Instructions Depakine Chrono 300 mg prolonged-release film-coated tablets 300 mg container No. 100
Composition
active ingredients: sodium valproate and valproic acid;
1 tablet contains 199.8 mg of sodium valproate, 87.0 mg of valproic acid (equivalent to 300 mg of sodium valproate);
excipients: hypromellose 4000 (3000 mPa.s), ethylcellulose 20 mPa.s, colloidal silicon dioxide, sodium saccharin;
shell: hypromellose (6 mPa.s), polyethylene glycol 6000, talc, titanium dioxide (E 171), polyacrylate dispersion or dry extract.
Dosage form
Film-coated, prolonged-release tablets.
Main physicochemical properties: oblong, almost white, film-coated, divisible tablets.
Pharmacotherapeutic group
Antiepileptic drugs. ATC code N03A G01.
Pharmacological properties
Pharmacodynamics
In pharmacological studies in animals, valproate inhibited various experimentally induced seizures (generalized and focal). Similarly, in humans, the antiepileptic effect of valproate can also be observed in various types of epilepsy. Valproate most likely acts by enhancing GABAergic activity, inhibiting or restraining the spread of electrical discharge.
In some in vitro studies, valproate has been shown to promote HIV-1 replication. However, this effect is not very pronounced and is not reproducible in all experiments. The clinical implications of this observation in HIV-1 infected patients are unknown. These data should be taken into account when evaluating viral load measurements when sodium valproate is used in HIV-1 infected patients.
Pharmacokinetics
Absorption: The bioavailability of valproate in blood plasma after oral administration is approximately 100%.
The drug Depakine Chrono 300 mg is present in the blood plasma in the form of valproic acid. The drug Depakine Chrono 300 mg is immediately absorbed in the gastrointestinal tract. Its absorption is constant and prolonged. Therefore, there are no peaks in the drug's plasma concentrations, and therapeutic concentrations of valproic acid are better maintained over time.
Distribution. The volume of distribution of valproic acid is mainly limited to the blood and extracellular fluid, which undergoes rapid exchange. Valproic acid binds primarily to plasma albumin. Protein binding is dose-dependent and saturable. At total plasma drug levels of 40-100 mg/L, typically 6-15% of valproic acid is unbound.
The level of valproic acid in the cerebrospinal fluid is close to the concentration of unbound substance in blood plasma (about 10%).
Valproic acid is dialyzable, but the hemodialysed fraction is very limited (approximately 10%) due to the binding of the active substance to albumin.
Valproic acid crosses the placental barrier. When Depakine Chrono 300 mg is used by breastfeeding women, valproic acid is excreted in breast milk (1-10% of the total serum concentration).
It takes approximately 3-4 days, and in some cases more, to reach an equilibrium concentration of valproic acid in the blood serum when initiating long-term treatment with Depakine Chrono 300 mg.
The effective therapeutic range of valproic acid plasma levels is generally considered to be 40-100 mg/L (278-694 μmol/L). If the total plasma valproic acid level is maintained above 150 mg/L (1040 μmol/L), a reduction in the daily dose is necessary.
Metabolism. The metabolism of Depakine Chrono 300 mg occurs mainly in the liver. The main metabolic pathways are conjugation with glucuronic acid and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate its own degradation or the degradation of other substances, such as estrogens-progestogens. This property indicates that it does not induce enzymes that are part of the cytochrome P 450 metabolic system.
Elimination. During long-term treatment, the mean plasma half-life of valproic acid in adults is 10.6 hours (but can range from 5 to 20 hours), which is the basis for a twice-daily dosing regimen. In term infants, the half-life is 20 to 30 hours. However, it rapidly approaches adult values as the infant grows older. Valproic acid is excreted primarily by the kidneys. A small fraction is excreted unchanged, but most is found in the urine as metabolites.
Pharmacokinetics in certain patient groups.
In patients with renal insufficiency, the level of albumin binding is reduced. Therefore, the resulting increase in the free fraction of valproic acid in plasma should be taken into account and the dose should be reduced accordingly. Changes in pharmacokinetic parameters have been observed in elderly patients, but they were not significant. Therefore, the clinical response of the patient (seizure control) is decisive for dose selection.
Preclinical data: In animal studies, teratogenic effects of the drug were observed in mice, rats, and rabbits.
Carcinogenicity. Administration of valproate to rats and mice resulted in a small statistically significant increase in tumors. Depending on the species, sex, and valproic acid salt used, different types of tumors and affected organs and tissues were observed. Since the results are not reproducible and due to the chemical structure of the drug and the lack of genotoxicity, sodium valproate is not considered carcinogenic.
