MICROPAKINE LP 750 mg LP Granules in sachet-dose Sachet/30

▼This medicine is subject to additional monitoring which will allow rapid identification of new safety information. Healthcare professionals should report any suspected adverse reactions. See section Adverse effects for the reporting procedures for adverse reactions.

Prolonged-release granules.
Sachet-dose. Box of 30.

For 1 sachet-dose:

Sodium valproate: 750,00 mg
in the form of sodium valproate: 500,06 mg
and valproic acid: 217,75 mg

Excipient with known effect :

This medicine contains sodium (see section Warnings and precautions).

Excipients:

In adults:

Either as monotherapy or in combination with another antiepileptic treatment:

• Treatment of generalised epilepsies: clonic, tonic, tonic-clonic, absence seizures, myoclonic seizures, atonic seizures and Lennox-Gastaut syndrome.
• treatment of partial epilepsies: partial seizures with or without secondary generalisation.

In children:

Either as monotherapy or in combination with another antiepileptic treatment:

• Treatment of generalised epilepsies: clonic, tonic, tonic-clonic, absence seizures, myoclonic seizures, atonic seizures and Lennox-Gastaut syndrome.
• treatment of partial epilepsies: partial seizures with or without secondary generalisation.

In children:

• Prevention of seizure recurrence after one or more febrile convulsions presenting the criteria of complicated febrile convulsions, in the absence of efficacy of intermittent prophylaxis with benzodiazepines.

Female children and women of childbearing potential

Valproate treatment must be initiated and monitored by a physician specialised in epilepsy management with experience.

Valproate must not be used in female children and women of childbearing potential unless there is no efficacy or intolerance to other treatments. In this case, valproate must be prescribed and dispensed in accordance with the valproate pregnancy prevention programme (see sections Contraindications and Warnings and precautions).

Adolescents and men of childbearing potential

It is recommended that valproate treatment be initiated and monitored by a physician specialised in epilepsy management with experience (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding).

MICROPAKINE L.P. is a pharmaceutical form particularly suited to children (when they are able to swallow soft foods) and to adults with swallowing problems.

MICROPAKINE L.P. is a prolonged-release formulation of DEPAKINE that reduces peak plasma concentrations and ensures more regular plasma concentrations over the nychthemeron.

Among the oral pharmaceutical forms, the syrup, oral solution and prolonged-release granule forms are particularly suitable for administration to children under 11 years.

Dosage

The initial daily dosage is usually 10-15 mg/kg, then doses are increased up to the optimal dosage (see "Initiation of treatment").

The average dosage is 20 to 30 mg/kg per day. However, when seizure control is not achieved at this dosage, the dose may be increased and patients must be closely monitored.

• In infants and children, the usual dosage is 30 mg/kg per day.  
• In adults, the usual dosage is 20 to 30 mg/kg per day.  
• In elderly patients, the dosage must be determined according to seizure control.  

The daily dosage must be established according to age and body weight; however, the wide variability of individual sensitivity to valproate must be taken into account.

No good correlation has been established between the daily dose, serum concentrations and the therapeutic effect: the dosage must be determined essentially according to the clinical response. Determination of plasma valproic acid levels may be considered in addition to clinical monitoring when seizure control is not achieved or when adverse effects are suspected. The therapeutic efficacy range is usually between 40 and 100 mg/L (300 to 700 μmol/L).

Patients with renal impairment:

In patients with renal impairment, it may be necessary to reduce the dose, and in patients on haemodialysis, it may be necessary to increase it. Sodium valproate is dialysable (see section Overdose). The dose must be adjusted according to the patient's clinical monitoring (see section Warnings and precautions).

Method of administration

Oral use.

The daily dose is to be administered in 1 or 2 doses, preferably during meals.

Administration as a single dose is possible in the case of well-controlled epilepsy.

MICROPAKINE L.P. must be administered by sprinkling it on a soft food or a drink, cold or at room temperature (yogurt, orange juice, compote...).

MICROPAKINE L.P. must not be administered with hot foods or hot drinks (soup, coffee, tea...).

MICROPAKINE L.P. must not be administered in a feeding bottle because the granules may block the teat.

When MICROPAKINE L.P. is taken with liquids, granules which may remain stuck to the glass, it is recommended to rinse the glass with a little water and drink it.

In all cases, the mixture must be swallowed immediately and not chewed. It must not be stored for later use.

Given the prolonged-release process and the nature of the excipients in the formula, the inert matrix of the granules is not absorbed by the digestive tract; it is eliminated in the stools, the active ingredients having been released beforehand.

Initiation of treatment

• In patients for whom adequate control has been obtained with the immediate-release or prolonged-release forms of DEPAKINE, in case of substitution by MICROPAKINE L.P., the daily dose must be maintained.
• If the patient is already on treatment and receiving other antiepileptics, gradually introduce MICROPAKINE L.P. to reach the optimal dose in about two weeks, then possibly reduce the associated therapies depending on the control obtained.
• If the patient is not receiving other antiepileptics, the dosage increase is preferably carried out in successive steps every 2 or 3 days so as to reach the optimal dose in approximately one week.
• If necessary, the association of other antiepileptics must be carried out gradually (see section Interactions).

• Pregnant women, except in the absence of an appropriate therapeutic alternative (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding).
• Women of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding).
• History of hypersensitivity to valproate, divalproate, valpromide or to any of the excipients mentioned in section Composition.
• Acute hepatitis.
• Chronic hepatitis.
• Personal or family history of severe hepatitis, in particular drug-induced.
• Hepatic porphyria.
• Patients with known urea cycle disorders (see section Warnings and precautions).
• Patients with a primary systemic carnitine deficiency, not corrected (see section Warnings and precautions "Patients at risk of hypocarnitinaemia").
• Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma (POLG), e.g. Alpers-Huttenlocher syndrome, and in children under two years of age suspected of having a POLG-related disorder (see section Warnings and precautions).
• Association with St John's wort (see section Interactions).

Special warnings

Pregnancy prevention programme

Valproate is a potent teratogen causing a high risk of congenital malformations and neurodevelopmental disorders in children exposed in utero to valproate (see section Fertility, pregnancy and breastfeeding). Valproate must not be used in female children and women of childbearing potential unless there is ineffectiveness or intolerance to other treatments. If no other treatment is possible, comply with the pregnancy prevention programme below.

MICROPAKINE L.P. is contraindicated in the following cases: In pregnant women, except in the absence of an appropriate therapeutic alternative (see sections Contraindications and Fertility, pregnancy and breastfeeding). In women of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see sections Contraindications and Fertility, pregnancy and breastfeeding).

