Convulsophin-retard, 500 mg 50 pcs

Pharmacotherapeutic group: antiepileptic drug

TATX code: N03AG01

Pharmacological properties

Pharmacodynamics

Antieepileptic drug with central myorelaxant and sedative effects.

It exhibits antiepileptic activity in various types of epilepsy. The main mechanism of action seems to be related to the effect of valproic acid on the GABAergic system: increase of gamma-aminobutyric acid (GABA) content in the central nervous system (CNS) and activation of GABAergic transmission.

Pharmacokinetics

Absorption. Bioavailability of valproic acid when taken orally is close to 100%. Food intake does not affect the pharmacokinetic profile of the drug.

When taking Convulsophin-retard 500 mg tablets at a dose of 1000 mg/day, the minimum plasma concentration (C_min) is 44.7±9.8 µg/mL, and the maximum plasma concentration (C_max) is 81.6±15.8 µg/mL. The time to maximum plasma concentration (T_max) is 6.58±2.23 hours. The equilibrium plasma concentration is reached within 3-4 days of regular drug administration.

The average therapeutic range of serum valproic acid concentrations is 50-100 mg/l. If there is a reasonable need to achieve higher plasma concentrations, the ratio of expected benefit to risk of side effects should be carefully weighed, especially dose-dependent ones, since at concentrations above 100 mg/L an increase in side effects up to the development of intoxication is expected. At plasma concentrations greater than 150 mg/L, a reduction in the drug dose is required.

Distribution. The volume of distribution depends on age and is usually 0.13-0.23 L/kg body weight, or 0.13-0.19 L/kg body weight in young adults.

The binding of valproic acid to plasma proteins (mainly to albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency the binding to plasma proteins decreases. In severe renal failure the concentration of free (therapeutically active) fraction of valproic acid may increase up to 8.5-20%.

In hypoproteinemia the total concentration of valproic acid (free + bound to plasma proteins fraction) may not change, but may decrease due to increased metabolism of free (unbound to plasma proteins) fraction of valproic acid.

Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the CSF is 10% of its concentration in blood serum.

Valproic acid is excreted in the breast milk of nursing mothers. In the state of reaching an equilibrium concentration of valproic acid in serum, its concentration in breast milk is 1% to 10% of its serum concentration.

Metabolism. Metabolism of valproic acid occurs in the liver by glucuronidation as well as beta, omega, and omega-1 oxidation. More than 20 metabolites have been identified; metabolites after omega-oxidation have hepatotoxic effects.

Walproic acid has no inducing effect on enzymes that are part of the cytochrome P450 metabolic system. Unlike most other antiepileptic drugs, valproic acid does not affect the rate of both its own metabolism and that of other substances such as estrogens, progestagens, and indirect anticoagulants.

Elimation. Valproic acid is primarily excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted unchanged by the kidneys.

The plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min.

The elimination half-life (T_1/2) is 15-17 hours. When combined with antiepileptic agents inducing microsomal liver enzymes, plasma clearance of valproic acid is increased and T_1/2 decreased, the extent of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic agents.

The T_1/2 values in children older than 2 months are similar to those in adults.

In patients with liver disease, T_1/2 valproic acid is increased.

In overdose, an increase in T_1/2 up to 30 hours has been observed.

Hemodialysis only the free plasma fraction of valproic acid (10%).

According to the literature, some patients taking estrogen-containing medications have shown an increase in valproic acid clearance of approximately 20%, which may decrease its serum concentration (see section “Interaction with other medicinal products”).

Interindividual variability has been noted.

There is insufficient data to establish a reliable relationship between pharmacokinetic and pharmacodynamic parameters in relation to the identified interaction.

Peculiarities of pharmacokinetics in pregnancy. The renal and hepatic clearance of valproic acid is increased in the third trimester of pregnancy. In this case, despite taking the drug at a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the binding of valproic acid to plasma proteins may change, which may increase the serum free (therapeutically active) fraction of valproic acid.

The sustained release form has the following characteristics:

• absence of delayed absorption time after administration;
• longer absorption;
• identical bioavailability;
• lower C_max (decrease in C_max by approximately 25%), but with a more stable plateau phase from 4 to 14 hours after administration;
• more linear correlation between dose and plasma drug concentration.

Placental barrier

Valproic acid crosses the placental barrier in both animals and humans. Some publications have evaluated the concentration of valproate in the umbilical cord of newborn infants at delivery. The serum valproate concentration in the umbilical cord, reflecting the fetal valproate concentration, was the same or slightly higher than that in the mother’s serum.

