Before beginning the use of the drug Depakin® syrup and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed.
As with most antiepileptic drugs, when using valproic acid, a slight increase in the activity of "hepatic"enzymes, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. These patients need a more detailed study of biological indicators, including a prothrombin index, and a dose adjustment of the drug may be required, and if necessary, a re-clinical and laboratory examination.
Before starting therapy or before surgery, as well as with spontaneous subcutaneous hematoma or bleeding, it is recommended to determine the time of bleeding, the number of elements in the peripheral blood, including platelets.
Severe liver damage
Predisposing factors
Clinical experience shows that patients at risk are patients who take several antiepileptic drugs at the same time; children under the age of three with severe convulsive seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients taking salicylates at the same time (since salicylates are metabolized along the same metabolic pathway as valproic acid).
After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient's age increases. In most cases, this liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment, and usually with the use of valproic acid in combination antiepileptic therapy.
Symptoms Suspected of Liver Damage
For early diagnosis of liver damage, clinical monitoring of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk (see above):
- nonspecific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
- resumption of convulsive seizures in patients with epilepsy.
It is necessary to warn patients or their families (when using the drug by children) that they should immediately report the occurrence of any of these symptoms to the treating doctor.Patients should immediately carry out a clinical examination and a laboratory study of liver function indicators.
Identify
Determination of functional liver samples should be performed before treatment and then periodically during the first 6 months of treatment. Among the usual studies, the most informative studies reflecting the state of protein synthetic function of the liver, especially the definition of the prothrombin index.
Confirmation of the deviation from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory indicators (a significant decrease in fibrinogen and coagulation factors, an increase in bilirubin concentration and an increase in the activity of "liver" transaminases), and the appearance of other symptoms indicative of liver damage see above), requires the termination of the use of the drug Depakin® syrup. For the purpose of precaution, if patients take concomitant salicylates, their administration should also be discontinued.
Pancreatitis
There are registered rare cases of severe forms of pancreatitis in children and adults that developed regardless of age and duration of treatment.Several cases of hemorrhagic pancreatitis have been observed with a rapid progression of the disease from the first symptoms to the fatal outcome.
Children are at increased risk of developing pancreatitis, with increasing age of the child, this risk is reduced. Risk factors for pancreatitis can be severe seizures, neurological disorders, or anticonvulsant therapy. Hepatic insufficiency, combined with pancreatitis, increases the risk of death.
Patients who experience severe abdominal pain, nausea, vomiting, and / or anorexia should be examined immediately. In case of confirmation of pancreatitis, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued, and appropriate treatment should be started.
Suicidal thoughts and attempts
There have been reports of suicidal thoughts and attempts in patients taking antiepileptic drugs for certain indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed an increased risk of suicidal thoughts and attempts at 0.19% in all patients taking antiepileptic drugs (including,an increase in this risk by 0.24% in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking placebo.
The mechanism of this effect is unknown. Therefore, patients taking the drug Depakin® syrup should be constantly monitored for suicidal thoughts and attempts, and, if they occur, it is necessary to conduct appropriate treatment. Patients and caregivers are advised when the patient has suicidal thoughts or attempts to immediately consult a doctor.
Carbapenems
Simultaneous use of carbapenems is not recommended (see section "Interaction with other drugs").
Patients with established mitochondrial diseases or suspected of them. Valproic acid can initiate or weight the manifestations of the patient's mitochondrial diseases caused by mitochondrial DNA mutations, as well as the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations of the gene encoding the γ-polymerase (POLG); for example, patients with Alpers-Huttenlohera syndrome with valproic acid associated a higher incidence of acute hepatic impairment and liver-related deaths.
Diseases due to γ-polymerase defects can be suspected in patients with a family history of such diseases or with suspicious symptoms, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others. In accordance with modern clinical practice for the diagnosis of such diseases should test the test for mutations of the γ-polymerase gene (POLG) (see the section "Contraindications").