Conditions of the pregnancy prevention programme

The prescriber must ensure that: individual situations are assessed on a case-by-case basis, involving the patient in the discussion to ensure her commitment, discussing therapeutic options and ensuring that she has understood the risks and the measures necessary to reduce these risks; the risk of pregnancy is assessed in all female patients; the patient has fully understood and is aware of the risks of congenital malformations and neurodevelopmental disorders, including the extent of these risks for children exposed to valproate; in utero in utero; the patient understands the need to carry out a pregnancy test before starting treatment and during treatment, as needed; the patient has been counselled on contraception and is able to comply with the need to use effective contraception (for more details, see the sub-section "Contraception" in this box), without interruption, throughout the entire duration of valproate treatment; the patient understands the need for an experienced specialist physician in the management of epilepsy to regularly reassess the treatment (at least every year); the patient understands the need to consult her doctor as soon as she is considering a pregnancy in order to discuss it in good time and to use alternative therapeutic options before conception, and this before stopping contraception; the patient understands the need to urgently consult her doctor in case of pregnancy; the patient has received the patient information leaflet; the patient has acknowledged that she has understood the risks and necessary precautions associated with the use of valproate (shared information attestation).

These conditions also apply to women who are not sexually active, unless the prescriber considers that there are indisputable reasons indicating that there is no risk of pregnancy.

Female children

Prescribers must ensure that parents/caregivers of female children understand the need to contact the specialist physician as soon as the first menstruation occurs in the female child using valproate. The prescriber must ensure that parents/caregivers of female children who have had their first menstruation receive complete information on the risks of congenital malformations and neurodevelopmental disorders, including the magnitude of these risks, for children exposed to valproate in utero. In patients in whom the first menstruation has occurred, the prescribing specialist physician must reassess annually the need for valproate treatment and consider all alternative therapeutic options. If valproate is the only appropriate treatment, the need to use effective contraception and all other conditions of the pregnancy prevention programme must be discussed. All efforts must be made by the specialist physician to switch to an alternative treatment in female children, and this before puberty or adulthood.

Pregnancy test

Pregnancy must be ruled out before initiating valproate treatment. Valproate treatment must not be initiated in women of childbearing potential without obtaining a negative pregnancy test (plasma pregnancy test with a sensitivity of at least 25 mIU/mL), confirmed by a healthcare professional, in order to eliminate any possibility of unintentional use of the product during pregnancy. This pregnancy test must be repeated at regular intervals during treatment.

Contraception Women of childbearing potential receiving valproate must use effective contraception, without interruption and throughout the entire duration of valproate treatment. These patients must receive complete information on pregnancy prevention, as well as contraceptive counselling if they do not use effective contraception. At least one effective contraceptive method (preferably a method whose effectiveness does not depend on the user, such as an intrauterine device or an implant), or two complementary contraceptive methods including a barrier method, must be used. When choosing the contraceptive method, individual situations must be examined on a case-by-case basis, involving the patient in the discussion to ensure her commitment and compliance with the chosen measures. All advice relating to effective contraception must be followed, even in case of amenorrhoea.

Oestrogen-containing medicinal products

Concomitant use with oestrogen-containing medicinal products, including oestrogen-containing hormonal contraceptives, may potentially lead to a decrease in the effectiveness of valproate (see section Interactions). Prescribing physicians must monitor the clinical response (seizure control) when starting or stopping oestrogen-containing medicinal products.

Conversely, valproate does not reduce the effectiveness of hormonal contraceptives.

Annual evaluation of the treatment by a specialist physician

The specialist physician must reassess the valproate treatment at least annually to verify whether it remains the most appropriate treatment for the patient.

The specialist physician must discuss the shared information attestation at the time of treatment initiation and at each annual review, and must ensure the patient has understood its content. The shared information attestation must be duly completed and signed by the prescriber and the patient (or her legal representative).

Pregnancy planning

In women planning a pregnancy, an experienced specialist physician in the management of epilepsy must reassess valproate treatment and consider all alternative therapeutic options. All efforts must be made to switch to an appropriate alternative treatment before conception and this, before contraception is stopped (see section Fertility, pregnancy and breastfeeding).

If a change of treatment is not possible, the patient should receive additional counselling regarding the risks that valproate poses to the unborn child, in order to help her make an informed decision concerning her family plans.

In case of pregnancy

In case of pregnancy in a woman using valproate, she must be immediately referred to a specialist physician in order to reassess valproate treatment and consider alternative options. Patients whose pregnancy was exposed to valproate, as well as their partners, must be referred to a physician specialised in or experienced in teratology for assessment and counselling (see section Fertility, pregnancy and breastfeeding).

The pharmacist must ensure that: the patient card is given with each dispensing of valproate and that patients understand its content; patients are informed not to stop valproate treatment on their own and to immediately contact a specialist physician if they are planning or suspect a pregnancy.

Information materials

In order to help healthcare professionals and female patients avoid any foetal exposure to valproate, the marketing authorisation holder provides them with information materials aimed at reinforcing the warnings regarding the teratogenicity (congenital malformations) and foetotoxicity (neurodevelopmental disorders) of valproate, and at delivering recommendations to women of childbearing potential regarding the use of valproate, as well as details of the pregnancy prevention programme. A patient card and a patient information leaflet must be provided to all female patients using valproate.

A shared information acknowledgement form must be used, duly completed and signed at the time of treatment initiation and at each annual reassessment of valproate treatment by the specialist physician and the patient (or her legal representative).

Use in adolescents and men of reproductive potential

A retrospective observational study suggests an increased risk of neurodevelopmental disorders (NDD) in children whose father was treated with valproate in the 3 months preceding conception compared with those whose father was treated with lamotrigine or levetiracetam. However, other studies do not suggest an increased risk of NDD after paternal exposure to valproate. Consequently, the available evidence is conflicting and the causal role of valproate is uncertain (see section Fertility, pregnancy and breastfeeding).

As a precautionary measure, the prescriber must inform adolescents and men of reproductive potential of this potential risk (see section Fertility, pregnancy and breastfeeding) and discuss with them: the need to use effective contraceptive measures during valproate treatment and for at least three months after its discontinuation, including for their partner, not to donate sperm during valproate treatment and for at least three months after discontinuation of valproate (see section Fertility, pregnancy and breastfeeding).

Valproate treatment in adolescents and men of reproductive potential must be regularly reassessed by the prescriber to determine whether valproate remains the most appropriate treatment. For male patients planning to conceive a child, therapeutic alternatives must be considered and discussed with patients. Individual situations must be assessed on a case-by-case basis. It is recommended to seek advice from a physician specialised in the management of epilepsy.

Risk minimisation materials are available for healthcare professionals as well as for adolescents and men of reproductive potential.

A shared information acknowledgement form must be used, duly completed and signed at the time of treatment initiation by the specialist physician and at each annual reassessment of valproate treatment by any physician and the patient (or his legal representative).

