Encorat chrono: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENCORATE CHRONO (ENCORATECHRONO)

Composition:

Active substances: sodium valproate and valproic acid;

One tablet contains 133.5 mg of sodium valproate and 58 mg of valproic acid, equivalent to 200 mg of sodium valproate;

One tablet contains 200 mg of sodium valproate and 87 mg of valproic acid, equivalent to 300 mg of sodium valproate;

One tablet contains 333 mg of sodium valproate and 145 mg of valproic acid, equivalent to 500 mg of sodium valproate;

Excipients: hypromellose, maize starch, colloidal anhydrous silicon dioxide, talc, magnesium stearate, acrylic copolymer, titanium dioxide (E 171), Yellow FCF (E 110), polyethylene glycol 6000.

Pharmaceutical form. Prolonged-release coated tablets.

Main physicochemical properties:

Round, biconvex, orange-coated tablets, smooth on both sides (200 mg, 300 mg);

Capsule-shaped, orange-coated tablets, smooth on both sides (500 mg).

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03A G01.

Pharmacological properties.

Pharmacodynamics.

Pharmacological studies in animals have shown that sodium valproate has anticonvulsant properties in various models of experimental epilepsy (with generalized and focal seizures).

Similarly, clinical studies have demonstrated that sodium valproate exerts antiepileptic effects in different forms of human epilepsy. This action is likely based on GABAergic (mediated by gamma-aminobutyric acid) activity, which prevents or limits the spread of electrical discharges.

In some in vitro studies, sodium valproate was observed to potentially stimulate replication of HIV-1; however, this effect is weak and has not been reproducible in most studies. The clinical significance of this effect in patients infected with HIV-1 is unknown. When administering sodium valproate to patients infected with HIV-1, this information should be taken into account for correct interpretation of viral load test results.

Pharmacokinetics.

Absorption. After oral administration of Encorate Chrono, its bioavailability in plasma approaches 100%.

In plasma, the drug is present in the form of valproic acid. The absorption of Encorate Chrono, prolonged-release coated tablets, in the gastrointestinal tract begins immediately and proceeds in a uniform and prolonged manner. This ensures the absence of plasma concentration peaks of the active substance and allows for better maintenance of therapeutic concentrations of valproic acid over time.

Distribution. The volume of distribution of valproic acid is primarily limited to blood and rapidly exchanging extracellular fluids.

Protein binding occurs mainly with albumin and is dose-dependent and saturable. At total plasma concentrations of valproic acid of 40–100 mg/L, the free fraction typically ranges from 6% to 15%.

The concentration of valproic acid in cerebrospinal fluid is similar to that of its free fraction in plasma (approximately 10%).

Valproic acid is removed during dialysis, but the amount eliminated is significantly reduced due to its binding to albumin (approximately 10%).

Sodium valproate crosses the placental barrier. Valproic acid is excreted into breast milk (1–10% of the total serum concentration) in women receiving Encorate Chrono during lactation.

After initiation of long-term therapy with Encorate Chrono, steady-state concentrations of valproic acid in serum are reached within approximately 3–4 days, although in some cases this may take a longer period.

The therapeutic plasma concentration of valproic acid is generally within the range of 40–100 mg/L (278–694 µmol/L). If the total plasma concentration of valproic acid remains above 150 mg/L (1040 µmol/L), the daily dose of the drug should be reduced.

Metabolism. Encorate Chrono 500 mg is primarily metabolized in the liver. The main metabolic pathways are glucuronidation and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate its own metabolism or the metabolism of other substances such as estrogens and progestogens. This property is reflected in the absence of any enzyme-inducing effect on the cytochrome P450 system.

Elimination. During continuous administration of valproic acid, the average plasma half-life in adults is 10.6 hours (although it may range from 5 to 20 hours), necessitating the division of the daily dose into two administrations. In full-term neonates, the half-life initially ranges from 20 to 30 hours and gradually decreases with development, approaching adult values.

Valproic acid is excreted primarily by the kidneys. A small fraction is excreted unchanged, while the majority of the administered dose is eliminated as metabolites.

Pharmacokinetics in specific patient populations.

Renal impairment. Reduced albumin binding may occur. Increased serum concentration of the free fraction of valproic acid should be considered. In such cases, the dose of the drug should be appropriately reduced.

Elderly patients. Changes in pharmacokinetic parameters have been observed, but they were not particularly significant. Therefore, dosage should be determined based on clinical response (i.e., seizure control).

Preclinical safety data

In repeated-dose toxicity studies, testicular degeneration/atrophy, abnormalities in spermatogenesis, and reduced testicular weight were reported in adult rats and dogs following oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.

In young rats, reduced testicular weight was observed only at doses exceeding the maximum tolerated dose (from 240 mg/kg/day intraperitoneally or intravenously), without associated histopathological changes. No effects on male reproductive organs were observed at tolerated doses (up to 90 mg/kg/day). Based on these data, the effect on testes in young animals was not considered more pronounced than in adults. The significance of testicular sensitivity to valproates in the pediatric population is unknown.

In a rat fertility study, valproate at doses up to 350 mg/kg/day did not affect male reproductive function. However, male infertility has been identified as an adverse reaction in humans (see sections "Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility" and "Adverse reactions").

Clinical characteristics.

Indications.

The main indication for the use of Encorate Chrono, preferably as monotherapy, is primary generalized epilepsy: minor epileptic seizures/absence epilepsy, bilateral massive myoclonic seizures, major epileptic seizures with or without myoclonia, photosensitive forms of epilepsy.

Encorate Chrono is also effective, either as monotherapy or in combination with other antiepileptic agents, in the following conditions:

secondary generalized epilepsy, especially West syndrome (infantile spasms) and Lennox-Gastaut syndrome;
partial epilepsy with simple or complex symptomatology (psychosensory forms, psychomotor forms);
epilepsy with secondary generalization;
mixed forms of epilepsy (generalized and partial).