Indications

Adult patients (as monotherapy or in combination with other antiepileptic drugs):

Patients in pediatric patients over 6 years of age (as monotherapy or in combination with other antiepileptic drugs):

Active ingredient

Composition

How to take, the dosage

This dosage form is only for adults and children over 6 years of age with a body weight of more than 17 kg!

This dosage form is contraindicated in children under 6 years of age (risk of ingestion of the tablet)!

Convulsophin-retard is a sustained release pharmaceutical formulation. This prolonged release avoids the sudden spike in plasma concentrations of valproic acid after dosing and keeps the plasma concentration of valproic acid more constant overnight.

The sustained release tablet Convulsophin-Retard 300 mg/500 mg can be divided to make it easier to take an individual, tailored dose.

The tablets are taken without crushing or chewing.

Dosing regimen in epilepsy

The daily dose is adjusted by the treating physician individually.

The lowest effective dose should be chosen to prevent epilepsy seizures. Daily dose should be adjusted according to age and body weight. A stepwise (gradual) increase in dose is recommended until the minimum effective dose is reached.

No clear relationship has been established between the daily dose, plasma concentrations and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid concentrations may serve to supplement clinical follow-up if epilepsy is uncontrollable or side effects are suspected. The range of therapeutic plasma concentrations is usually 40-100 mg/L (300-700 µmol/L).

In monotherapy, the initial daily dose is usually 5-10 mg valproic acid per kg body weight, which is then gradually increased every 4-7 days at a rate of 5 mg valproic acid per kg body weight to the dose needed to achieve control of epilepsy attacks.

Median daily doses (in long-term use):

While the daily dose is determined according to the patient’s age and body weight, a wide range of individual sensitivities to valproate should be taken into account.

If epilepsy cannot be controlled at these doses, they can be increased, under control of the patient’s condition and plasma valproic acid concentrations.

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops over 4-6 weeks. Therefore, the daily dose should not be increased above the recommended average daily dose before this time.

The daily dose may be divided into 1-2 doses, preferably with meals. Single-dose use is possible in well-controlled epilepsy. Most patients who are already taking the sustained release formulation can be switched to the sustained release formulation immediately or over several days, and patients must continue to take the previously selected daily dose.

For patients who have previously taken other antiepileptic drugs, conversion to Convulsophin-retard should be done gradually, reaching the optimal dose within about 2 weeks. The dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is withdrawn, its withdrawal should be done gradually.

Since other antiepileptic drugs may reversibly induce hepatic microsomal enzymes, plasma valproic acid concentrations should be monitored for 4-6 weeks after the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effects of these drugs decrease), the daily valproic acid dose should be reduced.

If combination of valproic acid with other antiepileptic drugs is necessary, they should be added to the treatment gradually (see “Interaction with other medicinal products”).

Dosing regimen for manic episodes in bipolar affective disorder

Adults

The daily dose is adjusted by the treating physician individually.

The recommended starting daily dose is 750 mg. In addition, in clinical studies, a starting dose of 20 mg of sodium valproate per kg of body weight has also shown an acceptable safety profile.

The sustained-release forms can be taken once or twice daily. The dose should be increased as quickly as possible until the minimum therapeutic dose that produces the desired clinical effect is reached.

The average daily dose is in the range of 1000-2000 mg of sodium valproate. Patients taking a daily dose above 45 mg/kg/day should be under close medical supervision.

The continuation of treatment for manic episodes in bipolar disorder should be done by taking an individualized minimum effective dose.

Children and adolescents

The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorder in patients younger than 18 years has not been evaluated.

The use of the drug in patients in special groups

Children over 6 years of age and adolescent females, women of childbearing potential, and pregnant women

The treatment with the drug should be started under the supervision of a specialist experienced in the treatment of epilepsy and bipolar disorders. Treatment should be started only if other treatments are ineffective or intolerable (see sections “Special Precautions”, “Use in pregnancy and lactation”), and the benefit-risk ratio should be carefully reassessed during regular treatment evaluation. The drug should be administered in compliance with the Pregnancy Prevention Program (see “Special Precautions”, “Use in Pregnancy and Breastfeeding”).

The drug is preferably used in monotherapy and in the lowest effective doses and, if possible, in sustained release dosage forms. During pregnancy, in the absence of alternative treatments for epilepsy, the daily dose should be divided into at least 2 single doses.

