Instructions Depakine Chrono 500 mg prolonged-release film-coated tablets 500 mg No. 30
Composition
active ingredients: sodium valproate and valproic acid;
1 tablet contains sodium valproate 333 mg, valproic acid 145 mg (equivalent to sodium valproate 500 mg);
excipients: hypromellose, ethylcellulose, colloidal silicon dioxide, anhydrous colloidal silicon dioxide, sodium saccharin;
shell: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), polyacrylate dispersion.
Dosage form
Film-coated, prolonged-release tablets.
Main physicochemical properties: oblong, almost white tablets with a score on both sides, coated.
Pharmacotherapeutic group
Antiepileptic drugs. ATC code N03A G01.
Pharmacological properties
Pharmacodynamics
The pharmacological activity of valproate is primarily directed at the central nervous system. It exhibits anticonvulsant properties against a wide range of seizures in animals and epilepsy in humans.
Experimental and clinical studies have identified 2 mechanisms of anticonvulsant action of valproate.
The first is a direct pharmacological effect, which depends on the concentration of valproate in blood plasma and brain tissues.
The second is indirect - possibly related to valproate metabolites that remain in the brain, or to modifications of neurotransmitters, or to a direct effect on the membrane.
The most likely hypothesis is that after valproate administration, the level of gamma-aminobutyric acid (GABA) increases.
In pharmacological studies in animals, sodium valproate has been shown to have anticonvulsant properties in various models of experimental epilepsy (with generalized and focal seizures).
Similarly, sodium valproate has been shown in studies to have antiepileptic effects in various forms of epilepsy in humans. This action is likely based on GABAergic (gamma-aminobutyric acid-mediated) activity, which prevents or limits the diffusion of discharges. The active form of sodium valproate, which is administered intravenously or orally, is valproic acid.
In some in vitro studies, sodium valproate has been shown to stimulate HIV-1 replication, but this effect is weak and has not been reproducible in most studies. The clinical implications of this effect in HIV-1 infected patients are unknown. When sodium valproate is used in HIV-1 infected patients, this information should be taken into account for the correct interpretation of viral load assay results.
Valproate reduces the duration of intermediate sleep phases with a simultaneous increase in the slow-wave sleep phase.
Pharmacokinetics
Various pharmacokinetic studies conducted with valproate have shown the following results.
After oral administration of Depakine Chrono 500 mg, its bioavailability in blood plasma approaches 100%.
In the blood plasma, Depakine Chrono 500 mg is in the form of valproic acid. Absorption of Depakine Chrono 500 mg, film-coated tablets, prolonged action, in the gastrointestinal tract begins immediately and has a uniform and prolonged nature. This results in the absence of peaks in the plasma concentration of the active substance and better maintenance of therapeutic concentrations of valproic acid over time.
Distribution: The volume of distribution of valproic acid is limited mainly to the blood and rapidly renewing extracellular fluids. Valproate penetrates into the cerebrospinal fluid and brain tissues.
Valproate crosses the placental barrier in both animals and humans:
In animals, valproate crosses the placental barrier to the same extent as in humans; several publications have evaluated the concentration of valproate in the umbilical cord blood of newborns during childbirth in humans: the concentration of valproate in the serum of the umbilical cord blood was the same or slightly higher than that in the maternal serum.
The half-life is 15-17 hours.
Binding to blood proteins occurs mainly with albumin and is dose-dependent and saturable. At a total plasma concentration of valproic acid of 40-100 mg/l, the proportion of its free fraction is usually 6-15%. In patients with renal failure, there is a tendency for the proportion of the unbound fraction to increase due to a decrease in albumin levels and, consequently, the number of available binding sites.
The concentration of valproic acid in the cerebrospinal fluid is similar to the concentration of its free fraction in blood plasma (about 10%).
Valproic acid is removed by dialysis, but the volume of the removed fraction is significantly reduced due to its binding to albumin (about 10%).
Sodium valproate crosses the placental barrier. Valproic acid passes into breast milk (1-10% of the total serum concentration) of women who received Depakine Chrono® 500 mg during lactation.
After the start of long-term therapy with Depakine Chrono 500 mg, the equilibrium concentration of valproic acid in the blood serum is reached after approximately 3-4 days, in some cases - after a longer period of time.