Fertility. In chronic toxicity studies at high doses in rats and dogs, testicular atrophy and reduced spermatogenesis were observed. However, fertility studies did not reveal any adverse effects of the drug in rats. Embryotoxic and teratogenic effects were observed in all species tested (rats, mice, rabbits and monkeys).
Indication
The main indication for the use of Depakine Chrono 300 mg, preferably as monotherapy, is primary generalized epilepsy: petit mal seizures/absence epilepsy, massive bilateral myoclonic seizures, grand mal seizures with or without myoclonus, photosensitive forms of epilepsy.
Also, the drug Depakine Chrono 300 mg as monotherapy or in combination with other antiepileptic drugs is effective in the following diseases:
secondary generalized epilepsy, especially West syndrome (convulsions in young children) and Lennox-Gastaut syndrome; partial epilepsy with simple or complex symptoms (psychosensory forms, psychomotor forms); epilepsy with secondary generalization; mixed forms of epilepsy (generalized and partial).
Treatment of manic episodes associated with bipolar affective disorders in the presence of contraindications to or intolerance to lithium. Prevention of recurrence of dysthymic episodes in adult patients with bipolar disorder who have responded to valproate therapy for the treatment of manic episodes.
Pregnancy, except in cases where other treatments are ineffective (see sections "Special instructions" and "Use during pregnancy or breastfeeding").
Women of reproductive age for whom the conditions of the Pregnancy Prevention Program are not met (see sections “Special instructions for use” and “Use during pregnancy or breastfeeding”).
History of hypersensitivity to valproate, divalproate, valpromide or any of the components of the drug.
Acute hepatitis.
Chronic hepatitis.
Severe hepatitis in the patient's individual or family history, especially caused by drugs.
Hepatic porphyria.
Combination with mefloquine and St. John's wort extract (see section "Interaction with other medicinal products and other types of interactions").
Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma, such as Alpers-Huttenlocher syndrome, in children under two years of age suspected of having a polymerase gamma-related disorder, and in patients with a history of ornithine cycle disorders (see section 4.4).
Urea cycle enzyme deficiency (see section "Special warnings and precautions for use").
Interaction with other medicinal products and other types of interactions
Contraindicated combinations.
St. John's wort. Risk of decreased plasma concentrations and reduced efficacy of the anticonvulsant.
Not recommended combinations.
Lamotrigine: Increased risk of serious skin reactions (toxic epidermal necrolysis). In addition, plasma concentrations of lamotrigine may be increased (reduction of its hepatic metabolism by sodium valproate).
If concomitant use of these drugs cannot be avoided, careful clinical monitoring of the patient's condition is required.
Penems: Risk of seizures due to rapid decrease in plasma valproic acid concentrations, which may reach levels below the detection threshold.
Combinations that require special precautions for use.
Acetazolamide. Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Aztreonam. Risk of seizures due to decreased plasma valproic acid concentrations. Clinical monitoring of the patient, determination of plasma drug concentrations, and possible dose adjustment of the anticonvulsant during treatment with the antibacterial drug and after its withdrawal is necessary.
Carbamazepine. Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, decreased plasma concentrations of valproic acid due to increased hepatic metabolism by carbamazepine. Clinical monitoring, determination of plasma drug concentrations, and dose adjustment of both anticonvulsants are indicated.
Nimodipine (oral and, by extrapolation, parenteral). Risk of increasing plasma concentrations of nimodipine by 50%. Therefore, the dose of nimodipine should be reduced in patients with arterial hypertension.
Phenobarbital and, by extrapolation, primidone. Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Phenytoin and, by extrapolation, fosphenytoin. Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Propofol: Possible increase in propofol blood levels. When used concomitantly with valproate, a reduction in the propofol dose should be considered.
Rifampicin: Risk of seizures due to increased hepatic metabolism of valproate. Clinical monitoring, laboratory monitoring, and possible dose adjustment of the anticonvulsant are indicated during and after rifampicin therapy.
Rufinamide: Increased rufinamide concentrations may occur, especially in children weighing less than 30 kg. For children weighing less than 30 kg, after titration, the total dose should not exceed 600 mg/day.
Topiramate: Increased risk of encephalopathy and hyperammonemia. Regular monitoring of clinical and laboratory parameters is indicated.
Zidovudine. Risk of increased adverse reactions of zidovudine, especially hematological, due to a decrease in its metabolism by valproic acid. Regular monitoring of clinical and laboratory parameters is indicated. During the first two months of combined treatment, a complete blood count should be performed to check for anemia.
