Summary of medicine characteristics - SYONELL 500 MG GASTRO-RESISTANT TABLETS
^^This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1 NAME OF THE MEDICINAL PRODUCT
Syonell 500mg Gastro-Resistant Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Containing 538.12mg of valproate semisodium* per tablet (equivalent to 500mg of valproic acid).
*Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship.
Excipient(s) with known effect:
Sodium 37.03 mg (see section 4.4).
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Gastro-resistant tablet.
500mg: Pink, oval shaped, biconvex coated tablet with slight vanilla flavour, imprinted with ‘500’ on one side and plain on other side.
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 Therapeutic indications
Treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to valproate semisodium for acute mania.
4.2 Posology and method of administration
Posology
For oral administration. The tablets should be swallowed whole with a drink of water, and not crushed or chewed.
The daily dosage should be established according to age and body weight. The wide variation in individual sensitivity to valproate semisodium should also be considered.
Dosage
Manic episodes in bipolar disorder:
Adults
The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg in 2–3divided doses. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1000 and 2000 mg valproate. Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored.
Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.
Elderly
Although the pharmacokinetics of valproate semisodium are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response.
Paediatric population
The efficacy of valproate semisodium in children below 18 years of age in the treatment of manic episodes of bipolar disorder has not been established. With respect to safety information in children see section 4.8.
In patients with renal insufficiency
It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Valproate semisodium is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4).
It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2 Pharmacokinetic Properties).
In patients with hepatic insufficiency
Salicylates should not be used concomitantly with valproate semisodium since they employ the same metabolic pathway (see also sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).
Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 Contraindications and 4.4 Special Warnings and Precautions for Use).
Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome). In addition, in conjunction with valproate semisodium, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).
Female children and women of childbearing potential
Valproate semisodium must be initiated and supervised by a specialist experienced in the management of bipolar disorder. Valproate semisodium should not be used in female children or women of childbearing potential unless other treatments are ineffective or not tolerated (see section 4.3, 4.4 and 4.6).
Valproate semisodium is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (sections 4.3 and 4.4). The benefits and risks should be carefully reconsidered at regular treatment reviews (see section 4.4)
Valproate semisodium should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).
Combined Therapy (see section 4.5)
When starting Syonell in patients already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Syonell therapy should then be gradual, with target dose being reached after about 2 weeks. Faster titration may be permissible if plasma level monitoring is available. In certain cases, it may be necessary to raise the dose by 5–10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of Syonell. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.
When using Syonell with other psychotropics, a reduced dose may be required, (see section 4.5.1 Effects of Syonell on other drugs).
Optimum dosage is mainly determined by control. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2 Pharmacokinetic Properties).
4.3 Contraindications
Syonell is contraindicated in the following situations:
In pregnancy (see sections 4.4 and 4.6).
In women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.4 and 4.6).
Hypersensitivity to valproate semisodium or any other excipients listed in section 6.1.
Active liver disease
Personal or family history of severe hepatic dysfunction, drug related
Patients with known urea cycle disorders (see section 4.4).
Porphyria
In patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase y (POLG), e.g. AlpersHuttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).
4.4 Special warnings and precautions for use
To ensure the correct medication is prescribed for the patient’s condition, care must be taken not to confuse Syonell with Epilim or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets which clearly indicate specific indications for these differing medications.
Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
4.4.1 Special Warnings
Conditions of occurrence:
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation.
After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.
The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome).
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2–12 weeks.
Suggestive signs:
Clinical symptoms are essential for early diagnosis. In particular, the following conditions which may precede jaundice should be taken into consideration, especially in patients at risk (see above: ‘Conditions of occurrence’):
– non specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.
– in patients with epilepsy, recurrence of seizures.
These are an indication for immediate withdrawal of the drug. Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection:
Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease. Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant. 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 treatment. As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
Increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Pancreatitis: Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase). Young children are at particular risk; this risk decreases with increasing age. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate semisodium should be discontinued.
Female children, Women of childbearing potential and pregnant women:
Pregnancy Prevention Programme
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).
Syonell is contraindicated in the following situations:
In pregnancy (see sections 4.3 and 4.6).