A patient information brochure must be provided to adolescents and men of reproductive potential using valproate.

Worsening of seizures

As with other antiepileptic drugs, valproate may be followed, instead of an improvement, by a reversible worsening of the frequency and severity of seizures (including status epilepticus) or the appearance of new types of seizures in the patient. In case of worsening seizures, the patient should be advised to immediately consult their physician (see section Adverse effects).

These seizures must be distinguished from those that may occur during a pharmacokinetic interaction (see section Interactions), toxicity (hepatopathy or encephalopathy - see sections Warnings and precautions and Adverse effects) or overdose.

As this medicine is transformed in the body into valproic acid, it should not be combined with other medicines undergoing the same transformation in order to avoid an overdose of valproic acid (for example: divalproate, valpromide).

Severe hepatic disorders

Conditions of occurrence

Hepatic disorders with a severe course, sometimes fatal, have been reported exceptionally.

Infants and young children under 3 years of age with severe epilepsy, in particular epilepsy associated with brain lesions, mental retardation and/or congenital metabolic disease, including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections Contraindications and Warnings and precautions) or a degenerative disease of genetic origin, are the most exposed to this risk. Beyond the age of 3 years, the incidence of occurrence decreases significantly and progressively declines with age.

In the vast majority of cases, these hepatic disorders have been observed during the first 6 months of treatment, most often between the 2th and 12th week and, generally during antiepileptic polytherapy.

Suggestive signs

Early diagnosis remains primarily based on clinical findings. In particular, 2 types of manifestations that may precede jaundice should be considered, especially in at-risk patients (see "Conditions of occurrence"):

• on the one hand, non-specific general signs, generally of sudden onset such as asthenia, anorexia, malaise, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain,
• on the other hand, a reappearance of epileptic seizures although the treatment is being correctly followed.

It is recommended to inform the patient, or his family if the patient is a child, that the onset of such a picture must prompt an immediate consultation. This consultation will include, in addition to the clinical examination, the immediate performance of a biological check of liver functions.

Detection

Monitoring of liver function must be carried out before the start of treatment and regularly during the 6 first months of treatment, particularly in patients at risk.

In case of modification of associated treatments known for their hepatic toxicity (increase in dose or new treatment), biological liver monitoring must be set up again (see also section Interactions on the risk of liver damage with salicylate derivatives, other anticonvulsants including cannabidiol).

Among the standard tests, those reflecting protein synthesis and in particular the PT (prothrombin rate) are the most relevant. Confirmation of an abnormally low prothrombin rate, especially if accompanied by other biological abnormalities (significant decrease in fibrinogen and coagulation factors, increase in bilirubin, elevation of transaminases - see sub-section "Precautions for use"), must lead to stopping treatment with this medicine (as well as, as a precaution and if co-prescribed, salicylate derivatives, since they use the same metabolic pathway).

Pancreatitis

Cases of pancreatitis, sometimes fatal in outcome, have been very rarely reported. They may occur regardless of age and duration of treatment, with young children appearing to be particularly exposed to this risk.

Pancreatitis with an unfavourable outcome is generally observed in young children, or in patients with severe epilepsy, brain lesions or antiepileptic polytherapy.

Liver failure associated with pancreatitis increases the risk of a fatal outcome.

In case of acute abdominal pain syndrome as well as digestive manifestations such as nausea, vomiting and/or anorexia, the diagnosis of pancreatitis must be considered and, in case of elevated pancreatic enzymes, treatment must be interrupted while implementing the appropriate alternative therapeutic measures.

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptics for several indications. A meta-analysis of randomised, placebo-controlled trials of antiepileptics also showed a slight increase in the risk of suicidal ideation and behaviour. The causes of this risk are not known and the data available do not exclude the possibility of an increase in this risk for valproate.

Consequently, patients must be closely monitored for any signs of suicidal ideation and behaviour and appropriate treatment must be considered. Patients (and their carers) should be advised to seek medical advice should signs of suicidal ideation and behaviour occur.

Patients with known or suspected mitochondrial disease

Valproate may trigger or worsen clinical signs of underlying mitochondrial disease caused by mutations in mitochondrial DNA as well as in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG).

In particular, cases of valproate-induced acute liver failure and related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the POLG gene, e.g. Alpers-Huttenlocher syndrome.

POLG-related disorders should be suspected in patients with a family history or symptoms suggestive of a POLG-related disorder, including, among others, unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delay, psychomotor regression, sensory-motor axonal neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or migraine with occipital aura. For a diagnostic evaluation of such disorders, POLG mutation testing should be performed, in accordance with current clinical practice (see section Contraindications).

Severe cutaneous adverse reactions and angioedema:

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema have been reported in association with valproate treatment. Patients must be informed of the signs and symptoms of serious skin manifestations and must be closely monitored.

If signs of severe cutaneous adverse reactions or angioedema are observed, rapid assessment is required and treatment must be discontinued if a diagnosis of severe cutaneous adverse reactions or angioedema is confirmed.

Drug interactions

The use of this medicine is not recommended in combination with lamotrigine and/or penems (carbapenems) (see section Interactions).

Cognitive or extrapyramidal disorders

Cognitive or extrapyramidal disorders may be associated with imaging of cerebral atrophy. Such a clinical picture may thus be confused with a dementia-type disease or Parkinson's disease. These disorders are reversible on discontinuation of treatment (see section Adverse effects).

Information related to the presence of sodium

This medicine contains 69 mg of sodium per sachet-dose, which is equivalent to 3,5 % of the maximum daily dietary intake of sodium recommended by the WHO of 2 g of sodium per adult. This should be taken into account in patients on a strict low-sodium diet.

Precautions for use

Perform a biological check of liver functions before the start of treatment (see section Contraindications) followed by periodic monitoring during the 6 first months, especially in patients at risk (see section Warnings and precautions "Severe hepatic impairment - Detection").

It should be noted that, as with most antiepileptics, a moderate, isolated and transient increase in transaminases may be observed, particularly at the start of treatment, in the absence of any clinical signs.

In this case, it is advised to carry out a more complete biological assessment (in particular prothrombin level), to possibly reconsider the dose and to repeat the checks depending on the evolution of the parameters.

A haematological examination (FBC including platelets, bleeding time and coagulation panel) is recommended prior to treatment, then at 15 days and at the end of treatment, as well as before a surgical procedure and in case of haematomas or spontaneous bleeding (see section Adverse effects).

In patients with renal impairment, account should be taken of the increase in serum free concentrations of valproic acid and the dose should be reduced accordingly.

