Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: G.L. Pharma GmbH, Schlossplatz 1, 8502 Lannach, Austria
Convulex is contraindicated in the following situations:
Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).
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).
Convulex is contraindicated in the following situations:
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.
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.
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).
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.
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, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 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, the incidence of occurrence is significantly reduced and progressively decreases with age.
The concomitant use of salicylates should be avoided in children under 3 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).
Monotherapy is recommended in children under the age of 3 years when prescribing Convulex, but the potential benefit of Convulex should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks.
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’):
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.
Liver function should be measured before 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 Convulex therapy.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
As with most antiepileptic drugs, 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. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.
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 valproic acid.
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.
Haematological: Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8 Undesirable Effects).
Renal insufficiency: In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 Posology and Method of Administration and 5.2. Pharmacokinetic Properties).
Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of Convulex, the potential benefit of Convulex should be weighed against its potential risk in patients with systemic lupus erythematosus (see also section 4.8 Undesirable Effects).
Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate.
Weight gain: Convulex very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects).
Carbapenem agents: The concomitant use of valproic acid/sodium valproate and carbapenem agents is not recommended (see section 4.5).
Diabetic patients: Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.
Patients with known or suspected mitochondrial disease: 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, 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).
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.
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. Co-administration of lamotrigine and Convulex might increase the risk of rash.
Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
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.
Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to blood levels in case of combined therapy.
On the other hand, combination of felbamate and valproate may increase valproic acid plasma concentration. Valproate dosage should be monitored.
Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Convulex may need adjustment.
In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4).
Cholestyramine may decrease the absorption of valproate.
Caution is advised when using Convulex in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Valproate usually has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.
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).
Convulex should not be used in female children, in female adolescents, in women of child-bearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of child-bearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.
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.
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 dysmorphia, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalities involving various body systems.
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)
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.
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 therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy.
Valproate is excreted in human milk with a concentration ranging from 1% to 10% of total 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 Convulex therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.No adverse effects in the nursing infant have been reported. The decision to allow the patient to breast-feed should be taken with regard to all the known facts.
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 Convulex may provide seizure control such that the patient may be eligible to hold a driving licence.
Patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).
Rare cases of liver dysfunction (see section 4.4.1 Warnings).
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also 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).
Gastrointestinal disorders (nausea, gastralgia, diarrhoea) frequently occur at the start of treatment. These problems can usually be overcome by taking Convulex capsules with or after food.
Very rare cases of pancreatitis, sometimes lethal, have been reported (see section 4.4 Special Warnings and Special Precautions for Use).
Frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.
Isolated reduction of fibrinogen or reversible increase in bleeding time have been reported, usually without associated clinical signs and particularly with high doses (valproate has 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 Pregnancy and Lactation).
Allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.
Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, 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 Convulex should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered. Rarely obesity has been noted.
Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy and confusion occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Diplopia has been reported rarely.
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 other anticonvulsants, notably phenobarbitone. They have usually been reversible on withdrawal of treatment or reduction of dosage.
Very rare cases of reversible extrapyramidal symptoms including parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.
Cutaneous reactions such as exanthematous rash rarely occur with valproate. In very rare cases toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.
Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously. Also nail and nail bed disorders have been reported commonly. Hirsutism and acne have been very rarely reported.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with medicinal products containing valproate. The mechanism by which valproate affects bone metabolism has not been identified.
There have been isolated reports of a reversible Fanconi’s syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy, but the mode of action is as yet unclear.
Amenorrhoea and irregular periods have been reported. Very rarely gynaecomastia has occurred.
Vascular disorders: The occurrence of vasculitis has occasionally been reported.
Congenital malformations and developmental disorders (see section 4.4 and section 4.6).
Very rare cases of non-severe peripheral oedema have been reported.
Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 Special Warnings and Special Precautions for Use).
Reporting suspected adverse reactions after authorization 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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