The minimum serum concentration of valproate required for therapeutic effect is usually 40-50 mg/l. Therapeutic plasma concentration of valproic acid is usually in the range of 40-100 mg/l (278-694 μmol/l). If it is necessary to achieve a higher concentration, the expected benefit should be weighed against the likelihood of side effects, especially dose-dependent ones. If the total plasma concentration of valproic acid is maintained at a level above 150 mg/l (1040 μmol/l), the daily dose of the drug should be reduced.
Metabolism. Depakine Chrono 500 mg is metabolized mainly in the liver. The main metabolic pathways are glucuronidation and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate either its own breakdown or the breakdown of other substances, such as estrogen and progesterone. This property is reflected in the absence of any inducing effect on enzymes involved in the cytochrome P450 system. There are more than 10 known metabolites, some of which have demonstrated anticonvulsant properties in animal studies. The main pathway of valproate metabolism is glucuronidation (approximately 40%), which occurs mainly with the participation of the enzymes UGT1A6, UGT1A9 and UGT2B7. Enterohepatic circulation is present.
Elimination. With continuous use of valproic acid, its average plasma half-life in adults is 10.6 hours (although it can range from 5 to 20 hours), which is why the daily dose must be divided into two doses. The drug is excreted mainly by the kidneys after metabolism by conjugation with glucuronic acid and beta-oxidation: 70% - in the form of glucuronide and ± 7% - in the form of unchanged valproic acid. The remainder of the substance is excreted through the respiratory tract and with feces. The half-life in premature newborns increases significantly, reaching 30-70 hours depending on the degree of prematurity (while it is 20-30 hours in full-term newborns and infants during the first month of life), and gradually reaches the values characteristic of children and adults, i.e. 8-22 hours with an average of 12 hours.
The valproate molecule is dialyzable, but hemodialysis is effective only against the free fraction of valproate in the blood (approximately 10%). Valproate does not induce enzymes of the cytochrome P450 metabolic system; therefore, unlike most other antiepileptic drugs, it does not accelerate its own degradation or the degradation of other substances, such as estrogen-progestogen drugs and oral anticoagulants.
Valproic acid is excreted mainly by the kidneys. A small portion is excreted unchanged, and most of the administered dose is excreted in the form of metabolites.
Kinetics in certain groups of patients.
Renal failure. The degree of binding to albumin decreases. It is necessary to remember about the possibility of increasing the serum concentration of the free fraction of valproic acid. In the event of such an increase, the dose of the drug should be reduced accordingly.
Elderly: Changes in pharmacokinetic parameters have been observed, but they were not particularly significant. Therefore, the dose should be based on clinical response (i.e., seizure control).
Compared to the gastro-resistant form of valproate, this extended-release dosage form at equivalent doses demonstrates the following characteristics:
disappearance of the absorption lag time; longer absorption; identical bioavailability; lower total maximum plasma concentration (Cmax) and free fraction plasma concentration (Cmax is approximately 25% lower with a relatively stable plateau 4-14 hours after taking the drug); this “peak smoothing” effect provides more stable and more evenly distributed valproic acid concentrations over a 24-hour period: when taking the drug twice a day at the same dose, the severity of plasma concentration fluctuations is halved; more linear correlation between dose and total plasma concentration and free fraction plasma concentration.
Preclinical safety data
Animal studies have shown that in utero exposure to valproate results in physical and functional impairment of the auditory system of rats and mice.
Indication
The main indication for the use of Depakine Chrono 500 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 500 mg as monotherapy or in combination with other antiepileptic drugs is effective in the following diseases:
Treatment of manic episodes associated with bipolar affective disorders. Prevention of recurrence of dysthymic episodes in adult patients with bipolar disorder who have responded to valproate in the treatment of manic episodes.
Contraindication
Pregnancy, except in cases where other treatments are ineffective (see sections "Special warnings and precautions for use" 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, semisodium 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 gene encoding the mitochondrial enzyme polymerase gamma, such as Alpers-Huttenlocher syndrome; in children under two years of age in whom a polymerase gamma-related disorder is suspected; in patients with a history of ornithine cycle disorders (see section "Special warnings and precautions for use").
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 antiepileptic drug.
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. Possible exacerbation of 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. Possible increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, a decrease in plasma concentrations of valproic acid due to increased hepatic metabolism by carbamazepine. Clinical monitoring, determination of plasma concentrations of the drug and dose adjustment of both anticonvulsants are indicated.