Treatment of manic episodes associated with bipolar affective disorders when contraindications exist or intolerance to lithium is present. Prevention of relapses of dysthymic episodes in adult patients with bipolar disorders who have shown a therapeutic response to valproate during treatment of manic episodes.

Contraindications.

Pregnancy, except in cases where other treatment methods are ineffective (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Women of childbearing potential who do not meet the requirements of the Pregnancy Prevention Programme (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Hypersensitivity to valproate, divalproex, valpromide, or to any component of the medicinal product in the patient's history.
Acute hepatitis.
Chronic hepatitis.
Severe hepatitis in personal or family history, particularly if drug-induced.
Hepatic porphyria.
Combination with mefloquine and St. John's wort extract (see section "Interaction with other medicinal products and other forms of interaction").
Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial gamma-polymerase enzyme, e.g., Alpers-Huttenlocher syndrome, children under two years of age suspected of having a disorder associated with gamma-polymerase, and patients with a history of urea cycle disorders (see section "Special precautions for use").
Deficiency of enzymes in the urea cycle (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Effect of valproate on other medicinal products.

Neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants, and benzodiazepines. The drug may potentiate the effects of other neurotropic agents such as neuroleptics, MAOIs, antidepressants, and benzodiazepines. Therefore, clinical monitoring and possible dose adjustment are required. Data from clinical studies have shown that adding olanzapine to valproate or lithium therapy may significantly increase the risk of adverse reactions associated with olanzapine, such as neutropenia, tremor, dry mouth, increased appetite, weight gain, speech disorders, and somnolence.

Lithium. Valproate does not affect serum lithium levels.

Olanzapine. Valproate may reduce plasma concentrations of olanzapine.

Phenobarbital. Valproate increases plasma concentrations of phenobarbital due to inhibition of hepatic metabolism, resulting in somnolence, especially in children. Therefore, clinical monitoring is required during the first 15 days of combination therapy. If somnolence occurs, the dose of phenobarbital should be immediately reduced and, if necessary, its plasma concentration determined.

Primidone. Valproate increases plasma concentrations of primidone, thereby intensifying associated adverse effects (such as somnolence). This interaction diminishes with prolonged therapy. Clinical monitoring is recommended, especially at the beginning of combination therapy, with dose adjustment of primidone if necessary.

Phenytoin. Valproate reduces total plasma concentrations of phenytoin; in particular, it increases the concentration of the free fraction of phenytoin, possibly leading to signs of overdose (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When analyzing plasma concentrations of phenytoin, measurement of the free fraction level should be performed.

Carbamazepine. Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. Additionally, decreased plasma concentrations of valproic acid due to enhanced hepatic metabolism induced by carbamazepine. Clinical monitoring, measurement of plasma drug concentrations, and dose adjustment of both anticonvulsants are indicated.

Lamotrigine. Increased risk of serious skin reactions (toxic epidermal necrolysis). Additionally, possible increase in lamotrigine plasma concentrations (due to reduced hepatic metabolism by sodium valproate).

If concomitant use of these drugs cannot be avoided, careful clinical monitoring of the patient is required.

Felbamate. Valproate may reduce the average clearance of felbamate by 16%.

Rufinamide. Possible increase in rufinamide concentrations, especially in children with body weight less than 30 kg. For children weighing less than 30 kg, the total daily dose should not exceed 600 mg after titration.

Propofol. Possible increase in blood levels of propofol. When used concomitantly with valproate, consideration should be given to reducing the dose of propofol.

Zidovudine. Increased risk of zidovudine adverse reactions, especially hematological ones, due to reduced metabolism by valproic acid. Regular monitoring of clinical and laboratory parameters is indicated. Complete blood count should be performed monthly during the first two months of combination therapy to detect anemia.

Zonisamide. Enhanced hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Nimodipine (oral and, by extrapolation, parenteral). In patients receiving sodium valproate and nimodipine simultaneously, plasma concentration of nimodipine may increase by 50%; therefore, in case of arterial hypotension, the dose of nimodipine should be reduced.

Temazolomide. Concomitant use of temazolomide and valproate may lead to a slight reduction in temazolomide clearance, which is not clinically significant.

Effect of other medicinal products on valproic acid.

St. John's wort. Risk of reduced plasma concentrations and decreased efficacy of the anticonvulsant.

Aztreonam. Risk of seizures due to reduced plasma concentrations of valproic acid. Clinical monitoring of the patient, measurement of plasma drug concentrations, and possible dose adjustment of the anticonvulsant during and after antibiotic treatment are required.

Phenobarbital and, by extrapolation, primidone. Enhanced hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Phenytoin and, by extrapolation, fosphenytoin. Enhanced hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Mefloquine and chloroquine enhance the metabolism of valproic acid. Additionally, they may provoke seizures, increasing the risk of epileptic seizures when these two drugs are used concomitantly. Therefore, dose adjustment of Encorate Chrono may be necessary.

Concomitant use of Encorate Chrono with medicinal products that have a high degree of plasma protein binding (e.g., with acetylsalicylic acid) may lead to increased concentrations of the free fraction of valproic acid in plasma.

Valproic acid may increase the concentration of the free fraction of warfarin and other coumarin anticoagulants due to competition for albumin binding sites. Therefore, in patients receiving vitamin K antagonists, prothrombin time should be monitored more closely.

Concomitant use with cimetidine or erythromycin is highly likely to increase serum concentrations of valproic acid (due to reduced hepatic metabolism of valproic acid).

Carbapenems. Reports indicate reduced blood levels of valproic acid when used concomitantly with carbapenem agents (panipenem, meropenem, imipenem), leading to a 60–100% reduction in valproic acid levels within two days and risk of seizure occurrence. Due to the rapid and significant decrease in drug concentration, concomitant use of carbapenems in stabilized patients taking valproic acid should be avoided (see section "Adverse reactions"). If treatment with these antibiotics cannot be avoided, careful monitoring of valproic acid blood levels is required.