Zonisamide: Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Other types of interaction
Oral contraceptives: Since valproate does not induce enzymes, it does not reduce the effectiveness of estrogen-progestogen hormonal contraception in women.
Lithium. Depakine Chrono 300 mg does not affect the level of lithium in the blood serum.
Application features
Pregnancy prevention program.
Due to the high teratogenic potential and the risk of developmental disorders in infants exposed to valproate in utero, Depakine Chrono 300 mg should not be used in female children and adolescents, women of reproductive age and pregnant women, except in cases where other treatments are ineffective or intolerable. If treatment with other drugs is not possible, valproate is prescribed in accordance with the requirements of the Pregnancy Prevention Program (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Pregnancy Prevention Program Terms.
The doctor who prescribes the drug must:
in each case, assess the individual circumstances, involve the patient in the discussion, ensure her involvement, discuss treatment options and ensure understanding of the risks and measures needed to minimise the risks; assess the possibility of pregnancy in all patients; ensure that the patient understands and is aware of the risks of congenital malformations and neurodevelopmental disorders, in particular the significance of these risks for children exposed to valproate in utero; ensure that the patient understands the need for pregnancy testing before starting treatment and, if necessary, during treatment; advise the patient to use contraception and check the patient's ability to adhere to the continuous use of effective contraception (for further information, see the Contraception section of this boxed warning) throughout the course of valproate treatment; ensure that the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the treatment of epilepsy; ensure that the patient understands the need to consult a doctor if she is planning a pregnancy, to discuss this issue in a timely manner and to switch to alternative treatment methods before conception and before the cessation of contraceptive methods; ensure that the patient understands the need to urgently consult her doctor in the event of pregnancy; issue an Information booklet for the patient; ensure that the patient understands the dangers and necessary precautions associated with the use of valproate (Annual Risk Information Form).
These conditions also apply to women who are not currently sexually active, except in cases where, in the opinion of a doctor, there are compelling reasons to assert the absence of risk during pregnancy.
Female children
The prescribing physician should ensure that parents/guardians of female children understand the need to seek medical attention immediately after a female child taking valproate begins menstruating.
In patients who have already started menstruating, the prescribing physician should reassess the need for valproate treatment annually and consider alternative treatments. If valproate is the only acceptable treatment, the need for effective contraception and all other terms of the Pregnancy Prevention Program should be discussed. The physician should make every effort to transfer female children to alternative treatments before they reach puberty or adulthood.
Pregnancy test. Pregnancy should be ruled out before starting valproate therapy. Valproate treatment should not be initiated in women of childbearing potential who have not had a negative pregnancy test using a plasma sample with a sensitivity of at least 25 mIU/ml, approved by a healthcare professional, to rule out unintended use during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.
Contraception. Women of childbearing potential who are prescribed valproate should use effective contraception continuously throughout the duration of valproate treatment. These patients should be given comprehensive information on pregnancy prevention and referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user-independent form such as an intrauterine device or implant) or two complementary methods of contraception should be used, one of which should be a barrier method. When choosing a contraceptive method, the individual circumstances should be assessed in each case, with the patient's active participation and adherence to the chosen precautions. Even if the patient is amenorrhoeic, she should follow all recommendations for effective contraception.
Annual review of treatment by a specialist. The specialist should reassess at least annually whether valproate is the most appropriate treatment for the patient. The specialist should discuss the Annual Risk Disclosure Form at the start of treatment and at each annual review of treatment and ensure that the patient understands the information provided. The Annual Risk Disclosure Form should be duly completed and signed by the prescribing physician and the patient (or her legal representative).
Pregnancy planning. If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy should re-evaluate valproate treatment and consider alternative treatments. Every effort should be made to switch the patient to acceptable alternative treatments before conception and before stopping contraception (see section "Use during pregnancy or breastfeeding"). If such a switch is not possible, the woman should receive further advice on the risks of valproate to the unborn child, in order to provide her with adequate information to make an informed decision about family planning.
Pregnancy: If a woman taking valproate becomes pregnant, she should be referred immediately to a specialist to re-evaluate valproate treatment and consider alternative treatments. Pregnant patients who have received valproate during pregnancy and their partners should be referred to a specialist with experience in teratology for evaluation and advice on treatment with the drug during pregnancy (see section “Use during pregnancy or lactation”).
The pharmacist must ensure that:
The patient is given a patient card with each valproate dispensed and the patient understands the information provided therein; patients are advised not to stop taking valproate and to consult a specialist immediately in case of a planned or suspected pregnancy.