Urea cycle disorders and risk of hyperammonaemia

This medicine is contraindicated in patients with an enzymatic deficiency of the urea cycle. When an enzymatic deficiency of the urea cycle is suspected, metabolic investigations must be carried out before treatment due to the risk of hyperammonaemia with valproate. A few cases of hyperammonaemia associated with a stupor or coma have been described in these patients (see section Contraindications and Warnings and precautions "Patients at risk of hypocarnitinaemia" and "Severe hepatic impairment").

Patients at risk of hypocarnitinaemia

Administration of valproate may trigger the onset or worsening of hypocarnitinaemia, which may lead to hyperammonaemia (liable to cause hyperammonaemic encephalopathy). Other symptoms such as hepatic toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis and Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinaemia or pre-existing hypocarnitinaemia. Patients at increased risk of symptomatic hypocarnitinaemia when treated with valproate are patients with metabolic disorders, including carnitine-related mitochondrial disorders (see also section Warnings and precautions "Patients with known or suspected mitochondrial disease" and "Urea cycle disorders and risk of hyperammonaemia"), patients with impaired nutritional intake of carnitine, patients under 10 years of age, and patients concomitantly treated with pivalate-conjugated medicinal products or with other antiepileptic drugs.

Patients must be warned that they should immediately report any sign of hyperammonaemia, such as ataxia, altered consciousness or vomiting. Carnitine supplementation should be considered when symptoms of hypocarnitinaemia are observed.

Patients with primary systemic carnitine deficiency and corrected hypocarnitinaemia may only be treated with valproate if the benefits of valproate treatment outweigh the risks for these patients and in the absence of a therapeutic alternative. In these patients, carnitine monitoring should be put in place.

Patients with an underlying type II carnitine palmitoyltransferase (CPT) deficiency must be warned of the increased risk of rhabdomyolysis when taking valproate. Carnitine supplementation should be considered in these patients. See also the sections Interactions, Adverse effects and Overdose.           

            

Although this medicine is known to cause immunological manifestations only exceptionally, its use in a subject with disseminated lupus erythematosus should be weighed against the benefit/risk ratio.

At the start of treatment, patients must be informed of the risk of weight gain and of the appropriate measures, essentially dietary, that should be adopted to minimise it.

Valproate is excreted mainly in the urine, partly as ketone bodies; testing for ketonuria may give false positives in diabetic patients.

Alcohol consumption is not recommended during the course of treatment with MICROPAKINE L.P.

Children

In children under 3 years of age, it is recommended to use valproate only as monotherapy, after assessing the therapeutic benefit against the risk of hepatopathy and pancreatitis in patients of this age group before starting treatment (see section Warnings and precautions "Severe hepatic impairment" and also section Interactions).

In children under 3 years of age, avoid concomitant prescription of salicylate derivatives given the risk of hepatotoxicity (see also section Warnings and precautions) and the risk of bleeding.

In children with unexplained hepato-digestive history (anorexia, vomiting, episodes of cytolysis), episodes of lethargy or coma, mental retardation, or in case of family history of neonatal or childhood deaths, metabolic investigations, in particular fasting and postprandial blood ammonia, must be carried out before any treatment with valproate.

Contraindicated combinations

+ St John's wort

Risk of decreased plasma concentrations and efficacy of the anticonvulsant.

Combinations not recommended

+ Lamotrigine

Increased risk of severe skin reactions (Lyell's syndrome).

Furthermore, increase in plasma concentrations of lamotrigine (decreased hepatic metabolism of lamotrigine by sodium valproate).

If the combination proves necessary, close clinical monitoring.

+ Penems (carbapenems)

Risk of convulsive seizures due to rapid decrease in plasma concentrations of valproic acid, which may become undetectable.

Administration of valproic acid in combination with carbapenems resulted in a decrease in plasma concentrations of valproic acid of the order of 60 to 100 % within approximately two days. Due to the rapid onset and magnitude of the decrease in plasma concentrations, concomitant administration of carbapenems in patients stabilised on valproic acid, where monitoring is not possible, should therefore be avoided (see section Warnings and precautions).

Associations requiring precautions for use

+ Acetazolamide

Increase in hyperammonaemia, with increased risk of encephalopathy.

Regular clinical and biological monitoring.

+ Aztreonam

Risk of convulsive seizures due to decrease in plasma concentrations of valproic acid.

Clinical monitoring, plasma assays and possible adjustment of the anticonvulsant dosage during treatment with the anti-infective and after its discontinuation.

+ Carbamazepine

Increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, decrease in plasma concentrations of valproic acid due to increased hepatic metabolism of valproic acid by carbamazepine.

Clinical monitoring, plasma assays and dosage adjustment of both anticonvulsants.

+ Clozapine

Concomitant treatment with valproate and clozapine may increase the risk of neutropenia and clozapine-induced myocarditis. If concomitant use of valproate and clozapine is necessary, close monitoring of these two effects is required.

+ Felbamate

Increase in plasma concentrations of valproic acid, with risk of overdose.

Clinical monitoring, biological control and possible adjustment of the valproate dosage during treatment with felbamate and after its discontinuation.

+ Medicinal products containing oestrogens, including hormonal contraceptives containing oestrogens

Oestrogens are inducers of the UDP-Glucuronosyl Transferase (UGT) isoforms involved in the glucuro-conjugation of valproate and may increase its clearance; this could lead to a decrease in serum valproate concentration and potentially a decrease in its efficacy (see section Warnings and precautions). Consider monitoring serum valproate concentrations.

Conversely, due to the absence of enzyme-inducing effect, valproate does not reduce the efficacy of oestroprogestogens in women using hormonal contraception.

+ Metamizole

Metamizole may decrease serum valproate concentrations when co-administered, which may lead to a potential decrease in the clinical efficacy of valproate.

Monitor clinical response (seizure control or mood control) and consider monitoring serum valproate concentrations, where appropriate.

+ Methotrexate

Some cases describe a significant decrease in serum valproate levels after administration of methotrexate, with occurrence of convulsions.

Prescribers should monitor clinical response (seizure control or mood control) and consider appropriate monitoring of serum valproate levels.

+ Nimodipine (oral route and by extrapolation, injectable route)

Risk of increase in plasma concentrations of nimodipine by 50 %. Therefore, the nimodipine dosage should be reduced in case of hypotension.

+ Phenobarbital, and by extrapolation primidone

Increase in hyperammonaemia, with increased risk of encephalopathy.

Regular clinical and biological monitoring.

+ Phenytoin, and by extrapolation fosphenytoin

Increase in hyperammonaemia, with increased risk of encephalopathy.

Regular clinical and biological monitoring.

+ Propofol

Possible increase in blood concentrations of propofol. A reduction of the propofol dose should be considered in case of co-administration with valproate.

+ Rifampicin

Risk of occurrence of convulsive seizures, due to increased hepatic metabolism of valproate by rifampicin.