Rifampicin. Risk of seizures due to enhanced hepatic metabolism of valproate. Clinical monitoring, laboratory testing, and possible dose adjustment of the anticonvulsant are indicated during and after rifampicin therapy.

Felbamate reduces the clearance of valproic acid by 22–50%, thereby increasing serum concentrations of valproic acid with risk of overdose. Clinical monitoring, laboratory testing, and possible dose adjustment of valproate are indicated during and after felbamate therapy.

Concomitant use with protease inhibitors such as lopinavir and ritonavir increases plasma concentrations of valproate.

Cholestyramine. Concomitant use with cholestyramine may lead to reduced plasma concentrations of valproate.

Estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives. Estrogens are inducers of UDP-glucuronosyltransferase isoenzymes involved in valproate glucuronidation and may increase valproate clearance, potentially leading to reduced plasma concentrations of valproate and reduced efficacy (see section "Special precautions for use"). Monitoring of plasma valproate levels is recommended.

On the other hand, valproic acid does not exert enzyme-inducing effects; therefore, it does not reduce overall plasma concentrations of estrogen and progesterone in women using hormonal contraceptives.

Other interactions.

Caution is recommended when using valproate in combination with new antiepileptic drugs whose pharmacodynamics may not be fully understood.

Topiramate. Increased risk of encephalopathy and hyperammonemia. Regular monitoring of clinical and laboratory parameters is indicated.

Acetazolamide. Enhanced hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Quetiapine. Concomitant use of valproate and quetiapine may increase the risk of neutropenia/leukopenia.

Special precautions for use.

Pregnancy prevention programme.

Due to the high teratogenic potential and risk of developmental disorders in infants exposed to valproate in utero, the medicinal product Encorate Chrono should not be used in female children and adolescents, women of childbearing potential, or pregnant women, except when other treatments are ineffective or not tolerated. If treatment with other medicinal products is not possible, valproate may be prescribed only in accordance with the requirements of the Pregnancy Prevention Programme (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Conditions of the Pregnancy Prevention Programme.

The prescribing physician must:

assess individual circumstances in each case, involve the patient in discussions, ensure her engagement, discuss treatment options, and ensure understanding of the risks and measures required to minimise risks;
assess the possibility of pregnancy in all female patients;
ensure that the patient understands and is aware of the risks of congenital malformations and neurodevelopmental disorders, particularly the significance of these risks for children exposed to valproate in utero;
ensure that the patient understands the necessity of a pregnancy test prior to initiating treatment and, if necessary, during treatment;
advise the patient to use contraception and verify her ability to comply with continuous use of effective contraceptive methods (additional information is provided in the subsection "Contraception" of this warning) throughout the entire course of valproate treatment;
ensure that the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in epilepsy management;
ensure that the patient understands the need to consult her physician if she plans a pregnancy, to allow timely discussion and transition to alternative treatments before conception and before discontinuing contraception;
ensure that the patient understands the need to seek immediate medical advice if pregnancy occurs;
provide the Patient Information Leaflet;
ensure that the patient understands the dangers and necessary precautionary measures associated with valproate use (Annual Risk Communication Form).

These conditions also apply to women who are currently not sexually active, except in cases where, in the physician’s opinion, there are compelling reasons to consider pregnancy risk absent.

Female children.

The prescribing physician must ensure that parents/guardians of female children understand the necessity of immediately consulting a specialist once menstruation begins in a female child receiving valproate.
The prescribing physician must ensure that parents/guardians of female children have received comprehensive information about the risks of congenital malformations and neurodevelopmental disorders, including the magnitude of these risks for children exposed to valproate during fetal development.
In patients who have already started menstruation, the prescribing physician must annually reassess the necessity of valproate treatment and consider the possibility of switching to alternative treatments. If valproate remains the only acceptable treatment, the necessity of using effective contraception and all other conditions of the Pregnancy Prevention Programme must be discussed. The specialist should take all possible measures to transition female children to alternative treatments before they reach sexual maturity or adulthood.

Pregnancy testing. Pregnancy must be excluded before initiating valproate therapy. Valproate treatment should not be initiated in women of childbearing potential unless a negative pregnancy test result has been obtained using plasma with a sensitivity of at least 25 mIU/mL, as confirmed by a healthcare professional, to prevent unintended exposure during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.

Contraception. Women of childbearing potential prescribed valproate must use effective contraceptive methods continuously throughout the entire duration of valproate treatment. These patients should be provided with comprehensive information on pregnancy prevention and referred for contraceptive counselling if they are not using effective contraceptive methods. At least one effective contraceptive method (preferably user-independent, such as an intrauterine device or implant) or two complementary methods, one of which is a barrier method, should be used. The choice of contraceptive method should be individualised, with patient involvement in the discussion, to ensure active participation and adherence to the chosen preventive measures. Even in patients with amenorrhoea, all recommendations for effective contraception must be followed.

Annual specialist review of treatment. The specialist must reassess at least annually whether valproate remains the most appropriate treatment for the patient. The Annual Risk Communication Form should be discussed at the beginning of treatment and during each annual review, and the specialist must ensure that the patient understands the information provided. The Annual Risk Communication Form must be properly completed and signed by both the prescribing physician and the patient (or her legal representative).

Pregnancy planning. If a woman plans to become pregnant, a specialist experienced in epilepsy management should reassess valproate treatment and consider the possibility of switching to alternative treatments. All possible measures should be taken to transition the patient to acceptable alternative treatments before conception and before discontinuing contraception (see section "Use during pregnancy or breastfeeding"). If such transition is not possible, the woman should receive additional counselling regarding the risks associated with valproate exposure to the unborn child, to ensure she has adequate information for making an informed decision about family planning.