Felbamate: Possible increase in serum valproic acid concentrations with risk of overdose. Clinical monitoring, monitoring of laboratory parameters and possible dose adjustment of valproate are indicated during and after felbamate therapy.
Estrogen-containing drugs, including hormonal contraceptives containing estrogens. Estrogens are inducers of UDP-glucuronyltransferase (UGT) isoforms involved in the glucuronidation of valproate and may increase the clearance of valproate, which is thought to lead to decreased serum valproate concentrations and potentially reduce the efficacy of valproate (see section 4.4). Monitoring of serum valproate levels should be considered. In contrast, valproate does not induce enzymes; consequently, valproate does not reduce the efficacy of estrogen-progestogen hormonal contraceptives in women.
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. Possible exacerbation of hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Phenytoin and, by extrapolation, fosphenytoin. Possible exacerbation of 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.
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. Possible increase in hyperammonemia and increased risk of encephalopathy. 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 500 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 high risk of congenital malformations and disorders of the nervous system in infants exposed to valproate in utero, Depakine Chrono 500 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").
The drug Depakine Chrono 500 mg is contraindicated in the following situations:
During pregnancy, except when other treatments are ineffective (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Women of reproductive age for whom the conditions of the Pregnancy Prevention Program are not met (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 during treatment if necessary; 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.
The prescribing physician should ensure that parents/guardians of female children are fully informed about the risks of congenital malformations and neurodevelopmental disorders, including the extent of these risks for children exposed to valproate during their intrauterine development.
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.
Estrogen-containing drugs. The simultaneous use of Depakine Chrono 500 mg with drugs containing estrogens, including estrogen-containing hormonal contraceptives, may potentially reduce the effectiveness of valproate (see section "Interaction with other medicinal products and other types of interactions"). Physicians who prescribe Depakine Chrono 500 mg should monitor the clinical response (seizure control) when starting and stopping estrogen-containing drugs. However, valproate does not reduce the effectiveness of hormonal contraceptives.
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).
Liver damage.
Conditions of occurrence. Exceptional 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 congenital metabolic or degenerative diseases.
In children aged 3 years and older, the risk is significantly reduced and progressively decreases with age.
In most cases, such liver damage occurred within the first 6 months of treatment, usually within 2-12 weeks, and most often with complex antiepileptic therapy.
Signs to watch for. Clinical symptoms are important for early diagnosis. In particular, two conditions that may precede jaundice should be considered, especially in patients at risk (see “Precipitating conditions” above):
nonspecific symptoms that usually appear suddenly, such as asthenia, anorexia, lethargy, drowsiness, sometimes accompanied by 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, especially in patients at high risk. It should be emphasized that, as with most antiepileptic drugs, isolated and transient elevations of transaminases without clinical signs may occur during treatment with the drug, especially at the beginning of therapy. In such cases, it is recommended to perform a more detailed laboratory study (in particular, with the determination of prothrombin time), revise the dosage of the drug if necessary, and repeat the tests based on the dynamics of the indicators. In addition to conventional studies, the most informative are studies that reflect protein synthesis, especially prothrombin time. If a pathologically low level of prothrombin time is confirmed, especially in connection with other biological pathological indicators (significant decrease in fibrinogen and coagulation factors, increased bilirubin and liver enzymes - see the section "Special instructions"), therapy with Depakine Chrono 500 mg should be immediately discontinued.
As a precaution and with concomitant therapy with salicylates, their use should also be discontinued, as they share the same metabolic pathway.
Pancreatitis: Severe pancreatitis, which may be fatal, has been reported very rarely. Young children are at particular risk, but pancreatitis can occur regardless of the patient's age or duration of treatment.
Pancreatitis with an adverse clinical outcome is typically seen in young children or in patients with severe seizures, neurological disorders, or those receiving polytherapy with anticonvulsants.
In the event of liver failure with pancreatitis, the risk of death is significantly increased.
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 500 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.
Concomitant administration of salicylate derivatives to children should be avoided due to the risk of hepatotoxicity and bleeding.
In patients with renal insufficiency, increased concentrations of valproic acid in the blood should be taken into account and the dose of the drug should be reduced accordingly.
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 immunological disorders have been reported in exceptional cases with the use of this medicinal product, the benefit/risk ratio of the use of this medicinal product should be considered 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.
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 at the time of examination, 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 e