The paradoxical increase in the frequency and severity of seizures (including the development of epileptic status) or the appearance of new types of seizures
As with other antiepileptic drugs,with the intake of valproic acid, in some patients, a reversible increase in the frequency and severity of convulsive seizures (including the development of epileptic status) or the appearance of new types of seizures was observed, instead of improving. In case of increased seizures, patients should consult the doctor immediately (see "Side effect").
Children and adolescents female, women with childbearing potential and pregnant women
The drug Depakin® Syrup should not be used by children and adolescent females, women with childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenic effects and mental and physical developmental disorders in children who have been in utero exposed to valproic acid. The benefit / risk ratio should be carefully reassessed in the following cases: during regular revision of treatment, when the girl achieves puberty and, as a matter of urgency, in the case of planning or pregnancy from a woman taking valproic acid.
During treatment with valproic acid, women with childbearing potential should use reliable contraceptive methods and should be informed of the risks associated with taking the drug Depakin® syrup during pregnancy (see section "Use during pregnancy and during breastfeeding"). To help the patient understand these risks, the doctor who prescribes valproic acid should provide the patient with comprehensive information about the risks associated with taking the drug Depakin® syrup during pregnancy.
In particular, the physician prescribing valproic acid should make sure that the patient understands:
- the nature and magnitude of the risks associated with the use of valproic acid during pregnancy, particularly the risks of teratogenic effects, as well as the risks of mental and physical developmental disorders;
- the need to use effective contraception;
- the need for regular revision of treatment;
- the need for urgent consultation with your doctor if she suspects she has become pregnant, or when she suggests the possibility of pregnancy.
A woman planning a pregnancy should definitely try, if possible, to switch to alternative treatment before she attempts to conceive (see the section on "Use during pregnancy and during breastfeeding").
Treatment with valproic acid should be continued only after a doctor who has experience in the treatment of epilepsy and bipolar disorders, will reassess her the relationship between the benefits and risks of drug treatment.
Children (information refers to the dosage form of Depakin®, which can be taken by children under the age of three)
Children under the age of three years, if necessary, use the drug, its use in monotherapy and in the recommended dosage form for children is recommended. In this case, before the start of treatment should weigh the ratio of the potential benefits of valproic acid and the risk of liver damage and the development of pancreatitis when it is used.
Children under 3 years of age should be treated with valproic acid and salicylates because of the risk of toxic effects on the liver.
Renal insufficiency
It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. In case of impossibility of monitoring plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.
Enzyme insufficiency of carbamide cycle (urea cycle)
If the enzyme deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Such patients described several cases of hyperammonemia with a stupor or coma. In these cases, metabolic studies should be performed prior to treatment with valproic acid (see "Contraindications").
In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), lethargy or coma in history, with mental retardation or with a family history of death of a newborn or child, studies of metabolism should be conducted prior to treatment with valproic acid, in particular, determination of ammonia (the presence of ammonia and its compounds in the blood) on an empty stomach and after eating (see "Contraindications").
Patients with systemic lupus erythematosus
Although it has been shown that during the treatment with Depakin®, the syrup of the immune system is extremely rare, the potential benefit from its use should be compared with the potential risk when using the drug in patients with systemic lupus erythematosus.
Weight gain
Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mostly dietary, should be taken to minimize this phenomenon.
Patients with diabetes mellitus
Given the potential for adverse effects of valproic acid on the pancreas, the use of the drug in patients with diabetes should carefully monitor the concentration of glucose in the blood. In the study of urine for the presence of ketone bodies in patients with diabetes mellitus, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partially in the form of ketone bodies.
Patients, infected with the human immunodeficiency virus (HIV)
AT in vitro it was found that valproic acid stimulates HIV replication under certain experimental conditions.
The clinical significance of this fact, if any, is unknown. In addition, the value of these data obtained in the studies in vitro, for patients receiving maximum suppressive antiretroviral therapy. However, these data should be taken into account when interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.
Patients with the current insufficiency carnitine palmitoyltransferase (CBT) type II
Patients with existing type II CPT deficiency should be warned about a higher risk of developing rhabdomyolysis with valproic acid.
Ethanol
During treatment with valproic acid, ethanol is not recommended.