Pregnancy. If a woman taking valproate becomes pregnant, she must be referred immediately to a specialist for reassessment of valproate treatment and consideration of alternative treatments. Pregnant patients who have received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding valproate use during pregnancy (see section "Use during pregnancy or breastfeeding").

The pharmacist must ensure that:

at each dispensing of valproate, the patient receives the patient card and understands the information provided;
patients are advised not to discontinue valproate and to seek immediate specialist advice in case of planned or suspected pregnancy.

Educational materials. To assist healthcare professionals and patients in avoiding valproate use during pregnancy, the marketing authorisation holder provides educational materials to draw additional attention to the warnings regarding teratogenicity (the ability to cause congenital malformations) and fetotoxicity (the ability to cause neurodevelopmental disorders) of valproate, and to provide instructions on the use of valproate in women of childbearing potential, along with detailed information on the requirements of the Pregnancy Prevention Programme. The Patient Information Leaflet and patient card must be provided to all women of childbearing potential using valproate.

The Annual Risk Communication Form must be used, properly completed, and signed at the initiation of treatment and during each annual specialist review of valproate treatment by both the specialist and the patient (or her legal representative).

Despite the lack of specific evidence for unexpected recurrence of primary symptoms after discontinuation of valproate, treatment should generally be discontinued only under medical supervision, with gradual dose reduction. This is due to the possibility of sudden changes in plasma drug concentration, which may lead to symptom recurrence.

Severe liver damage.

Conditions of occurrence. Cases of severe liver damage, sometimes leading to fatal outcomes, have been reported. Experience shows that the highest risk, particularly with concomitant use of other antiepileptic drugs, occurs in infants and children under 3 years of age with severe epilepsy, especially those with brain damage, intellectual disability, and/or genetically determined metabolic or degenerative disorders.

The frequency of such complications decreases significantly in children aged 3 years and older and gradually declines with age.

Encorate Chrono should be used in children under 3 years of age only as monotherapy. For patients in this age group, treatment should be initiated only after careful consideration of clinical benefits versus the risk of liver damage or pancreatitis. Additionally, salicylates should not be used in children under 16 years of age (see reference information on acetylsalicylic acid/salicylates regarding Reye's syndrome).

In most cases, such liver damage occurred within the first 6 months of treatment, usually between 2 and 12 weeks, and most frequently during combination antiepileptic therapy.

Signs to watch for. Early diagnosis is based on clinical presentation. Symptoms that may precede jaundice, especially in patients at risk (see above "Conditions of occurrence"), include:

sudden onset of non-specific symptoms such as asthenia, anorexia, lethargy, somnolence, sometimes associated with recurrent vomiting and abdominal pain;
in patients with epilepsy – recurrence of epileptic seizures despite adequate adherence to therapy.

Patients (or their caregivers, if the patient is a child) should be informed of the need to seek immediate medical attention if these symptoms occur. The patient should be examined promptly, including clinical evaluation and liver function laboratory tests.

Detection. Liver function tests should be performed before initiating therapy and then regularly during the first 6 months of treatment. It should be emphasised that isolated and transient elevations of transaminases are frequently observed, especially at the beginning of therapy, without clinical signs. In addition to routine tests, the most informative are those reflecting protein synthesis, particularly prothrombin levels. If pathologically low prothrombin levels are confirmed, especially in conjunction with other abnormal biological parameters (significant decrease in fibrinogen and coagulation factors, elevated bilirubin and liver enzymes), valproate therapy must be discontinued immediately. As a precautionary measure and in cases of concomitant use, salicylate therapy should also be discontinued, as they share the same metabolic pathway. Laboratory tests should be repeated depending on the observed changes.

As with other antiepileptic drugs, isolated and transient elevations of transaminases are frequently observed, especially at the beginning of therapy. In such patients, a more comprehensive laboratory evaluation (including prothrombin level determination) is recommended; dose reduction may be considered if necessary, and laboratory tests should be repeated.

Pancreatitis.

Severe pancreatitis, sometimes with fatal outcomes, has been reported very rarely. It may occur independently of patient age and duration of treatment, with particularly high risk in young children.

Pancreatitis with unfavourable clinical outcomes is usually observed in younger children or patients with severe epilepsy, brain damage, or those receiving polytherapy with antiepileptic drugs.

If pancreatitis develops on the background of liver failure, the risk of a fatal outcome increases significantly.

In case of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting, and/or loss of appetite, pancreatitis should be considered; the drug should be discontinued in patients with elevated pancreatic enzymes, and appropriate alternative therapy measures should be taken.

A blood test (complete blood count with platelet count, assessment of bleeding time and coagulation parameters) is recommended before initiating treatment, then after 15 days and at the end of treatment, as well as before any surgical procedures and in case of haematoma or spontaneous bleeding (see section "Adverse reactions").

Exacerbation of seizures.

As with other antiepileptic agents, valproate may paradoxically lead to reversible worsening of seizure frequency and severity (including status epilepticus) or emergence of new seizure types instead of improvement. Patients should be advised to seek immediate medical advice if seizures worsen (see section "Adverse reactions").

These seizures must be differentiated from those that may occur due to pharmacokinetic interactions (see section "Interaction with other medicinal products and other forms of interaction"), toxicity (liver damage or encephalopathy, see sections "Special precautions for use" and "Adverse reactions") or overdose.

Since this medicinal product is metabolised to valproic acid, it should not be combined with other medicinal products undergoing the same transformation to avoid valproic acid overdose (e.g., sodium valproate, valpromide).

Suicidal thoughts and behaviour.

Cases of suicidal thoughts and behaviour have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of data from randomised placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behaviour. The mechanism of this effect is unknown, and current data do not allow exclusion of an increased risk with valproate use.