Simultaneous use with estrogen-containing drugs

Valproic acid does not decrease the therapeutic effectiveness of hormonal contraceptives.

Overtheless, products containing estrogen, including estrogen-containing hormonal contraceptives, can increase clearance of valproic acid which can decrease its serum concentration and therefore decrease its effectiveness. Serum valproic acid concentrations and clinical efficacy (seizure control and mood control) should be monitored when prescribing or withdrawing estrogen-containing medications (see section “Interaction with other medications”).

Elderly Patients

While there are changes in valproic acid pharmacokinetics in elderly patients, these are of limited clinical significance and the valproic acid dose in elderly patients should be adjusted according to achieving seizure control.

Patients with renal insufficiency and/or hypoproteinemia

.In patients with renal insufficiency and/or hypoproteinemia, the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be considered and, if necessary, the dose of valproic acid should be reduced, guided primarily by the clinical picture rather than the total serum valproic acid concentration (both free and plasma protein-bound fractions) when adjusting the dose to avoid possible dosing errors.

Interaction

Effects of valproic acid on other drugs

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines. Walproic acid may potentiate the effects of other psychotropic medications such as neuroleptics, MAOI inhibitors, antidepressants and benzodiazepines, therefore close medical supervision and, if necessary, dose adjustment, is recommended when they are used concomitantly with valproic acid.

Lithium preparations. Valproic acid has no effect on serum concentrations of lithium.

Phenobarbital. Walproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism); therefore, it is possible to develop the sedative effect of the latter, especially in children. Therefore, it is recommended that the patient be closely monitored during the first 15 days of combined therapy with immediate reduction of the dose of phenobarbital if sedation develops and, if necessary, determination of plasma concentrations of phenobarbital.

Primidone. Walproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation), these symptoms disappear with long-term treatment. Close clinical monitoring of the patient is recommended, especially at the beginning of combination therapy (first 15 days), with adjustment of the primidone dose if necessary.

Phenytoin. Valproic acid decreases total plasma concentrations of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of overdose (valproic acid displaces phenytoin from plasma proteins and slows its hepatic catabolism). Therefore, when concomitant use of phenytoin and valproic acid, close clinical observation of the patient is recommended, and when determining phenytoin concentrations, the concentration of its free plasma fraction should also be determined.

Carbamazepine. Concomitant use of valproic acid and carbamazepine has been reported to result in clinical manifestations of carbamazepine toxicity because valproic acid may potentiate the toxic effects of carbamazepine. Close clinical monitoring of such patients is recommended, especially at the beginning of combination therapy with dose adjustment of carbamazepine if necessary.

Lamotrigine. Walproic acid slows down lamotrigine metabolism in the liver and increases T1/2 lamotrigine almost 2-fold. This interaction may lead to increased lamotrigine toxicity, particularly the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, adjustment (reduction) of the lamotrigine dose is recommended.

Zidovudine. Walproic acid may increase plasma concentrations of zidovudine, resulting in increased toxicity of zidovudine, especially hematologic effects, due to slowing of its metabolism by valproic acid. Continuous clinical observation and monitoring of laboratory parameters is necessary. Blood tests should be done to rule out anemia during the first two months of combined therapy.

Felbamate. Walproic acid may decrease average felbamate clearance values by 16%.

Olanzapine. Valproic acid may decrease plasma concentrations of olanzapine.

Rufinamide. Valproic acid may increase plasma concentrations of rufinamide. This increase depends on the blood concentration of valproic acid. Caution should be exercised, particularly in children, as this effect is more pronounced in this patient population.

Propofol Valproic acid may increase plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when used concomitantly with valproic acid.

Nimodipine (oral and, by extrapolation, parenteral solution). Increased hypotensive effect of nimodipine due to the fact that concomitant use of nimodipine and valproic acid may increase plasma concentrations of nimodipine by 50% (due to inhibition of nimodipine metabolism by valproic acid).

Temozolomide. The co-administration of temozolomide with valproic acid may result in a mild but statistically significant decrease in the clearance of temozolomide.

Effects of other drugs on valproic acid

.Antiepileptic drugs capable of inducing microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and plasma concentrations of valproic acid.

The plasma concentrations of valproic acid metabolites may be increased if it is used concomitantly with phenytoin or phenobarbital. Therefore, patients treated with these two drugs should be monitored closely for signs and symptoms of hyperammonemia, as some valproic acid metabolites may inhibit enzymes of the urea cycle.