Clinical and biological monitoring, and possible adjustment of the anticonvulsant dosage during treatment with rifampicin and after its discontinuation.

+ Rufinamide

Possible increase in rufinamide concentrations, particularly in children weighing less than 30 kg. In children weighing less than 30 kg: do not exceed the total dose of 600 mg/day after the titration period.

+ Topiramate

Increase in hyperammonaemia, with increased risk of encephalopathy.

Regular clinical and biological monitoring.

+ Zidovudine

Risk of increased adverse effects, particularly haematological, of zidovudine due to decreased metabolism by valproic acid.

Regular clinical and biological monitoring. A complete blood count to look for anaemia should be performed during the first two months of the combination.

+ Zonisamide

Increase in hyperammonaemia, with increased risk of encephalopathy.

Regular clinical and biological monitoring.

Other forms of interactions

+ Lithium

MICROPAKINE has no effect on lithemia.

+ Risk of hepatic damage

Concomitant use of salicylate derivatives should be avoided in children under 3 years due to the risk of hepatic toxicity (see section Warnings and precautions).

Simultaneous use of valproate and other anticonvulsants increases the risk of hepatic damage, particularly in young children (see section Warnings and precautions).

Use in combination with cannabidiol increases the incidence of transaminase elevation. In clinical trials in patients of all ages receiving cannabidiol concomitantly at doses of 10 to 25 mg/kg and valproate, an increase in ALAT of more than 3 times the upper limit of normal was reported in 19 % of patients. Appropriate liver monitoring should be performed when valproate is used in combination with other potentially hepatotoxic antiepileptic drugs, including cannabidiol.

Dose reductions or treatment discontinuation should be considered in case of significant abnormalities in liver parameters (see section Warnings and precautions).

+ Pivalate-conjugated medicinal products

Concomitant administration of valproate and pivalate-conjugated medicinal products (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to the increased risk of carnitine depletion (see section Warnings and precautions « Patients at risk of hypocarnitinaemia »). Patients for whom concomitant administration cannot be avoided must be placed under close monitoring in order to detect any sign or symptom of hypocarnitinaemia.

Valproate is contraindicated (see sections Contraindications and Warnings and precautions) : during pregnancy, unless there is no appropriate therapeutic alternative; in women of childbearing potential, unless all conditions of the pregnancy prevention programme are met.

Use in adolescents and men of reproductive age: see section Warnings and precautions "Special warnings" and the paragraph "Adolescents and men of reproductive age" below.

Pregnancy and women of childbearing potential:

Teratogenicity and neurodevelopmental effects following in utero exposure

In women, the use of valproate, whether as monotherapy or in polytherapy with other antiepileptics, is frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders, both with valproate monotherapy and polytherapy, compared with the population not exposed to valproate. Valproate has been shown to cross the placental barrier in animals and in humans (see section Pharmacokinetics).

In animals, teratogenic effects have been demonstrated in mice, rats and rabbits (see section Preclinical safety). In preclinical studies, a dose-dependent decrease in foetal weight has been demonstrated in animals exposed to valproate in utero compared with unexposed animals (see section Preclinical safety).

• Congenital malformations following in utero exposure

A meta-analysis (including registries and cohort studies) showed that approximately 11 % of children born to epileptic mothers treated with valproate in monotherapy during pregnancy had major congenital malformations. This is higher than the risk of major malformations encountered in the general population (approximately 2-3 %).

The risk of major congenital malformations in children exposed in utero to a polytherapy of antiepileptics including valproate is higher than that associated with a polytherapy of antiepileptics without valproate.

This risk is dose-dependent during monotherapy with valproate, and available data suggest that it is dose-dependent during polytherapy with valproate. However, no threshold dose excluding this risk could be determined.

Available data show an increased incidence of minor and major malformations. The malformations most often encountered include neural tube closure defects (on the order of 2 to 3 %), facial dysmorphism, cleft lip and cleft palate, craniosynostosis, cardiac, renal and urogenital malformations (notably hypospadias), limb malformations (notably bilateral radial aplasia) and polymalformation syndromes affecting various parts of the body.

Exposure in utero to valproate may also cause hearing impairment or deafness due to malformations of the ear and/or nose (side effect) and/or direct toxicity to auditory function. Cases describe unilateral and bilateral deafness or hearing impairment. Outcomes have not been reported for all cases. When outcomes are reported, there was no recovery in the majority of cases.

Exposure in utero to valproate may cause ocular malformations (notably coloboma and microphthalmia), which have been reported together with other congenital malformations. These ocular malformations may affect visual capacity.

• Neurodevelopmental disorders following in utero exposure

Studies show that valproate causes an increased risk of neurodevelopmental disorders in exposed children in utero. The risk of neurodevelopmental disorders (including autism) appears to be dose-dependent when valproate is used in monotherapy, but the available data do not allow determination of a dose excluding this risk.

When valproate is administered in polytherapy with other antiepileptic medicinal products during pregnancy, the risks of neurodevelopmental disorders in the child have also been significantly increased compared with those of the general population or those born to untreated epileptic mothers.

The period of risk for these effects is uncertain, and the possibility of a risk throughout pregnancy cannot be excluded.

When valproate is administered in monotherapy, studies conducted in preschool-age children exposed in utero to valproate show that up to 30 to 40 % of them present developmental delays in early childhood, such as delays in speech and walking acquisition, reduced intellectual abilities, reduced verbal abilities (speech and comprehension) as well as memory disorders.

The intelligence quotient (IQ) measured in school-age children (6 years) exposed in utero to valproate is on average 7 to 10 points lower than that of children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, it is established that this decrease in IQ observed in exposed children in utero is independent of maternal IQ.

Data on the long-term course of these disorders are limited.

Available data from a population-based study show that children exposed in utero to valproate have an increased risk of presenting autism spectrum disorders (approximately 3 times more frequent) and childhood autism (approximately 5 times more frequent), compared with the unexposed population in the study.

Available data from another population-based study show that children exposed in utero to valproate have an increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1,5 times more frequent), compared with the unexposed population in the study.

• Newborn small for gestational age (SGA) following in utero exposure

Some epidemiological studies have suggested a higher risk of being born with a low weight for gestational age (SGA defined as a birth weight below the 10^e percentile adjusted for gestational age, stratified by sex) for children exposed to valproate in utero compared with unexposed children or children exposed to lamotrigine. SGA was observed in approximately 11-15 % of children exposed to valproate in utero, 8-9 % of children exposed to lamotrigine, and 5-10 % of children not exposed.

Data available in humans do not allow a conclusion on a potential dose-dependent effect.