Therefore, patients should be monitored for early detection of suicidal thoughts and behaviour, and appropriate therapy should be initiated. Patients and caregivers should be warned that if signs of suicidal thoughts or behaviour occur, immediate medical help should be sought.

Effect of long-term treatment on bone metabolism.

Cases of decreased bone mineral density, indicating possible osteopenia or osteoporosis and even leading to atypical fractures, have been reported in patients undergoing long-term treatment with valproic acid. The mechanism of valproic acid's effect on bone metabolism is not yet fully understood (see section "Adverse reactions").

Interaction with other medicinal products.

Concomitant use of Encorate Chrono with lamotrigine and carbapenems is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

This medicinal product contains 18.5 mg of sodium in one 200 mg tablet, 28 mg of sodium in one 300 mg tablet, and 46 mg of sodium in one 500 mg tablet. This should be considered for patients on a strict low-sodium diet.

Cognitive or extrapyramidal disorders.

Cognitive or extrapyramidal disorders may be accompanied by signs of brain atrophy on imaging studies. Therefore, this type of clinical presentation may be misinterpreted as dementia or Parkinson's disease. These disorders are reversible after discontinuation of the drug (see section "Adverse reactions").

Patients with known or suspected mitochondrial disorders.

Valproate may trigger or worsen clinical symptoms of existing mitochondrial disorders caused by mutations in mitochondrial DNA or in the nuclear gene encoding mitochondrial polymerase gamma (POLG).

In particular, cases of valproate-induced acute liver failure and fatal outcomes due to liver dysfunction have been reported in patients with inherited neurometabolic syndromes caused by POLG gene mutations (e.g., Alpers-Huttenlocher syndrome). POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or those with symptoms suggesting such a disorder, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Testing for POLG mutation should be performed according to current clinical practice for diagnostic evaluation of such disorders (see section "Contraindications").

Haematological investigations.

Before initiating therapy, a blood test (complete blood count including platelet count, bleeding time, and coagulation time) should be performed, especially if surgery is planned or in case of haematoma or spontaneous bleeding (see section "Adverse reactions").

Renal impairment.

Dose reduction may be necessary in patients with renal impairment. Since plasma concentration data may sometimes be difficult to interpret, the dose should be adjusted according to the clinical response obtained.

Concomitant use of salicylate derivatives in children should be avoided due to the risk of hepatotoxicity and bleeding.

This medicinal product is contraindicated in patients with deficiencies of urea cycle enzymes. Several cases of hyperammonaemia with stupor or coma have been reported in such patients (see section "Contraindications").

In children with a history of unexplained hepatic and gastrointestinal disorders (loss of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, developmental delay, or a family history of neonatal or infant death, metabolic tests, particularly ammonia levels in blood on an empty stomach and after food intake, should be performed before initiating any valproate therapy.

Although this medicinal product is known to cause immunological disorders only in exceptional cases, the benefit-risk ratio should be carefully considered in patients with systemic lupus erythematosus.

At the beginning of treatment, patients should be informed about the risk of weight gain. Appropriate measures, primarily related to dietary adjustments, should be taken to minimise this effect.

Systemic lupus erythematosus.

Urea cycle disorders.

Weight gain.

At the beginning of treatment, patients should be informed about the risk of weight gain. Appropriate measures, primarily related to dietary adjustments, should be taken to minimise this effect.

Patients with diabetes mellitus.

Since valproate is excreted mainly by the kidneys, partly in the form of ketone bodies, urine tests for ketone bodies may yield false-positive results in patients with diabetes mellitus.

Patients with concomitant carnitine palmitoyltransferase (CPT) deficiency.

Patients with concomitant CPT type II deficiency should be warned of the increased risk of rhabdomyolysis when taking valproate.

Alcohol.

Alcoholic beverages should not be consumed during valproate treatment.

Excipients. The medicinal product contains the azo dye tartrazine (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

Valproate is contraindicated (see sections "Contraindications" and "Special precautions for use"):

during pregnancy, except when other treatments are ineffective;
in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme.

Risk associated with valproate exposure during pregnancy.

Both valproate monotherapy and polytherapy containing valproate are associated with adverse pregnancy outcomes. Available data indicate that antiepileptic polytherapy including valproate is associated with a higher risk of congenital malformations than valproate monotherapy.

Congenital malformations.

Meta-analysis data from registry and cohort studies show that 10.73% of children born to women with epilepsy who received valproate monotherapy during pregnancy had congenital malformations (95% CI: 8.16–13.29). This risk of common malformations is higher than in the general population, where the risk is approximately 2–3%. This risk is dose-dependent, but a threshold dose below which the risk is absent cannot be established.

Available data indicate increased frequency of rare and common malformations. The most common malformations include neural tube defects (approximately 2–3%), facial dysmorphisms, cleft lip and palate, craniosynostosis, cardiac, renal and urogenital malformations, limb malformations (including bilateral aplasia of the radius), and multiple anomalies affecting various organ systems.

Neurodevelopmental disorders.

Available data indicate that in utero exposure to valproate may cause adverse effects on the intellectual and physical development of exposed children. This risk is likely dose-dependent, but a threshold dose below which the risk is absent cannot be established based on current data. The exact period of pregnancy during which these effects may occur is not defined, and the possibility of risk throughout the entire pregnancy cannot be excluded.

Studies involving preschool children exposed to valproate in utero have shown developmental delay in approximately 30–40% of cases: delayed speech and walking, reduced intellectual functions, impaired language skills (speech and language comprehension), and memory disorders.

The intelligence quotient (IQ) measured in school-aged children (6 years old) exposed to valproate in utero was on average 7–10 points lower than in children exposed to other antiepileptic drugs. Although the role of other factors cannot be excluded, there is evidence that the risk of reduced intellectual function in valproate-exposed children may not depend on maternal IQ.

Data on long-term outcomes are limited.