Aztreonam. Risk of seizures due to decreased plasma concentrations of valproic acid. Clinical monitoring, determination of plasma concentrations of valproic acid and possible correction of anticonvulsant dose during treatment with this antibiotic and after discontinuation is necessary.

Felbamate. Concomitant use of felbamate and valproic acid decreases valproic acid clearance by 22-50% and correspondingly increases plasma concentrations of valproic acid. Control of plasma concentrations of valproic acid is necessary.

Mefloquine. Mefloquine accelerates metabolism of valproic acid and may itself cause seizures, therefore simultaneous use may cause an epileptic seizure.

Drugs of St. John’s Wort. Concomitant use of valproic acid and St. John’s Wort preparations may decrease the anticonvulsant effectiveness of valproic acid.

Drugs with high and strong binding to blood plasma proteins (acetylsalicylic acid). In case of concomitant use of valproic acid and drugs with high and strong binding to blood plasma proteins (acetylsalicylic acid), the concentration of free fraction of valproic acid may increase.

Direct anticoagulants (warfarin and other coumarin derivatives). Careful monitoring of INR and prothrombin index is required with concomitant use of valproic acid and indirect anticoagulants.

Cimetidine, erythromycin.

Special Instructions

Hepatic function tests should be performed prior to starting Convulsophin-retard and periodically during the first 6 months of treatment, particularly in patients at risk of liver damage.

As with most antiepileptic drugs, valproic acid may cause a slight increase in hepatic transaminases, particularly at the start of treatment, which are without clinical manifestations and are transient. In such patients a more detailed study of biological parameters, including prothrombin index, should be performed and a dose adjustment and, if necessary, a repeat clinical and laboratory examination may be required.

Before initiating therapy or before surgical intervention, and if subcutaneous hematomas or bleeding occurs spontaneously, we recommend determination of bleeding time and peripheral blood platelet counts, including platelets.

Severe liver damage

Predisposing factors

Some cases of severe liver damage, sometimes fatal, have been described. Clinical experience shows that patients taking several antiepileptic drugs at a time are at risk; patients taking salicylates at the same time (because salicylates are metabolized by the same metabolic pathway as valproic acid).

Suspicion of liver damage

Patients must be clinically monitored for early diagnosis of liver damage. In particular, attention should be paid to the appearance of the following symptoms, which may precede the occurrence of jaundice, especially in patients at risk:

Patients or family members (if using the drug in pediatric patients) should be warned to immediately report the occurrence of any of these symptoms to the attending physician. Patients should have immediate clinical examination and laboratory testing of liver function parameters.

Detection

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among the usual tests, those reflecting the state of protein-synthetic liver function are the most informative, especially the determination of the prothrombin index. Confirmation of prothrombin index deviation from the norm towards its decrease, especially in combination with deviations from the norm of other laboratory values (significant decrease of fibrinogen and clotting factors, increase of bilirubin concentration and activity of “liver” transaminases), as well as appearance of other symptoms indicating liver damage, require discontinuation of the drug. As a precaution, if patients have taken salicylates concomitantly, their administration should also be discontinued.

Pancreatitis

There have been rare reported cases of severe pancreatitis in children and adults that developed regardless of age and duration of treatment.

There have been several cases of hemorrhagic pancreatitis with rapid progression of the disease from initial symptoms to death.

Children are at increased risk of developing pancreatitis, and this risk decreases with increasing age of the child. Risk factors for pancreatitis may include severe seizures, neurologic disorders, or anticonvulsant therapy.

Hepatic failure combined with pancreatitis increases the risk of death.

Patients who have severe abdominal pain, nausea, vomiting, and/or anorexia should be evaluated immediately. If the diagnosis of pancreatitis is confirmed, particularly if pancreatic plasma enzyme activity is elevated, valproic acid should be discontinued and appropriate treatment initiated.

Suicidal thoughts and attempts

Suicidal thoughts and attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increased risk of suicidal thoughts and suicide attempts in all patients taking antiepileptic drugs (including a 0.24% increased risk in patients taking antiepileptic drugs for epilepsy) compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.

Patients taking the drug should therefore be monitored constantly for suicidal thoughts and suicide attempts, and if they occur, appropriate treatment should be given. Patients and caregivers are advised to see a physician immediately if a patient has suicidal thoughts or attempts.