Educational materials: To assist healthcare professionals and patients in avoiding the use of valproate during pregnancy, the marketing authorisation holder shall provide educational materials to draw additional attention to the warnings regarding the teratogenicity (potential to cause birth defects) and fetotoxicity (potential to cause developmental disorders of the nervous system) of valproate and to provide instructions on the use of valproate in women of childbearing potential and detailed information on the requirements of the Pregnancy Prevention Programme. A patient information leaflet and a patient card should be provided to all women of childbearing potential taking valproate.
Increased seizures. As with any antiepileptic drug, valproate may lead to a reversible increase in the frequency and severity of seizures (including status epilepticus) or the emergence of a new type of seizure, rather than an improvement in the condition. Patients should be advised to contact their doctor immediately if seizures worsen (see section 4.8).
These seizures must be differentiated from those that may be due to pharmacokinetic interactions (see section "Interaction with other medicinal products and other types of interactions"), toxicity (liver damage or encephalopathy, see sections "Special warnings and precautions for use" and "Adverse reactions") or overdose.
Since this drug is metabolized to valproic acid, it should not be combined with other drugs that undergo the same transformation to avoid valproic acid overdose (e.g. with semisodium valproate, valpromide).
Severe liver damage.
Conditions of occurrence: Cases of severe liver damage, sometimes fatal, have been reported. Experience shows that the highest risk, especially in the case of concomitant use of other antiepileptic drugs, is observed in infants and children under 3 years of age with severe epilepsy, in particular children with brain damage, mental retardation and/or genetically determined metabolic or degenerative diseases.
In children aged 3 and over, the risk is significantly reduced and gradually decreases with age.
In most cases, such liver damage was observed within the first 6 months of treatment, usually within 2-12 weeks, and most often with complex antiepileptic therapy.
Signs to look out for. Early diagnosis is based on the clinical picture. In particular, the following symptoms should be considered, which may precede jaundice, especially in patients at risk (see above "Conditions of occurrence"):
non-specific symptoms that appear suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes associated with repeated episodes of vomiting and abdominal pain. In patients with epilepsy - recurrence of epileptic seizures, despite proper adherence to therapy recommendations.
The patient (or their relatives if the patient is a child) should be informed of the need to seek immediate medical attention if such symptoms occur. The patient should be promptly evaluated, including clinical examination and laboratory tests of liver function.
Detection. Liver function tests should be performed before starting therapy and then regularly during the first 6 months of treatment. It should be emphasized that isolated and transient increases in transaminase levels without clinical signs are often observed, especially at the beginning of therapy. In addition to conventional studies, the most informative are studies that reflect protein synthesis, in particular prothrombin levels. In the event of confirmation of a pathologically low prothrombin level, especially in connection with other biological pathological indicators (significant decrease in fibrinogen and coagulation factors, increased bilirubin and liver enzymes), therapy with Depakine Chrono 300 mg should be discontinued immediately. As a precautionary measure and with simultaneous therapy with salicylates, their use should also be discontinued, since they have the same metabolic pathway. Laboratory tests should be repeated depending on the changes in the indicators detected.
Pancreatitis: Severe pancreatitis, sometimes fatal, has been reported very rarely. It can occur regardless of the patient's age or duration of treatment, and is particularly likely in young children.
Pancreatitis with an adverse clinical outcome is typically seen in young children or in patients with severe epilepsy, brain damage, or those receiving polytherapy with antiepileptic drugs.
If pancreatitis develops against the background of liver failure, the risk of fatal cases increases significantly.
In the event of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting and/or loss of appetite, the diagnosis of pancreatitis should be considered and for patients with elevated pancreatic enzyme levels, the drug should be discontinued and appropriate alternative therapy should be instituted.
In children under 3 years of age, Depakine Chrono 300 mg should only be used as monotherapy. In patients of this age group, therapy should be initiated only after comparing the clinical benefits with the risk of liver damage or pancreatitis.
It is recommended to perform blood tests (complete blood count with platelet count, assessment of bleeding time and blood clotting parameters) before prescribing the drug, then after 15 days and upon completion of treatment, as well as before any surgical interventions and in case of hematomas or spontaneous bleeding (see section "Adverse reactions").
Renal impairment: In patients with renal impairment, a dose reduction may be necessary. Since plasma concentration data are sometimes difficult to interpret, the dose should be adjusted according to the clinical response.
This medicinal product is contraindicated in patients with urea cycle enzyme deficiency. Several cases of hyperammonemia with stupor or coma have been described in such patients (see section 4.3).
In children with a history of hepatic and gastrointestinal disorders of unknown origin (lack of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, mental retardation, or a family history of neonatal or infant death, metabolic tests and especially fasting and postprandial ammonia tests should be performed before starting any valproate therapy.