Available data indicate that children exposed to valproate in utero have an increased risk of autism spectrum disorders (approximately 3 times) and childhood autism (approximately 5 times) compared to the general studied population.

Limited data suggest that children exposed to valproate in utero are more likely to develop symptoms of attention deficit hyperactivity disorder (ADHD).

Women of childbearing potential (see information above and section "Special precautions for use").

Encorate Chrono should not be used in women of childbearing potential, except when other treatments are ineffective or poorly tolerated. If other treatments cannot be used, Encorate Chrono may be prescribed only if the conditions of the Pregnancy Prevention Programme are met (see section "Special precautions for use"), including:

the patient is not pregnant (negative pregnancy test results using plasma with sensitivity of at least 25 mIU/mL at the start of treatment and periodically during treatment);
the patient uses at least one effective contraceptive method;
the patient has been informed of the risks of valproate use during pregnancy.

Women of childbearing potential should have the benefit-risk ratio reassessed at regular intervals during treatment (at least annually).

If a woman plans pregnancy.

Valproate treatment in women planning pregnancy or who are pregnant should be reassessed. Whenever possible, all measures should be taken to switch women planning pregnancy to an appropriate alternative treatment before conception and before discontinuing contraception (see section "Special precautions for use"). If such transition is not possible, the woman should receive additional counselling regarding the risks of valproate use for the unborn child to ensure she has adequate information for making an informed decision about family planning.

Folic acid supplementation before and during early pregnancy may reduce the risk of neural tube defects, which can occur in any pregnancy. However, current data do not confirm that this prevents birth defects or developmental abnormalities due to valproate exposure.

Pregnant women.

The use of valproate for epilepsy treatment is contraindicated during pregnancy, except when other treatments are ineffective (see sections "Contraindications" and "Special precautions for use").

If a woman taking valproate becomes pregnant, she must be referred immediately to a specialist for consideration of alternative treatments.

During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the woman may be associated with a particular risk of death for both the mother and the unborn child.

If, after careful risk-benefit assessment, continuation of valproate treatment during pregnancy is decided, the following is recommended: the lowest effective dose should be used, and the daily dose of valproate should be divided into several doses throughout the day. The use of a prolonged-release formulation is preferable compared to other formulations to avoid high peak plasma concentrations (see section "Dosage and administration").

All pregnant patients who received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the case of drug treatment during pregnancy.

Specialised prenatal monitoring should be performed to detect possible fetal neural tube defects or other malformations.

In utero exposure to valproates may also lead to hearing impairment or deafness due to malformations of the ear and/or nose (secondary effect) and/or direct toxic effects on hearing function. Cases of both unilateral and bilateral deafness or hearing impairment have been reported. Outcomes were not known in all cases. In most cases with known outcomes, recovery did not occur.

In utero exposure to valproates may lead to eye malformations (including coloboma, microphthalmia), reported in combination with other congenital malformations. These eye malformations may affect vision.

Before delivery.

Before delivery, coagulation tests should be performed in the woman, including platelet count, fibrinogen level, and coagulation time (activated partial thromboplastin time, aPTT).

Folic acid supplementation before pregnancy may reduce the risk of fetal neural tube defects, which is characteristic of any pregnancy. However, current evidence does not confirm that this prevents birth defects or developmental abnormalities due to valproate exposure.

Risk for newborns.

Isolated cases of haemorrhagic syndrome have been reported in newborns whose mothers received sodium valproate/valproic acid during pregnancy. This haemorrhagic syndrome is caused by thrombocytopenia and hypofibrinogenemia. Cases of afibrinogenemia have also been reported, some of which were fatal. However, this syndrome should be differentiated from vitamin K-dependent coagulation factor deficiency caused by phenobarbital and enzyme inducers. Normal coagulation test results in the mother do not exclude coagulation disorders in her newborn.

Therefore, newborns should undergo blood tests including platelet count, plasma fibrinogen level, coagulation tests, and determination of coagulation factor levels.

Cases of hypoglycaemia have been reported in newborns whose mothers took valproate during the third trimester of pregnancy.

Cases of hypothyroidism have been reported in newborns whose mothers took valproate during pregnancy.

Withdrawal abstinence syndrome (including agitation, irritability, hyperexcitability, increased neuromuscular excitability, hyperkinesia, muscle tone disturbances, tremor, seizures, and feeding difficulties) may occur in newborns whose mothers took valproate during the last trimester of pregnancy.

Monitoring of newborns/older children.

Children exposed to valproate during fetal development should undergo careful monitoring of neurodevelopmental parameters, and appropriate treatment should be initiated as early as possible if necessary.

Breastfeeding period. Excretion of sodium valproate into breast milk is approximately 1–10% of its serum concentration. Blood disorders have been observed in newborns/infants whose mothers received treatment with this medicinal product. The decision whether to discontinue breastfeeding or discontinue/abstain from Encorate Chrono should be based on the benefit of breastfeeding for the child and the benefit of treatment for the woman.

Fertility.

Cases of amenorrhoea, polycystic ovary syndrome, and elevated testosterone levels have been reported in women taking valproate (see section "Adverse reactions"). Valproate use may also lead to impaired fertility in men (see section "Adverse reactions"). In reported cases, fertility dysfunction was reversible and resolved after discontinuation of the drug.

Ability to influence reaction speed when driving or operating machinery.

Due to possible adverse effects, Encorate Chrono may negatively affect the ability to drive vehicles or operate machinery.

Patients should be warned of the risk of somnolence, particularly in cases of combination anticonvulsant therapy or when the drug is used in combination with benzodiazepines (see section "Interaction with other medicinal products and other forms of interaction").

Dosage and Administration.

Female adolescents, women of reproductive age.

Valproate therapy should be initiated and supervised by a specialist experienced in the treatment of epilepsy.

