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long term outcomes.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).
Available data point to an increased incidence of minor and major malformations (see above) in children born to mothers under valproate therapy as compared to other antiepileptic treatment.
Oestrogen-containing products:
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4 and 4.5).
If a woman plans a pregnancy:
For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.
For the indication bipolar disorder if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4).
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy, it is recommended to:
All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy. Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Valproate is excreted in human milk with a concentration ranging from 1% and 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Epival CR therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8). Valproate administration may also impair fertility in men (see section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Use of Epival CR prolonged-release tablets may provide seizure control such that the patient may be eligible to hold a driving license.
However, patients should be warned when driving a vehicle or using machines of the risk of transient drowsiness especially in cases of anticonvulsant polytherapy or association with benzodiazepines.
The following frequency rating is used, when applicable: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from available data).
| System organ class | Very common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | myelodysplastic syndrome | |||
| Blood and lymphatic system disorders | anaemia, thrombocytopenia | pancytopenia**, leucopenia** | bone marrow dysfunction (including pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis) | |
| Immune system disorders | allergic reactions (ranging from rash to hypersensitivity reactions) | |||
| Endocrine disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenaemia (hirsutism, virilism, acne, male alopecia and/or increased androgen level) | Hypothyroidism Increase in testosterone levels | ||
| Metabolism and nutrition disorders | hyponatraemia, anorexia**, increased appetite**, weight gain** | hyperammonaemia**, obesity | ||
| Psychiatric disorders | irritability*, hallucinations*, confusional state*, aggression*, agitation*, disturbance in attention* | abnormal behaviour*, psychomotor hyperactivity*, learning disorder* | ||
| Nervous system disorders | tremor** | extrapyramidal disorder, stupor**, somnolence**, convulsions, memory impairment, headache, nystagmus, dizziness | coma**, spasticity, ataxia, encephalopathy, lethargy**, reversible parkinsonism, paraesthesia, aggravated convulsions (see section 4.4) | chronic encephalopathy**, reversible dementia**, cerebral atrophy**, cognitive impairment diplopia |
| Ear and labyrinth disorders | hearing loss | |||
| Vascular disorders | haemorrhage | vasculitis | ||
| Respiratory, thoracic and mediastinal disorders | pleural effusion | |||
| Gastrointestinal disorders | nausea | vomiting, gingival disorder, especially gingival hyperplasia, upper abdominal pain**, diarrhoea** | hypersalivation, pancreatitis** | |
| Hepatobiliary disorders | impaired hepatic function (see section 4.4) | |||
| Skin and subcutaneous tissue disorders | hypersensitivity reactions, transient and/or dose-related hair loss, nail and nail bed disorders | angioedema, rash, hair disorder (e.g. altered hair texture, change of hair colour, abnormal hair growth) | Toxic Epidermal Necrolysis, Stevens-J ohnson syndrome, Erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) | |
| Musculoskeletal and connective tissue disorders | decreased bone mineral density**, osteopenia**, osteoporosis and fractures** | systemic lupus erythematosus, rhabdomyolysis | ||
| Renal and urinary disorders | urinary incontinence | renal insufficiency | Enuresis*, tubulo- interstitial nephritis, reversible Fanconi syndrome** | |
| Reproductive system and breast disorders | dysmenorrhoea | amenorrhoea | male infertility, polycystic ovarian syndrome | |
| General disorders and administration site conditions | hypothermia, peripheral oedema | |||
| Investigations | coagulation factors decreased**, abnormal coagulation tests** biotin deficiency / biotinidase deficiency |
* These undesirable reactions have been observed predominantly in children and adolescents.
Valproic acid inhibits the second stage of platelet aggregation leading to prolongation of bleeding time and frequently to thrombocytopenia. These are usually associated with doses above those recommended and are reversible. Thrombocytopathia due to a deficiency in factor VIII/von Willebrand factor may also lead to a prolongation of bleeding time. Isolated reduction of fibrinogen may also occur.
Frequently mild reversible bone marrow suppression may occur. Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations. Agranulocytosis, occasionally lymphocytosis may occur. Red cell hypoplasia and pancytopenia have been reported rarely, leucopenia has been reported commonly; the blood picture returned to normal when the drug was discontinued.
Hyperammonaemia without changes in liver function tests may occur. Isolated and moderate hyperammonaemia may occur frequently, is usually transient and should not cause treatment discontinuation. However, it may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur sodium valproate should be discontinued. Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4). In such cases further investigations are recommended.
Weight increase should be closely monitored since this may pose a risk for the development of polycystic ovarian syndrome. Anorexia or increased appetite may also occur.
Depression may occur with the frequency not known.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Paraesthesias have been reported. Postural fine tremor, somnolence, ataxia and vertigo may occur as transient and/or dose-dependent effects.
Sedation has been reported, usually when in combination with other anticonvulsants. In monotherapy it has occurred early in treatment on rare occasions and is usually transient. Lethargy, occasionally progressing to stupor, and confusion up to transient coma (encephalopathy) sometimes with associated hallucinations or convulsions hasbeen reported. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
Encephalopathy may develop shortly after the use of valproate-containing medicinal products. This effect is reversible upon discontinuation of the drug; its pathogenesis remains unclear. In association with this effect increased ammonium levels and, with concomitant use of phenobarbital, increased levels of phenobarbital have been reported.
Chronic encephalopathies with neurological symptoms and disorders of higher cortical functions may occur especially with larger doses or polytherapy. The pathogenesis of these effects remains unclear.
Cases of reversible extrapyramidal symptoms including parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported.
Tinnitus and hearing loss, either reversible or irreversible, have been reported, though a causal relationship has not been established.
Cases of pancreatitis, sometimes fatal, have been reported. The risk is considerably increased in children, especially under combination therapy with other antiepileptic agents (see section 4.4). Appetite may increase and valproate very commonly causes weight gain which may be marked and progressive. (see section 4.4) Weight loss has been reported. Frequently at the start of treatment minor gastrointestinal irritation, upper abdominal pain and nausea may occur. These problems can usually be overcome by taking Epival CR prolonged-release tablets with or after food or by using enteric-coated sodium valproate capsules. Vomiting, diarrhoea, anorexia and constipation may occur.
Initially transient increases of transaminases may occur. Uncommonly severe hepatic damage has been reported after the intake of sodium valproate, occasionally with fatal results (see section 4.4). Rarely porphyria has been reported.
Transient hair loss has commonly been noted in some patients, but is dose dependent. Regrowth normally begins within six months, although the hair may become more curly than previously.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with sodium valproate. The mechanism by which sodium valproate affects bone metabolism has not been identified.
A reversible Fanconi´s syndrome (a defect in proximal renal tubular function giving rise to metabolic acidosis, glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy has been reported, but the mode of action is as yet unclear.
Very rarely, gynaecomastia has occurred.
Coagulation factors may be decreased, abnormal coagulation tests (e.g. prolonged prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, or INR prolonged) are possible.
Congenital malformations and developmental disorders may occur (see section 4.4 and section 4.6).
The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see Section 4.4). Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population. Based on a limited number of post-marketing cases, Fanconi Syndrome, enuresis and gingival hyperplasia have been reported more frequently in paediatric patients than in adult patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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