Lamictal pills 50 mg 30 pcs
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Active ingredients
Lamotrigine
Release form
Pills
Composition
Lamotrigine 50 mg Auxiliary substances: lactose monohydrate — 49.4 mg, microcrystalline cellulose — 49.4 mg, sodium carboxymethyl starch — 5 mg, povidone — 5 mg, magnesium stearate — 0.8 mg, iron yellow dye — 0.4 mg.
Pharmacological effect
Antiepileptic drug. Lamotrigine is a blocker of potential-dependent sodium channels. In the culture of neurons, it causes a potential-dependent blockade of continuously repeated impulses and suppresses the pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), and also inhibits glutamate-induced depolarization. Lamictal's effectiveness in preventing mood disorders in patients with bipolar disorders was demonstrated in two fundamental clinical studies. As a result of a combined analysis of the obtained results, it was found that the duration of remission, defined as the time until the first episode of depression occurred and before the first mania / hypomania / mixed episode after stabilization, was longer in the lamotrigine group compared to placebo. The duration of remission is more pronounced for depression.
Pharmacokinetics
AbsorptionAfter ingestion, lamotrigine is rapidly and completely absorbed from the gastrointestinal tract, practically not undergoing the first-pass metabolism of the system. Cmax in plasma is reached approximately 2.5 hours after taking the drug. The time to achieve Cmax increases slightly after a meal, but the degree of absorption remains unchanged. The pharmacokinetics of lamotrigine is linear when taking a single dose of up to 450 mg (the highest dose studied). Significant interindividual Cmax fluctuations are observed in the equilibrium state, however, with rare fluctuations in each individual person. DistributionLamotrigine is associated with plasma proteins by approximately 55%. It is unlikely that the release of the drug from the connection with the protein could lead to the development of a toxic effect. Vd is 0.92-1.22 l / kg. Metabolism The enzyme uridine diphosphate glucuronyltransferase (UDP-glucuronyltransferase) participates in the metabolism of lamotrigine.Lamotrigine slightly increases its own metabolism, depending on the dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs and that there is an interaction between lamotrigine and other drugs metabolized by the cytochrome P450 system, on average, 39 ± 14 ml / min. Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted by the kidneys unchanged, about 2% through the intestines. Clearance and T1 / 2 do not depend on the dose. T1 / 2 in healthy adults averages from 24 hours to 35 hours. Patients with Gilbert's syndrome showed a 32% reduction in drug clearance compared with the control group, which, however, did not go beyond the limits of normal values for the general population. T1 / 2 lamotrigine is greatly influenced by co-medications. The average T1 / 2 is reduced to approximately 14 hours while taking it with drugs that stimulate glucuronization, such as carbamazepine and phenytoin, and increases to an average of 70 hours when taken together with valproatom. Pharmacokinetics in special clinical cases of children have lamotrigine clearance when calculating body weight higher than in adults; it is highest in children under 5 years old. In children, T1 / 2 lamotrigine is usually less than in adults. Its average value is approximately 7 hours while taking it with drugs that stimulate glucuronization, such as carbamazepine and phenytoin, and increases to 45-50 hours on average when taken together with valproat. The clinically significant differences in the clearance of lamotrigine in elderly patients compared to young patients were not detected. In case of kidney dysfunction, the initial dose of lamotrigine is calculated in accordance with the standard regimen of antiepileptic drug administration. Dose reduction may be required only with a significant reduction in renal function. Initial, increasing and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic insufficiency (class B on the Child-Pugh scale) and 75% in patients with severe liver failure (class C on the Child-Pugh scale). Increasing the dose and maintenance dose should be adjusted depending on the clinical effect.
Indications
Epilepsy for adults and children over 12 years of age — epilepsy (partial and generalized seizures, including tonic-clonic convulsions, and seizures in Lennox-Gastaut syndrome) as part of combination therapy or monotherapy. For children from 3 to 12 years old, epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy. Once control of epilepsy has been achieved during combination therapy, concomitant antiepileptic drugs can be discontinued and lamotrigine can be continued in monotherapy; monotherapy of typical absans. Bipolar disorders for adults (18 years and older) prevent mood disorders (depression, mania, hypomania, mixed episodes) in patients with bipolar affective disorders.
Contraindications
Hypersensitivity to lamotrigine or any component of the drug.