Women of childbearing potential

In women of childbearing potential, treatment with MICROPAKINE L.P. must not be used except in cases of inefficacy or intolerance to other treatments. If no other treatment is possible, MICROPAKINE L.P. may only be initiated provided the pregnancy prevention programme is complied with (see section Warnings and precautions), in particular:

• that they are not pregnant (plasma pregnancy test with a sensitivity of at least 25 mIU/mL negative at treatment initiation and at regular intervals during treatment);
• that they use at least one effective method of contraception;
• and that they are informed of the risks associated with valproate use during pregnancy.

In these women, the benefit-risk balance must be carefully reassessed at regular intervals during treatment (at least annually).

Medicinal products containing estrogens:

Medicinal products containing estrogens, including hormonal contraceptives containing estrogens, may increase the clearance of valproate, which could lead to a decrease in serum valproate concentration and potentially a decrease in its efficacy (see sections Warnings and precautions and Interactions).

If pregnancy is planned

In women planning a pregnancy, an experienced specialist physician in the management of epilepsy must reassess valproate treatment and consider all alternative therapeutic options. All efforts must be made to switch to an appropriate alternative treatment before conception and before contraception is discontinued (see section Warnings and precautions). If switching treatment is not possible, the patient must receive additional counselling on the risks valproate presents to the unborn child in order to help her make an informed decision regarding her family plans.

Folic acid supplementation before pregnancy and in early pregnancy may reduce the risk of neural tube defects inherent to any pregnancy. For information, available data do not show a preventive effect of folic acid on malformations associated with valproate.

Pregnant women

Valproate used in the treatment of epilepsy is contraindicated during pregnancy, except in the absence of an appropriate therapeutic alternative (see sections Contraindications and Warnings and precautions).

In case of pregnancy in a woman using valproate, she must be immediately referred to a specialist physician in order to consider all alternative therapeutic options. During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the mother may result in serious or even fatal consequences for the mother and the unborn child.

If, in exceptional situations, despite the known risks associated with valproate use during pregnancy, and after careful evaluation of alternative treatments, valproate absolutely had to be maintained to control epilepsy in a pregnant woman:

• it is essential to use the minimum effective dose
• it is recommended to divide the daily dose into several smaller doses throughout the day. The use of a prolonged-release formulation may be preferable to other formulations in order to avoid plasma peaks (see section Dosage and administration).

All patients whose pregnancy was exposed to valproate, as well as their partners, must be referred to a specialist or physician experienced in teratology for evaluation and receive counselling regarding the exposed pregnancy:

• specialised prenatal monitoring must be instituted in order to detect possible abnormalities of the neural tube or other malformations.

Before delivery:

Perform a coagulation panel including, in particular, a platelet count, a fibrinogen assay and a coagulation time (Activated Partial Thromboplastin Time: APTT) in the mother before delivery.

Risk in the newborn

• Very rare cases of haemorrhagic syndrome have been reported in newborns of mothers treated with valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenaemia and/or a decrease in other coagulation factors. Afibrinogenaemia has also been reported and may be fatal. However, this syndrome must be distinguished from vitamin K-dependent coagulation factor deficiency induced by phenobarbital and enzyme inducers. A normal haemostasis panel in the mother does not rule out haemostatic abnormalities in the newborn. Therefore, at birth, a panel including a platelet count, a fibrinogen assay, coagulation tests and coagulation factors will be performed in newborns.
• Cases of hypoglycaemia have been reported in newborns of mothers treated with valproate during the third trimester of pregnancy.
• Cases of hypothyroidism have been reported in newborns of mothers treated with valproate during pregnancy.
• A withdrawal syndrome (in particular agitation, irritability, hyperexcitability, nervousness, hyperkinesia, tone disorders, tremor, convulsions and feeding disorders) may occur in newborns of mothers treated with valproate during the third trimester of pregnancy.

Postnatal/paediatric follow-up

In case of exposure during pregnancy, close monitoring of the child's neurobehavioural development must be instituted and appropriate management must be put in place as early as necessary.

Adolescents and men of childbearing potential:

Potential risk of neurodevelopmental disorders in children whose father was treated with valproate in the 3 months preceding conception

A retrospective observational study conducted in 3 Nordic countries suggests an increased risk of neurodevelopmental disorders (NDDs) in children (aged 0 to 11 years) born to fathers treated with valproate in monotherapy in the 3 months preceding conception, compared with those whose fathers were treated with lamotrigine or levetiracetam in monotherapy, with an adjusted Hazard Ratio (HR) of 1,50 (95% CI: 1,09-2,07). The adjusted cumulative risk of NDDs ranged between 4,0% and 5,6% in the valproate group versus 2,3% to 3,2% in the combined lamotrigine/levetiracetam group.

Other population-based observational studies did not show an increased risk of NDD in children born to men treated with valproate in monotherapy during the 3 to 4 months before conception, compared with men treated with lamotrigine or levetiracetam in monotherapy.

Differences in study design, including control of confounding factors and population selection, may contribute to differences in study results. Furthermore, available data suggest that factors other than exposure to valproate, including the underlying paternal disease, could contribute to the observed association. Overall, the evidence regarding an increased risk of NDD in children of fathers treated with valproate during the 3 months preceding conception is conflicting, and the causal role of valproate is uncertain.

As a precautionary measure, the prescriber must inform adolescents and men of reproductive age of this potential risk and discuss with them:

• the need to implement effective contraceptive measures during valproate treatment and for at least three months after its discontinuation, including for their partner (see section Warnings and precautions),
• not to donate sperm during valproate treatment and for at least three months after valproate discontinuation.

Valproate treatment in men and adolescents of reproductive age must be regularly reassessed by the prescriber to determine whether valproate remains the most appropriate treatment. For male patients planning to father a child, therapeutic alternatives must be considered and discussed with patients. Individual situations must be evaluated case by case. It is recommended to seek advice from a physician specialised in epilepsy management if necessary.

A shared information acknowledgement form must be used, duly completed and signed at the time of treatment initiation by the specialist physician and at each annual reassessment of valproate treatment by any physician and the patient (or his legal representative).

Breast-feeding

Valproate is excreted in breast milk at a concentration between 1% and 10% of maternal serum levels. Haematological disorders have been observed in newborns/infants breastfed by women under treatment (see section Adverse effects).

The decision to interrupt breastfeeding or to suspend treatment with MICROPAKINE L.P. must take into account the benefit of breastfeeding for the child and the benefit of the treatment for the woman.

Fertility

Cases of amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women treated with valproate (see section Adverse effects).

In men, administration of valproate may also impair fertility (particularly decreased sperm motility) (see section Adverse effects). In some cases, these fertility disorders are reversible after at least 3 months of treatment discontinuation. In a limited number of cases, a significant dose reduction has been reported to potentially improve fertility. However, in other cases, the reversibility of these male fertility disorders is not known.

Attention is drawn, particularly to drivers of vehicles and users of machinery, to the risk of drowsiness, especially in cases of anticonvulsant polytherapy or association with other medicinal products that may increase drowsiness.