Female children and adolescents, women of childbearing potential, and pregnant women

Pregnancy Prevention Program

Valproic acid has a high teratogenic effect; use of valproic acid leads to a high risk of congenital malformations and CNS abnormalities in the fetus.

The use of valproic acid is contraindicated:

When prescribing medications containing valproic acid, it is necessary to:

Synopsis

Contraindications

Side effects

The incidence of adverse reactions (AR) is given according to the World Health Organization classification: very common ≥10%; common ≥1% and < 10%; infrequent ≥0.1% and < 1%; rare ≥0.01% and < 0.1%; very rare < 0.01%; frequency unknown (no data available to estimate frequency).

Congenital, hereditary, and genetic disorders

Teratogenic risk (see “Use in pregnancy and during breastfeeding”).

Disorders of the blood and lymphatic system

Frequently: anemia, thrombocytopenia (see section “Special indications”). Infrequent: pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia may be with or without bone marrow depression. After withdrawal of the drug, the blood pattern returns to normal. Rarely: disruption of bone marrow hematopoiesis, including isolated erythrocyte aplasia/hypoplasia, agranulocytosis, macrocytic anemia, macrocytosis; decrease in blood clotting factors (at least one), deviation from normal blood clotting parameters (such as increased prothrombin time, increased activated partial thromboplastin time, increased thrombin time, increased INR [international normalized ratio]) (see

The occurrence of spontaneous ecchymoses and bleeding necessitates discontinuation of the drug and examination.

Laboratory and instrumental findings

Rarely: Biotin deficiency/biotinidase insufficiency.

Nervous system disorders

very often: tremor. Frequently:extrapyramidal disorders, stupor*, drowsiness, seizures*, memory disturbances, headache, nystagmus, dizziness (when administered intravenously, dizziness may occur within minutes and pass spontaneously within minutes). Infrequent: Coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia, aggravation of seizures (see section “Special Precautions”). Rarely:reversible dementia combined with reversible cerebral atrophy, cognitive disorders. Frequency unknown:Sedation.

*Stupor and lethargy sometimes resulted in transient coma/encephalopathy and were either isolated or combined with an increase in seizures on treatment, and decreased with drug withdrawal or dose reduction. Most of these cases have been described with combination therapy, especially when phenobarbital or topiramate were used concomitantly, or after a sharp increase in the valproic acid dose.

Hearing and labyrinth disorders

Chasto:reversible and irreversible deafness.

Visual disorders

Frequencyunknown:diplopia.

Disorders of the respiratory organs, chest and mediastinum

Infrequent:pleural effusion.

Disorders on the side .gastrointestinal tract

very often: nausea. Frequently:vomiting, gum changes, (mainly gum hyperplasia), stomatitis, epigastric pain, and diarrhea, which often occur in some patients at the beginning of treatment but usually disappear after a few days and do not require discontinuation of therapy. These reactions can be reduced by taking the drug with or after meals. Infrequent: pancreatitis, sometimes with fatal outcome (development of pancreatitis is possible during the first 6 months of treatment); in case of acute abdominal pain, serum amylase activity should be controlled (see section “Special indications”). Frequency unknown: Abdominal cramps, anorexia, increased appetite.

Disorders Renal and urinary tract disorders

Frequently: involuntary urination. Infrequent:renal failure. Seldom: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of proximal renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), whose mechanism of development is still unclear.

Disorders Skin and subcutaneous tissue

Frequently:hypersensitivity reactions such as urticaria, pruritus; transient (reversible) and/or dose-dependent pathological hair loss (alopecia), including androgenic alopecia in the background of developed hyperandrogenism or polycystic ovarian disease (see Genital and breast disorders and endocrine disorders, as well as alopecia due to hypothyroidism (see Endocrine Disorders, below), nail and nail bed disorders. Infrequent: Angioneurotic edema, rash, hair disorders (such as disorders of normal hair structure, changes in hair color, abnormal hair growth [disappearance of wavy and curly hair or, conversely, the appearance of curly hair in patients with initially straight hair]), hirsutism, acne (see “Endocrine system disorders” below). Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders

Infrequent: decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients taking valproic acid for a long time. The mechanism of effect of valproic acid on bone metabolism has not been established.

Overdose

Clinical manifestations of acute massive overdose usually present as a coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure and vascular collapse/shock.

Cases of intracranial hypertension associated with cerebral edema have been described.