In women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).
Conditions of Pregnancy Prevention Programme:
The prescriber must ensure that
Individual circumstances should be evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.
The potential for pregnancy is assessed for all female patients.
The patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details please refer to subsection contraception of this boxed warning), without interruption during the entire duration of treatment with valproate.
The patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of bipolar disorders.
The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued.
The patient understands the need to urgently consult her physician in case of pregnancy.
The patient has received the Patient Guide.
The patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).
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.
Female children
The prescribers must ensure that:
The Parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.
The parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
In patients who experienced menarche, the prescribing specialist must annually reassess the need for valproate therapy and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.
Pregnancy test
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.
Contraception
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 intrauterine 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.
Oestrogen-containing products
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 (mood control) when initiating or discontinuing oestrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.
Annual treatment reviews by a specialist
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.
Pregnancy planning.
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.
In case of pregnancy
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 prenatal medicine for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
Pharmacist must ensure that
The patient card is provided with every valproate dispensation and that the patients understand its content.
The patients are advised not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.
Educational materials
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, provide guidance regarding use of valproate in women of childbearing potential and provide details of the pregnancy prevention programmeme. 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.
Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of bipolar disorder.
As with other antiepileptic drugs, some patients with epilepsy 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).
Suicidal ideation and behaviour:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic 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 does not exclude the possibility of an increased risk for valproate semisodium.
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.
The concomitant use of valproate and carbapenem agents is not recommended.
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 y (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, opthalmoplegia, 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).
Excipients with known effect:
Sodium:
This medicinal product contains 37.03 mg sodium per tablet, equivalent to 1,8% of the WHO recommended daily intake of 2 g sodium for an adult.
4.5 Interaction with other medicinal products and other forms of interaction
4.5.1 Effects of valproate semisodium on other drugs
Valproate semisodium may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines;
therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.
No significant interaction was observed when clozapine and haloperidol were administered concurrently with valproate semisodium.
Co-administration of valproate semisodium and lithium does not appear to affect the steady state kinetics of lithium. Valproate semisodium has no effect on serum lithium levels.
Olanzapine
Valproic acid may decrease the olanzapine plasma concentration.
Valproate semisodium increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur. 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 semisodium 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 semisodium decreases phenytoin total plasma concentration.
Moreover, valproate semisodium increases phenytoin free form with possible overdose 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 semisodium was administered with carbamazepine as valproate semisodium may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate semisodium reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosage should be adjusted (lamotrigine dosage decreased) when appropriate.
Valproic acid may decrease the felbamate mean clearance by up to 16%.
– Rufinamide
Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
Propofol
Valproic acid may lead to an increased blood level of propofol. When coadministered with valproate, a reduction of the dose of propofol should be considered.
Valproate semisodium may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
Co-administration of temozolomide and valproate semisodium may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
4.5.2 Effects of other drugs on valproate semisodium
Anti-epileptics
Antiepileptics with enzyme inducing effects (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
On the other hand, combination of felbamate and valproate semisodium decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Valproate semisodium dosage should be monitored.
Anti-malarial agents
Mefloquine and Chloroquine increase valproic acid metabolism. Accordingly, the dosage of valproate semisodium may need adjustment.
Highly protein bound agents
In case of concomitant use of valproate semisodium and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
Vitamin K-dependent factor anticoagulants
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
Cimetidine or erythromycin
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Carbapenem antibiotics such as panipenem, imipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60%-100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level should be performed.
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.
Cholestyramine
Cholestyramine may lead to a decrease in plasma level of valproate when coadministered.
Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuoronidation 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.
4.5.3 Other Interactions
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
- Quetiapine
Co-administration of valproate semisodium and quetiapine may increase the risk of neutropenia/leucopenia.
4.6 Fertility, pregnancy and lactation
Valproate is contraindicated as treatment for bipolar disorder during pregnancy.
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).
Teratogenicity and developmental effects
Pregnancy exposure risk related to valproate
Both valproate monotherapy and valproate polytherapy including other antiepileptics are frequently associated with abnormal pregnancy outcomes. Available data suggest that anti-epileptic polytherapy including valproate may be 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).