Classification of expected frequencies:

Very common (≥ 10%); Common (≥ 1% to < 10%); Uncommon (≥ 0,1% to < 1%); Rare (≥ 0,01% to < 0,1%); Very rare (< 0,01%); Not known (cannot be estimated from the available data).

Congenital, familial and genetic disorders

• Congenital malformations, neurodevelopmental disorders (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding).

Blood and lymphatic system disorders

• Common: anaemia, thrombocytopenia.
  Cases of dose-dependent thrombocytopenia, generally discovered systematically and without clinical consequences, have been described.
  In cases of asymptomatic thrombocytopenia, if the platelet count and disease control allow, a simple dose reduction of this medicinal product most often leads to regression of this thrombocytopenia.
• Uncommon: leukopenia, pancytopenia.
• Rare: global bone marrow aplasia or pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis.

Investigations

• Common: weight gain*.
• Rare: decrease of at least one coagulation factor, abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased INR) (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding), vitamin B8 (biotin) deficiency/biotinidase deficiency.
• Frequency not known: acquired Pelger-Huët anomaly**.

* As weight gain is a risk factor for the occurrence of polycystic ovary syndrome, the weight of patients must be closely monitored (see section Warnings and precautions).

** An acquired Pelger-Huët anomaly has been reported, with and without myelodysplastic syndrome.

Nervous system disorders

• Very common: tremor
• Common: extrapyramidal disorders**, stupor*, sedation, convulsion*, memory impairment, headache, nystagmus, nauseous or dizzy sensations
• Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonian syndromes**, ataxia, paraesthesia
• Rare: diplopia, cognitive disorders of insidious and progressive onset (which may present as a complete picture of dementia syndrome), reversible a few weeks to a few months after stopping treatment**

* Cases of stupor or lethargy sometimes leading to transient coma (encephalopathy) under valproate have been observed, regressing on discontinuation of treatment or on dose reduction. These states most often occur during polytherapy (phenobarbital or topiramate in particular) or with a sudden increase in valproate doses.

** These symptoms may be associated with imaging showing cerebral atrophy.

Ear and labyrinth disorders

• Common: hearing loss.

Respiratory, thoracic and mediastinal disorders

• Uncommon: pleural effusion (eosinophilic).

Gastrointestinal disorders

• Very common: nausea.
• Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhoea, which may occur in some patients at the start of treatment but generally resolves within a few days without interruption of treatment.
• Uncommon: pancreatitis, the outcome of which may be fatal and which requires early discontinuation of treatment (see section Warnings and precautions).

Renal and urinary disorders

• Common: urinary incontinence.
• Uncommon: renal failure.
• Rare: enuresis, tubulointerstitial nephritis, Fanconi syndrome.

Skin and subcutaneous tissue disorders

• Common: transient and/or dose-dependent hair loss, nail and nail bed disorders.
• Uncommon: angioedema, skin reactions, hair disorders (such as abnormal hair texture, changes in hair colour, abnormal hair growth).
• Rare: Lyell's syndrome, Stevens-Johnson syndrome, erythema multiforme, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome or drug hypersensitivity syndrome.
• Frequency not known: hyperpigmentation.

Endocrine disorders

• Uncommon: syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilism, acne, androgenic-type alopecia, and/or increased androgen hormone levels).
• Rare: hypothyroidism (see section Fertility, pregnancy and breastfeeding).

Metabolism and nutrition disorders

• Common: hyponatraemia.
• Rare: hyperammonaemia* (see section Warnings and precautions), obesity.

* An isolated, moderate hyperammonemia without change in liver function tests may be observed, especially in cases of polytherapy, and should not lead to interruption of treatment. However, cases of hyperammonemia with neurological symptoms (which may progress to coma) have also been reported, requiring then further investigations (see sections: "Urea cycle disorders and risk of hyperammonemia" and "Patients at risk of hypocarnitinemia"). Contraindications and Warnings and precautions : "Urea cycle disorders and risk of hyperammonemia" and "Patients at risk of hypocarnitinemia").

• Frequency not known: hypocarnitinemia (see sections Contraindications and Warnings and precautions).

Benign, malignant and unspecified tumors (incl. cysts and polyps)

• Rare: myelodysplastic syndrome.

Vascular disorders

• Common: hemorrhage (see sections Warnings and precautions and Adverse effects).
• Uncommon: cutaneous vasculitis, mainly leukocytoclastic vasculitis.

General disorders and administration site conditions

• Uncommon: hypothermia, non-severe peripheral edema.

Hepatobiliary disorders

• Common: hepatic disorders (see section Warnings and precautions).

Disorders of the reproductive system and breast

• Common: menstrual irregularities.
• Uncommon: amenorrhoea.
• Rare: male fertility disorders (see section Fertility, pregnancy and breastfeeding), polycystic ovaries.

Musculoskeletal and systemic disorders

• Uncommon: decreased bone mineral density, osteopenia, osteoporosis and fractures in patients treated long-term with MICROPAKINE L.P. The mode of action of MICROPAKINE L.P. on bone metabolism is not known.
• Rare: disseminated acute lupus erythematosus (see section Warnings and precautions), rhabdomyolysis (see section Warnings and precautions).

Psychiatric disorders

• Common: confusional state, hallucinations, aggressiveness*, agitation*, attention disorders*.
• Rare: abnormal behavior*, psychomotor hyperactivity*, learning difficulties*.

* These effects are observed mainly in the pediatric population.

Paediatric population:

The safety profile of valproate in the pediatric population is comparable to that in adults, but certain adverse effects are more severe or are mainly observed in the pediatric population. There is a particular risk of severe hepatic damage in infants and young children, especially before the age of 3 years. Young children also have a particular risk of pancreatitis. These risks decrease with age (see section Warnings and precautions). Psychiatric disorders such as aggressiveness, agitation, attention disorders, abnormal behaviors, psychomotor hyperactivity and learning disorders are mainly observed in the pediatric population.  

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 the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/

The picture of acute massive poisoning usually includes a calm coma, more or less deep, with muscular hypotonia, hyporeflexia, miosis, decreased respiratory autonomy, metabolic acidosis, hypotension and cardiovascular collapse/shock.

A few cases of intracranial hypertension linked to cerebral oedema have been described.

Measures to be taken in a hospital setting are: gastric evacuation if indicated, maintenance of effective diuresis, cardiorespiratory monitoring. In very severe cases, extrarenal purification may be performed if necessary.

The prognosis of these poisonings is generally favourable; however, a few deaths have been reported.

The presence of sodium in formulations containing valproate may lead to hypernatraemia in cases of overdose.