The presence of sodium in valproic acid preparations in overdose may lead to hypernatriemia.

In a massive overdose, death may occur, but the prognosis for overdose is usually favorable.

Symptoms of overdose may vary, and seizures have been reported at very high plasma concentrations of valproic acid.

Treatment of overdose

Hospital overdose emergency care should be as follows: gastric lavage, which is effective within 10-12 hours of taking the drug. To reduce absorption of valproic acid activated charcoal administration may be effective, including its introduction through a nasogastric tube. Cardiovascular and respiratory system monitoring and maintenance of effective diuresis are required. Liver and pancreatic function should be monitored. Respiratory depression may require artificial respiration. Naloxone has been used successfully in individual cases. In very severe cases of massive overdose hemodialysis and hemoperfusion have been effective.

Pregnancy use

The use of valproic acid is contraindicated:

Pregnancy

.Risk associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia may pose a particular risk to both mother and fetus due to the possibility of death.

Risk associated with use of the drug during pregnancy

Experimental studies of reproductive toxicity conducted in mice, rats, and rabbits have shown teratogenic effects in valproic acid.

Valproic acid was found to penetrate the placental barrier in both animals and humans.

Teratogenicity and birth defects

.Available clinical data have demonstrated a greater incidence of small and severe malformations, particularly neural tube defects, craniofacial malformations, limb and cardiovascular malformations, hypospadias, and multiple malformations involving multiple organ systems, in children born to mothers who took valproic acid during pregnancy as compared to their incidence with some other antiepileptic drugs during pregnancy. For example, the risk of birth defects in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was approximately 1.5, 2.3, 2.3, and 3.7 times higher compared with phenytoin, carbamazepine, phenobarbital, and lamotrigine monotherapy, respectively.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of birth defects in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% confidence interval 8.16-13.29). This risk was greater than the 2-3% risk of severe birth defects in the general population. This risk is dose-dependent, but a threshold dose below which there is no such risk cannot be established.

The available data confirm an increase in the incidence of malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft palate, craniostenosis, heart, kidney, and genitourinary system malformations, limb defects (including bilateral radius aplasia and multiple anomalies of different body systems).

Valproic acid intrauterine exposure can also lead to hearing impairment or loss due to ear and/or nasal malformations (secondary defect), and/or direct toxic effects on the hearing organs. Both unilateral and bilateral deafness or hearing impairment have been described. Hearing has not been reported to be restored in most cases. Mental and physical development disorders in children

It has been shown that intrauterine exposure to valproic acid can have adverse effects on the mental and physical development of exposed children. This risk appears to be dose-dependent, but a threshold dose below which no such risk exists cannot be established. An exact gestational period for the risk of developing these effects has not been established, and the risk is not ruled out throughout pregnancy.

Studies of preschool children exposed intrauterine to valproic acid showed that up to 30-40% of such children had early developmental delays (such as delayed mastery of walking skills and delayed speech development) as well as lower intellectual ability, poor speech skills (own speech and understanding of speech) and memory problems.

The intelligence quotient (IQ index) determined in children aged 6 years with a history of intrauterine exposure to valproic acid was, on average, 7-10 points lower than in children who had intrauterine exposure to other antiepileptic drugs. Although the role of other factors that may adversely affect the intellectual development of children exposed to intrauterine valproic acid cannot be ruled out, it is clear that in such children the risk of intellectual disability may be independent of the maternal IQ index.

Data on long-term outcomes are limited

.There is evidence to suggest that children who have had intrauterine exposure to valproic acid have an increased risk of developing a spectrum of autistic disorders (approximately threefold increased risk), including childhood autism (approximately fivefold increased risk). Limited evidence suggests that children with intrauterine exposure to valproic acid are more likely to develop attention deficit/hyperactivity disorder (ADHD).

Both valproic acid monotherapy and combination therapy with valproic acid are often associated with adverse pregnancy outcomes. However, combination antiepileptic therapy including valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy (that is, the risk of fetal impairment is lower with valproic acid monotherapy).

The risk factors for fetal malformations are: a dose greater than 1000 mg/day (but a lower dose does not eliminate this risk) and combining valproic acid with other antiepileptic drugs.

In view of the above, the drug is contraindicated during pregnancy for epilepsy unless there is no alternative treatment (see Special Indications, Contraindications); during pregnancy for the treatment and prevention of bipolar affective disorder.