Although this drug is known to cause immunological disorders only in exceptional cases, the benefit/risk ratio should be weighed in patients with systemic lupus erythematosus.
At the beginning of treatment, the patient should be informed about the risk of weight gain, and appropriate measures should be taken to minimize this effect, which should mainly concern the diet.
Suicidal ideation and behavior: Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for multiple indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this effect is unknown, and the currently available data do not allow us to exclude an increased risk with valproate.
Therefore, patients should be monitored for the early detection of suicidal thoughts and behavior and appropriate treatment should be administered. Patients (and caregivers of patients) should be warned that if signs of suicidal thoughts or behavior appear, they should seek medical advice immediately.
Effects of long-term treatment on bone metabolism. Cases of decreased bone mineral density, which may indicate osteopenia or osteoporosis and even lead to atypical fractures, have been reported in patients receiving long-term treatment with valproic acid. The mechanism of action of valproic acid on bone metabolism is not yet clear (see section "Adverse reactions").
Carbapenems. Concomitant use of Depakine Chrono 300 mg and carbapenems is not recommended (see section “Interaction with other medicinal products and other types of interactions”).
Patients with known or suspected mitochondrial disease. Valproate may provoke or worsen the clinical signs of existing mitochondrial diseases caused by mutations in mitochondrial DNA, as well as the nuclear gene encoding the mitochondrial enzyme polymerase gamma (POLG).
In particular, valproate-induced acute liver failure and deaths due to hepatic dysfunction have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the POLG gene (e.g. Alpers-Huttenlocher syndrome). POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or who present with symptoms suggestive of such a disorder, including (but not limited to) encephalopathy of unknown origin, 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 mutations should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see Contraindications).
Interaction with other medicinal products: This medicinal product is not recommended for concomitant administration with lamotrigine and penems (see section “Interaction with other medicinal products and other forms of interaction”).
This medicinal product contains 47 mg of sodium per tablet. This should be taken into consideration by 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 picture may be mistaken for dementia or Parkinson's disease. These disorders are reversible after discontinuation of the drug (see section "Adverse reactions").
Patients with concomitant carnitine palmitoyltransferase (CPT) type II deficiency should be warned about the increased risk of rhabdomyolysis when taking valproate.
Alcohol: You should not drink alcoholic beverages during treatment with valproate.
Effects on laboratory and diagnostic tests: Since valproate is excreted mainly by the kidneys, partly in the form of ketone bodies, urine tests for ketone bodies may give false positive results in patients with diabetes.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients should also be warned about the risk of drowsiness, especially if they are receiving complex anticonvulsant therapy or concomitant therapy with benzodiazepines (see section “Interaction with other medicinal products and other types of interactions”).
Use during pregnancy or breastfeeding
Valproate is contraindicated (see sections "Contraindications" and "Special Instructions for Use"):
during pregnancy, except in cases where other treatment methods are ineffective; to women of reproductive age for whom the conditions of the Pregnancy Prevention Program are not met.
Congenital malformations. A meta-analysis of registries and cohort studies showed 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 the most common malformations is higher than in the general population, where the risk is approximately 2-3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which the risk is absent.
Available data indicate an increased incidence of rare and common birth defects. The most common birth defects include neural tube defects (approximately 2-3%), facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal, and genitourinary malformations (particularly hypospadias), limb defects (including bilateral radial aplasia), and multiple anomalies of various body systems.
Developmental disorders. Available data suggest that intrauterine exposure to valproate may cause adverse effects on the mental and physical development of exposed children. This risk is likely to be dose-related, but the available data do not allow a threshold dose below which there is no risk. The precise period of pregnancy during which the risk of these effects exists has not been determined, and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies involving preschool children exposed to valproate during fetal development have shown that approximately 30-40% of cases have developmental delays, such as delayed speech and walking, decreased intellectual function, poor language skills (spoken and understood), and memory impairment.
The intelligence quotient (IQ) of school-aged children (aged 6 years) exposed to valproate in utero was on average 7-10 points lower than that of 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 children exposed to valproate may not depend on maternal IQ.
Data on long-term effects are limited.
Available evidence suggests that children exposed to valproate in utero have an increased risk of autism spectrum disorders (approximately 3-fold) and childhood autism (approximately 5-fold) compared with the general population studied.
Limited data suggest that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit hyperactivity disorder.
Women of reproductive age. Depakine Chrono 300 mg should not be used in women of reproductive age, except in cases where other treatments are ineffective or poorly tolerated by the patient. If other treatments cannot be used, Depakine Chrono 300 mg may be prescribed only if the Pregnancy Prevention Program is followed (see section “Special precautions for use”).