Treatment

In cases of valproate overdose leading to hyperammonaemia, carnitine may be administered intravenously to attempt to normalise ammonium levels.

Pharmacotherapeutic class: ANTIEPILEPTIC, ATC code: N03AG01.

Valproate exerts its pharmacological effects essentially at the level of the central nervous system.

These anticonvulsant properties are exerted against very varied types of convulsive seizures in animals and epilepsies in humans.

Experimental and clinical studies of valproate suggest two types of anticonvulsant action.

The first is a direct pharmacological effect related to valproate concentrations in plasma and brain.

The second is apparently indirect and probably related to valproate metabolites persisting in the brain, or to changes in neurotransmitters, or to direct membrane effects. The most generally accepted hypothesis is the gamma-aminobutyric acid (GABA) hypothesis, whose level increases after administration of valproate.

Valproate decreases the duration of the intermediate stages of sleep with a concomitant increase in slow-wave sleep.

The various pharmacokinetic studies performed for valproate have shown that:

• The blood bioavailability of valproate after oral administration is close to 100 %.
• The volume of distribution is limited essentially to blood and extracellular fluids with rapid exchange. Valproate diffuses into the CSF and into the brain. Valproate concentrations in the CSF are close to those of the free plasma fraction.
• Passage across the placental barrier (see section Fertility, pregnancy and breastfeeding) :
  Valproate crosses the placental barrier in animals and in humans:
  • in animals, valproate crosses the placenta, in a manner similar to humans,
  • in humans, several publications have assessed the concentration of valproate in the umbilical cord of newborns at delivery. The serum concentration of valproate in the umbilical cord, representing the serum concentration of valproate in foetuses, was similar to or slightly higher than that of the mothers.
• The half-life is 15 to 17 hours.
• Therapeutic efficacy usually requires a minimum serum concentration of 40-50 mg/l, with a wide range between 40 and 100 mg/l. If higher plasma levels prove necessary, the expected benefits must be weighed against the risk of adverse effects, particularly dose-dependent ones. However, levels that remain above 150 mg/l require a dose reduction.
• The steady-state plasma concentration is reached in 3 to 4 days.
• Protein binding of valproate is very high. It is dose-dependent and saturable.
• The major pathway of valproate metabolism is glucuro-conjugation (approximately 40 %), mainly via UGT1A6, UGT1A9 and UGT2B7.
• Valproate is excreted essentially in the urine after metabolism by glucuro-conjugation and beta-oxidation.
• The valproate molecule is dialysable, but haemodialysis only affects the free fraction of blood valproate (approximately 10 %).
• Valproate is not an inducer of the enzymes involved in the cytochrome P 450 metabolic system, unlike most other antiepileptic drugs. It therefore does not accelerate its own degradation, nor that of other substances such as oestroprogestogens and vitamin K antagonists.

Compared with immediate-release forms of valproate, MICROPAKINE L.P. is characterised, at equivalent dose, by:

• prolonged absorption;
• similar bioavailability;
• a maximum plasma concentration reached approximately 7 hours after intake;
• lower maximum total and free plasma concentrations (C_max) (Cmax_max approximately 25 % lower but relatively stable at a plateau, between the 4^th and the 14^th hour); this clipping of peaks makes it possible to obtain more regular valproic acid concentrations distributed more homogeneously over the nychthemeron: after twice-daily administration of the same dose, the amplitude of plasma fluctuations is reduced by half;
• a more linear correlation between dose and plasma concentration (total and free).

The pharmacokinetic profile is not modified by food intake.

Paediatric population

From the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. In paediatric patients under 10 years of age, the systemic clearance of valproate varies with age. In newborns and infants up to the age of 2 months, valproate clearance is decreased compared with that of adults and is lowest immediately after birth. In a review of the scientific literature, the half-life of valproate in infants under two months of age showed considerable variability, ranging from 1 to 67 hours.

In children aged 2 to 10 years, valproate clearance is 50 % higher than in adults.

Animal studies show that exposure in utero to valproate results in morphological and functional alterations of the auditory system in rats and mice.

In vitro, valproate was not mutagenic in bacteria or in mouse lymphoma assays, and did not induce DNA repair in primary rat hepatocyte cultures. However, in vivo, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route in humans, valproate induced neither chromosomal aberrations in rat bone marrow nor major lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand breaks and chromosomal aberrations in rodents. In addition, an increase in sister chromatid exchanges in epileptic patients exposed to valproate has been reported in published studies compared with untreated healthy subjects. However, contradictory results were obtained when comparing data from epileptic patients treated with valproate with those from untreated epileptic patients. The clinical relevance of these DNA/chromosome findings is not known.

Non-clinical data from conventional carcinogenicity studies do not reveal any particular risk for humans.

Reproductive toxicity

Valproate induced teratogenic effects (malformations of several organ systems) in mice, rats and rabbits.

In mice, rats and rabbits, exposure in utero to valproate induced a dose-dependent decrease in fetal weight, intrauterine growth retardation and a reduction in crown-rump length compared with unexposed animals.

Behavioural abnormalities have been reported in first-generation offspring of mice and rats after exposure in utero. Certain behavioural changes were also observed in the second generation, and these were less pronounced in the third generation of mice after acute exposure in utero of the first generation to teratogenic doses of valproate. The underlying mechanisms and the clinical relevance of these findings are not known.

In repeated-dose toxicity studies, degeneration/atrophy of the testes, abnormal spermatogenesis and decreased testicular weight were reported in adult rats and dogs after oral administration of doses of 400 mg/kg/day and 150 mg/kg/day, respectively. The no observed adverse effect levels (NOAELs) associated with testicular effects are 270 mg/kg/day in adult rats and 90 mg/kg/day in adult dogs. Based on AUC (Area Under the Curve) extrapolations in rats and dogs, there may be no safety margin for humans.

In juvenile rats, decreased testicular weight was observed only at doses exceeding the maximum tolerated dose (from 240 mg/kg/day by intraperitoneal or intravenous route) and without associated histopathological changes. No effect on male reproductive organs was observed at tolerated doses (up to 90 mg/kg/day). In view of these data, juvenile animals were not considered more susceptible than adults to testicular disorders. The clinical relevance of these testicular findings for the paediatric population remains unknown.

In a fertility study in rats, administration of valproate at doses up to 350 mg/kg/day did not impair reproductive performance in males. However, male fertility disorders have been identified as an adverse effect in humans (see sections Fertility, pregnancy and breastfeeding and Adverse effects).

2 years.

Store at a temperature not exceeding 25 °C.

To be stored in the original outer packaging, protected from moisture.

Do not refrigerate. Do not freeze.

No particular requirements

List II

Marketing authorisation (AMM)

CIP 3400936551442 (Sach/30).

Price:

21,40 euros (Sach/30).

Social security reimbursement at 65%. Collective.