Valproate should not be used in female children and adolescents, women of reproductive age, or pregnant women, except when other treatment options are ineffective or not tolerated. In such cases, valproate should be prescribed in accordance with the requirements of the Pregnancy Prevention Programme (see sections «Contraindications» and «Special precautions for use»).

Epilepsy.

Usual dosage. The daily dose is determined according to the patient’s age and body weight. However, it should be noted that the range of individual sensitivity to valproate is quite wide. The optimal dose is established based on the clinical response achieved. In cases of inadequate seizure control or suspicion of possible adverse reactions, in addition to clinical monitoring, measurement of plasma drug concentration may be required.

As first-line monotherapy.

Due to the Chrono (prolonged-release) dosage form, the daily dose of the drug can be administered once daily. Ideally, the drug should be taken at the beginning of a meal. The following daily doses are generally recommended:

25 mg/kg for children;
20–25 mg/kg for adolescents;
20 mg/kg for adults;
15–20 mg/kg for elderly patients.

If possible, treatment with Encorate Chrono should be initiated gradually. The initial daily dose is 10–15 mg/kg, which should then be increased every 2–3 days, reaching the recommended daily dose in approximately one week. After achieving the required dose of the drug used as monotherapy — for example, 15 mg/kg/day for elderly patients; 20 mg/kg/day for adults or adolescents; 25 mg/kg/day for children — a certain period of observation may be necessary. If clinical efficacy at this stage is satisfactory, this dose should be maintained.

In rare cases, particularly during monotherapy, daily doses higher than 25 mg/kg for elderly patients, 30 mg/kg for adults or adolescents, or 25 mg/kg for children may be required.

If seizure control is still not achieved with these doses, dose escalation may be continued. If the daily dose exceeds 50 mg/kg, it is recommended to divide the dose into three administrations, with additional clinical monitoring and biochemical blood tests (see section «Special precautions for use»).

Use of Encorate Chrono in combination with other antiepileptic drugs.

Initiation of sodium valproate should follow the same approach as for first-line monotherapy. The average daily dose is usually identical to that recommended for monotherapy. However, in some cases, this dose may be increased by 5–10 mg/kg.

The effect of Encorate Chrono on other antiepileptic drugs should also be considered (see section «Interaction with other medicinal products and other forms of interaction»).

Switching from another antiepileptic drug to Encorate Chrono.

If a gradual and complete switch from a previous antiepileptic drug to Encorate Chrono is planned, the drug should be administered according to the recommendations for first-line monotherapy. The dose of certain previous drugs, particularly barbiturates, should be reduced immediately, followed by gradual tapering until complete discontinuation. The withdrawal process should take 2–8 weeks.

Manic episodes in patients with bipolar disorders.

The recommended initial dose is 20 mg/kg/day. This dose should be increased as rapidly as possible until the minimum therapeutic dose that achieves the desired clinical effect is reached.

Typically, the desired clinical effect is achieved at plasma valproate concentrations ranging from 45 to 125 µg/mL.

The recommended maintenance dose for the treatment of bipolar disorder is 1000–2000 mg/day. Rarely, the dose may be increased up to the maximum level of 3000 mg/day. The dose should be adjusted according to individual clinical response.

Children and adolescents: The efficacy and safety of Encorate Chrono for the treatment of manic episodes associated with bipolar disorders have not been studied.

Prevention of relapses of manic episodes in bipolar disorders.

The dose for relapse prevention corresponds to the lowest effective dose that adequately controls symptoms of acute mania in the individual patient. The maximum daily dose of 3000 mg should not be exceeded.

Special dosage instructions. The tablet should be swallowed whole, without crushing or chewing.

In patients with renal impairment

Patients with renal impairment may require dose reduction, or dose adjustment may be necessary for patients undergoing hemodialysis. Sodium valproate and valproic acid are dialyzable (see section «Overdose»). The dose should be adjusted based on clinical monitoring of the patient (see section «Special precautions for use»).

Female children, female adolescents, women of reproductive age, and pregnant women. Treatment with the drug should be initiated and conducted under the supervision of a specialist experienced in the treatment of epilepsy. The drug should be prescribed only when other treatment options are ineffective or not tolerated (see sections «Special precautions for use» and «Use during pregnancy or breastfeeding»); the benefit and risk of using this drug should be carefully reviewed during regular treatment evaluations. Encorate Chrono is generally prescribed as monotherapy at the lowest effective dose, and, if possible, in a prolonged-release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two administrations.

Children.

The drug is indicated for children with body weight above 20 kg.

This dosage form is not recommended for children under 6 years of age (risk of aspiration during swallowing).

For children under 3 years of age, valproate monotherapy is recommended, but a careful assessment of the therapeutic benefit of valproate versus the risk of liver damage or pancreatitis should be performed before initiating therapy (see section «Special precautions for use»).

Concomitant use of salicylates for the treatment of children under 3 years of age should be avoided due to the risk of hepatotoxicity.

The efficacy and safety of Encorate Chrono for the treatment of manic episodes associated with bipolar disorders have not been evaluated in patients under 18 years of age.

Overdose.

Plasma concentrations exceeding the therapeutic maximum by 5–6 times may cause nausea, vomiting, and dizziness.

Signs of acute massive overdose (plasma concentrations 10–20 times higher than maximum therapeutic levels) typically include: superficial or deep coma, muscular hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, arterial hypotension, circulatory collapse/shock.

Fatal outcomes have been reported following massive overdose. However, the prognosis in cases of overdose is generally favorable.

Symptoms of overdose may vary; seizures may occur with very high plasma levels of the active substance.

Cases of intracranial arterial hypertension due to cerebral edema have been reported.

The presence of sodium in valproate may lead to hypernatremia in overdose.

Hospital management of overdose: gastric lavage may be beneficial within 10–12 hours after drug ingestion; cardiac and respiratory function monitoring is required.