Simultaneous use with estrogen-containing drugs

Valproic acid does not decrease the therapeutic effectiveness of hormonal contraceptives. However, medications containing estrogen, including estrogen-containing hormonal contraceptives, can increase valproic acid clearance, which may decrease its serum concentrations and consequently decrease its effectiveness. Serum valproic acid concentrations and clinical efficacy (seizure control and mood control) should be monitored when prescribing or withdrawing estrogen-containing medications. The necessity of using or the possibility of discontinuing the drug should be decided before starting the drug or reconsidered if the woman taking the drug plans pregnancy (see sections “Caution”, “Interaction with other medicinal products”).

Pregnancy Planning

If a patient is planning a pregnancy, an epilepsy specialist should evaluate therapy with valproic acid drugs and consider alternative therapy. Every effort should be made to switch the patient from valproic acid-containing therapy prior to conception and until contraception is discontinued (see section “Special Considerations”). If no alternative therapy is available, the patient should be educated about any risks associated with the use of valproic acid-containing medications for the unborn child to help make an informed decision about family planning.

Pregnant women

The use of valproic acid-containing medications is contraindicated during pregnancy unless alternative treatments for epilepsy are available (see

If you become pregnant, see Contraindications and Precautions, and it is contraindicated for bipolar affective disorder.

If you become pregnant, you should see your physician immediately so that you can evaluate the therapy and consider an alternative therapy.

Women of childbearing potential should use effective contraception during treatment with the drug (see section “Special Precautions”).

Women of childbearing potential should be informed about the risks and benefits of using valproic acid-containing medications during pregnancy.

If, despite the known risks of using valproic acid-containing medications during pregnancy, a woman is planning a pregnancy, or has been diagnosed with a pregnancy, the need for valproic acid treatment should be reevaluated based on the indication:

When “bipolar affective disorder” is indicated, discontinuation of valproic acid treatment should be considered;

When “epilepsy” is indicated, continuation of valproic acid treatment or withdrawal of treatment is decided after reassessing the benefit-risk ratio. If, after reassessment of the benefit-risk ratio, treatment with the drug should still be continued during pregnancy, it is recommended to use it in the minimum effective daily dose divided into several doses. It should be noted that in pregnancy, the use of sustained-release dosage forms of the drug is preferable to other dosage forms;

If possible, even before pregnancy, folic acid (at a dose of 5 mg daily) should be started additionally, since folic acid may reduce the risk of neural tube malformations. However, current data do not support its preventive action against valproic acid-induced birth defects;

Prenatal special diagnostic tests to detect possible neural tube defects or other fetal malformations, including detailed ultrasonography, should be performed routinely (including in the third trimester of pregnancy).

Before delivery

.Before delivery, coagulation tests should be performed on the mother, such as determining the platelet count, fibrinogen concentration and clotting time (activated partial thromboplastin time: ACTV).

Risk for neonates

Hemorrhagic syndrome has been reported in single cases in newborns whose mothers have taken valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or decreased levels of other clotting factors. The development of afibrinogenemia, which can be fatal, has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other microsomal liver enzyme inducers.

Hence, coagulation tests (peripheral blood platelet count, plasma concentration of fibrinogen, clotting factors and coagulogram) should always be performed in newborns whose mothers were treated with valproic acid during pregnancy.

Hypoglycemia has been reported in infants whose mothers took valproic acid in the third trimester of pregnancy.

Hypothyroidism has been reported in infants whose mothers took valproic acid during pregnancy.

In newborns whose mothers have taken valproic acid in the last trimester of pregnancy, withdrawal syndrome (specifically, agitation, irritability, hyperreflexia, tremors, hyperkinesia, muscle tone disorders, tremors, seizures, and difficulty feeding) may occur.

Fertility

With regard to the possible development of dysmenorrhea, amenorrhea, polycystic ovaries, increased blood testosterone concentrations, decreased fertility in women may occur (see section “Side effects”). In men, valproic acid may decrease sperm motility and impair fertility (see section “Side effects”). These impairments in fertility have been found to be reversible after discontinuation of treatment.

Breastfeeding period

Excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in serum.

There are limited clinical data on the use of valproic acid in breastfeeding, and therefore use of the drug during this period is not recommended.

Based on the literature and limited clinical experience, breastfeeding with monotherapy of the drug may be considered, but the side effect profile of the drug, particularly the hematologic abnormalities it causes, must be taken into consideration.

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