Congenital malformations
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 defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies 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 the 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.
Developmental disorders
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 3040% 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 from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.
Female children and woman of childbearing potential (see above and section 4.4).
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
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.
Pregnant women
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy (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.
All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine 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 common to all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Risk in the neonate
– Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
– Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.
– Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
– Withdrawal syndrome (such as, in particular, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Breastfeeding
Valproate is excreted in human milk with a concentration ranging from 1% –10% of maternal serum levels. Haematological 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 valproate semisodium therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
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.
4.7 Effects on ability to drive and use machines
Patients should be warned of the risk of transient drowsiness, especially in cases of polytherapy or association with benzodiazepines (see section 4.5 Interactions with other Medicaments and Other Forms of Interaction).
4.8 Undesirable effects
The following CIOMS 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).
The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of valproate semisodium in the treatment of manic episodes have been identified.
Congenital malformations and developmental disorders (see sections 4.4 and 4.6).
Hepatobiliary disorders:
Common: liver injury (see section 4.4.1 )
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).
Very common: nausea,
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea
The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking valproate semisodium with or after food.
Uncommon: pancreatitis, sometimes lethal, (see section 4.4
Nervous system disorders:
Very common: tremor
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus,
Uncommon: coma*, encephalopathy*, lethargy* (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions (see section 4.4).
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder.
Sedation has been reported occasionally. In monotherapy it occurred early in treatment on rare occasions and is usually transient.
Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Psychiatric disorders:
Common: confusional state, hallucinations, aggression, agitation, disturbance in attention Rare: abnormal behaviour, psychomotor hyperactivity, learning disorder
Metabolism and nutrition disorders:
Common: hyponatraemia, weight increased.
Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4)
Rare: hyperammonaemia (see section 4.4.2 ), obesity
*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, but they are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur valproate semisodium should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2. ). In such cases further investigations should be considered.
Endocrine Disorders:
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase).
Rare: hypothyroidism (see section 4.6 )
Blood and lymphatic system disorders:
Common: anaemia, thrombocytopenia, (see section 4.4.2. ).
Uncommon: pancytopenia, leucopenia.
Rare: bone marrow failure, including red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis.
The blood picture returned to normal when the drug was discontinued.
Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (valproate semisodiumhas an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6).
Skin and subcutaneous tissue disorders:
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Reproductive system and breast disorders:
Common: dysmenorrhea
Uncommon: amenorrhea
Rare: male infertility, polycystic ovaries
Very rarely gynaecomastia has occurred.
Vascular disorders:
Common: haemorrhage (see sections 4.4.2 and 4.6 ).
Uncommon: vasculitis
Eye disorder:
Rare: diplopia
Ear and labyrinth disorders:
Common: Deafness, a cause and effect relationship has not been established.
Renal and urinary disorders:
Common: urinary incontince
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valpraote semisodium therapy, but the mode of action is as yet unclear.
General disorders and administration site conditions:
Uncommon: hypothermia, non-severe peripheral oedema.
Musculoskeletal and connective tissue disorders:
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate semisodium. The mechanism by which valproate semisodium affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2 )
Respiratory, thoracic and mediastinal disorders:
Uncommon: pleural effusion
Investigations:
Rare: Coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged), (see sections 4.4 and 4.6).
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: myelodysplastic syndrome
Paediatric population
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 of suspected adverse reactions
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
Signs of acute massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression, or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions and metabolic acidosis. hypotension and circulatory collapse/shock. A favourable outcome is usual however some deaths have occurred following massive overdose.
Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels in epileptic patients. Cases of intracranial hypertension related to cerebral oedema have beenreported.
The presence of sodium content in the Syonell formulations may lead to hypernatraemia when taken in overdose.
Hospital management of overdose should be symptomatic, including cardio-respiratogastric monitoring. Gastric lavage may be useful up to 10 to 12 hours following ingestion.
Haemodialysis and haemoperfusion have been usedsuccessfully.
Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.
In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics; Antipsychotics; Other Antipsychotics, ATC code: N05AX.
Valproate semisodium exerts its effects mainly on the central nervous system.
The most likely mode of action for valproate semisodium is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.