Naloxone has been successfully used in several individual cases. Hemodialysis and hemoperfusion have been successfully employed in cases of overdose.

Adverse Reactions

Adverse effects are classified according to frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Congenital, familial and genetic disorders, congenital malformations, and nervous system developmental disorders (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding").

Hepatobiliary System.

Common: liver injury (see section "Special Warnings and Precautions for Use").

Cases of severe liver injury, including liver failure, sometimes fatal, have been reported. Elevated liver enzymes, particularly at the beginning of therapy, which are usually transient.

Gastrointestinal Tract.

Very common: nausea.

Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, upper abdominal pain, diarrhea, which often occur in some patients at the beginning of treatment but usually resolve within a few days without discontinuation of therapy. The incidence of these disorders can be significantly reduced by taking the drug during or after meals.

Uncommon: pancreatitis, sometimes fatal, requiring immediate discontinuation of the drug (see section "Special Warnings and Precautions for Use").

Nervous System.

Very common: tremor.

Common: extrapyramidal disorders**, stupor*, somnolence, seizures*, memory impairment, headache, nystagmus, nausea, or dizziness.

Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism**, ataxia, paresthesia, increased seizure frequency (see section "Special Warnings and Precautions for Use").

Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorders. Cases of sedation have been reported (especially when taken with other antiepileptic drugs). With monotherapy, such cases were transient and rarely occurred at the beginning of treatment.

* Stupor and lethargy, which may lead to transient coma/encephalopathy; these may be isolated or associated with increased seizure frequency during therapy. Symptoms improve after discontinuation or dose reduction of the drug. These effects occur most frequently during combination therapy (especially with phenobarbital or topiramate) or after a rapid increase in valproate dose.

** These symptoms may be accompanied by signs of brain atrophy on imaging studies.

Psychiatric Disorders.

Common: confusion, hallucinations, aggression*, agitation*, attention disturbances*.

Rare: abnormal behavior*, psychomotor hyperactivity*, learning difficulties*.

* These adverse reactions are mainly observed in children.

Metabolism and Nutrition Disorders.

Common: hyponatremia; weight gain (since weight gain may worsen clinical symptoms of polycystic ovary syndrome, body weight should be carefully monitored).

Rare: hyperammonemia* (see section "Special Warnings and Precautions for Use"), obesity.

* Isolated cases of mild hyperammonemia without significant abnormalities in standard liver function tests have been reported, particularly during polytherapy. Discontinuation of treatment is not necessary in the absence of clinical symptoms. However, if hyperammonemia is accompanied by neurological symptoms, further investigations are required (see also section "Special Warnings and Precautions for Use").

Endocrine System.

Uncommon: syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilization, acne, alopecia in males and/or increased androgen hormone levels).

Rare: hypothyroidism (see section "Use in Pregnancy or Breastfeeding").

Blood and Lymphatic System.

Common: anemia, thrombocytopenia. Cases of dose-dependent thrombocytopenia have been reported, usually occurring in a predictable manner and without clinical consequences. In patients with asymptomatic thrombocytopenia, simple dose reduction, if possible, considering platelet levels and disease control, usually resolves thrombocytopenia.

Uncommon: pancytopenia, leukopenia.

Rare: bone marrow aplasia, including pure red cell aplasia, agranulocytosis; macrocytic anemia, macrocytosis.

Isolated cases of decreased fibrinogen levels and/or prolonged prothrombin time (especially with high-dose therapy) have been reported, usually without clinical consequences. Valproate inhibits the second phase of platelet aggregation (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding").

Skin and Subcutaneous Tissue.

Common: increased sensitivity, transient and/or dose-dependent alopecia (hair regrowth usually occurs within 6 months), nail and nail bed disorders.

Uncommon: angioneurotic edema, rash, hair growth disorders (unusual hair texture, hair color changes, abnormal hair growth).

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), or drug hypersensitivity syndrome.

Reproductive System.

Common: dysmenorrhea.

Uncommon: amenorrhea.

Rare: effects on spermatogenesis, particularly reduced sperm motility (see section "Use in Pregnancy or Breastfeeding"); polycystic ovaries.

Very rare: gynecomastia.

Vascular System.

Common: bleeding (see section "Special Warnings and Precautions for Use").

Uncommon: vasculitis.

Eye Disorders.

Rare: diplopia.

Ear Disorders.

Common: deafness, causal relationship not established.

Urinary System.

Uncommon: renal failure.

Rare: enuresis, urinary incontinence, tubulointerstitial nephritis, reversible Fanconi syndrome associated with valproate use, although the mechanism of action is not yet fully understood.

General Disorders.

Uncommon: hypothermia, mild peripheral edema.

Musculoskeletal System.

Uncommon: decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients receiving long-term valproate therapy. The mechanism by which valproate affects bone metabolism is not established.

Rare: systemic lupus erythematosus and rhabdomyolysis (see section "Special Warnings and Precautions for Use").

Respiratory System.

Uncommon: pleural effusion.

Investigations.

Rare: decreased levels of coagulation factors (at least one), abnormal coagulation test results (e.g., prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio) (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding"), biotin deficiency/biotinidase deficiency.

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Rare: myelodysplastic syndrome.

The excipient Yellow Sunset FCF (E 110) contained in the drug may cause allergic reactions.

Shelf Life. 3 years.

Storage Conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

200 mg tablets: 10 tablets per strip, 3 strips per cardboard box.

300 mg or 500 mg tablets: 10 tablets per strip, 1 or 3 strips per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Ltd.
Sun Pharma Laboratories Limited

Manufacturer's Address and Place of Business.

Survey No. 214, Plot No. 20, Gavt. Ind. Area, Phase II, Piparia, Silvassa – 396230, Dadra and Nagar Haveli, India.
6-9, EPID, Katuri, Bara Brahmana, Jammu - 181133, Jammu and Kashmir, India.