The effectiveness of valproate semisodium in acute mania was demonstrated in two, 3-week, double-blind, placebo-controlled trials conducted in bipolar patients. Valproate semisodium was initiated at a dose of 250mg tid and subsequently titrated up to a maximum daily dose not exceeding 2500mg; the concomitant use of a benzodiazepine was allowed during the first 10 days of treatment to manage associated symptoms such as severe agitation.
Pharmacological studies have demonstrated activity in experimental models of animal behaviour in mania.
5.2 Pharmacokinetic properties
Absorption
Following oral administration of valproate semisodium the absolute bioavailability of valproic acid approaches 100%. Mean terminal half life is about 14 hours, steady state conditions usually being achieved within 3 to 4 days. Peak plasma concentrations are achieved within 3 to 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.
Distribution
Plasma protein binding of Depakote ranges from 85 – 94% over plasma drug concentrations of 40 – 100 pg/ml. It is concentration-dependent, and the free fraction increases non-linearly with plasma drug concentration.
Placental transfer (see section 4.6)
| Valproate crosses the placental barrier in animal species and in humans: In animal species, valproate crosses the placenta to a similar extent as in humans. In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentrations in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers Metabolism Valproate semisodium is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from P-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 to 0.6L/h and is independent of hepatic blood flow.The major pathway of valproate biotransformation is glucuronidation (~ 40%), mainly via UGT1A6, UGT1A9 and UGT2B7. Elimination In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response. Haemodialysis reduces serum valproic acid concentrations by about 20%. Interaction with oestrogen-containing products Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction. | |
| 5.3 | Preclinical safety data Valproate was neither mutagenic in bacteria, nor in the mouse lymphoma assay in vitro and did not induce DNA repair in primary rat hepatocyte cultures. In vivo, however, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route of administration in humans, valproate did not induce chromosome aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand-breaks and chromosomal damage in rodents. In addition, increased sisterchromatid exchanges in epileptic patients exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in epileptic patients treated with valproate with those in untreated epileptic patients. The clinical relevance of these DNA/chromosome findings is unknown. Non-clinical data reveal no special hazard for humans based on conventional carcinogenicity studies. In repeat-dose toxicity studies, testicular degeneration/atrophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively. |
In juvenile rats, a decrease in testes weight was only observed at doses exceeding the maximum tolerated dose (from 240 mg/kg/day by intraperitoneal or intravenous route) and with no associated histopathological changes. No effects on the male reproductive organs were noted at tolerated doses (up to 90 mg/kg/day). Based on these data, juvenile animals were not considered more susceptible to testicular findings than adults. Relevance of the testicular findings to paediatric population is unknown.
In a fertility study in rats, valproate at doses up to 350 mg/kg/day did not alter male reproductive performance. However, male infertility has been identified as an undesirable effect in humans (see sections 4.6 and 4.8).
Reproductive and developmental toxicity
Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.
Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
Behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioural changes have also been observed in the second generation and those were less pronounced in the third generation of mice following acute in utero exposure of the first generation to teratogenic valproate doses. The underlying mechanisms and the clinical relevance of these findings are unknown.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Microcrystalline cellulose
Starch pregelatinised
Silicone dioxide, colloidal
Magnesium stearate
Hydroxypropylcellulose, low-substituted
Coating:
Hypromellose (E464)
Hydroxypropylcellulose (E463)
Hypromellose phthalate
Titanium dioxide (E171)
Triethyl citrate
Allura Red FD&C 40 (E129)
Indigo Carmine FD&C Blue 2 (E132)
Vanillin
Ink:
Shellac Glaze (modified) (E904)
Isopropyl alcohol
Black iron oxide (E172)
N-butyl alchol
Propylene glycol (E1520)
Ammonium hydroxide (E527)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Aluminium/PVC/Aclar blister packs containing 30, 60 or 90 tablets.
Aluminium/Aluminium blister packs containing 30, 60 or 90 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Lupin Healthcare (UK) Limited
The Urban Building, 2nd floor,
3–9 Albert Street, Slough, Berkshire,
SL1 2BE, United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 35507/0192
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
19/01/2018