Precautionary measures
Application for violations of liver function Violation of liver functionThe initial, increasing and maintenance doses should be reduced by approximately 50% and 75% in patients with moderate (stage B) and severe (stage C) degree of liver dysfunction, respectively. Increasing and maintenance doses should be adjusted depending on the clinical effect. Use in case of impaired renal function. Disruption of renal function. Patients with renal insufficiency should be given lamotrigine with caution. In patients with severe renal insufficiency, the initial dose of lamotrigine is calculated in accordance with the standard regimen of the drug; for patients with a significant reduction in renal function, a reduction in the maintenance dose may be recommended. Use in children It is possible to use it for some indications and in doses that are adjusted for the patient's age. Lamotrigine is not indicated for bipolar disorders in children and adolescents under 18 years of age. The safety and efficacy of lamotrigine in bipolar disorder in patients of this age group has not been evaluated. Use in elderly patients Patients of older age (over 65 years) The pharmacokinetics of lamotrigine in this age group practically does not differ from that in other adult patients, therefore, changes in the dose selection scheme of the drug are not required .
Use during pregnancy and lactation
Fertility Studies on the reproductive function of animals in the application of lamotrigine did not reveal any impairment of fertility. Studies on the effect of lamotrigine on human fertility have not been carried out. Pregnancy The risk associated with AEDs in generalWomen who are able to bear children should be consulted with experts. If a woman plans pregnancy, the need for treatment of AEDs should be reviewed. In women who are undergoing treatment for epilepsy, the sudden cessation of anti-epileptic therapy should be avoided, since this can lead to renewed seizures, which can have serious consequences for the woman and the unborn child. In the offspring of mothers who received AED, the risk of congenital malformations increases by 2-3 times compared with the expected incidence of the population as a whole, which is about 3%. The most frequently recorded defects are cleft lip, heart and vascular defects, defects of neural tube repair. Multiple PEP therapy is associated with a higher risk of congenital malformations than monotherapy, in this regard, monotherapy should be used whenever possible. Risk associated with lamotrigina therapy impaired development of the embryo and fetus due to reduced levels of folic acid. Consideration should be given to taking folic acid during pregnancy planning and early pregnancy. Data from post-registration observation from several prospective pregnancy registries made it possible to document the outcomes of pregnancies of about 8,700 women who received Lamictal monotherapy during the first trimester of pregnancy. In general, the data obtained do not confirm a general increase in the risk of congenital malformations. Although out of a limited number of pregnancy registers there are reports of an increased risk of developing malformations of the oral cavity, a completed case-control study did not reveal an increase in the risk of developing malformations of the oral cavity compared with other serious developmental defects arising after the use of lamotrigine. combination therapy is not enough to assess whether the risk of malformations is associated with other drugs used in combination with dzhinom.T.k.and other drugs, Lamictal should be prescribed during pregnancy only if the expected therapeutic benefit exceeds the potential risk. Physiological changes during pregnancy can affect the concentration of lamotrigine and / or its therapeutic effect. There are reports of a decrease in the concentration of lamotrigine in the blood during pregnancy. The purpose of Lamictal should be provided to pregnant women with appropriate management tactics. Breastfeeding periodLamotrigine penetrates to breast milk to varying degrees, the total concentration of lamotrigine in breastfed babies can reach approximately 50% of the concentration of lamotrigine registered in the mother. Thus, in some breastfed babies, serum concentrations of lamotrigine can reach levels at which pharmacological effects occur. It is necessary to correlate the potential benefits of breastfeeding with the potential risk of developing unwanted reactions in a child. If a woman taking the drug Lamictal decides to breastfeed, then the child should be monitored for the occurrence of any adverse reactions.
Dosage and administration
Tablets should be swallowed whole, not chewed, not broken. If the calculated dose of lamotrigine (for example, when used in children (only for epilepsy) or in patients with impaired liver function) cannot be divided into a whole number of lower dosage pills, the patient should be assigned such a dose, which corresponds to the nearest value of the whole tablet at a lower dosage. Renewal of the use of the drug: in case of resumption of taking the drug Lamictal, doctors should evaluate the need for higher maintenance dose in patients who have stopped taking the drug for any reason, since high initial doses and exceeding the recommended dose are associated with the risk of developing a severe rash. The more time has passed since the last dose of the drug, the more caution should be increased dose to support. If the time after stopping the administration exceeds 5 half-life,then the dose of lamotrigine should be increased to maintain according to the appropriate scheme. Lamictal therapy should not be resumed in patients whose cessation of lamotrigine was associated with the appearance of a rash, unless the potential benefits of such therapy exceed the possible risks. Epilepsy Epilepsy monotherapyAdult and children over 12 years (table 1) The initial dose of the drug Lamiktal in monotherapy is 25 mg 1 time / day for 2 weeks, followed by increasing the dose to 50 mg 1 time / day during s 2 weeks. Then the dose should be increased to a maximum of 50-100 mg every 1-2 weeks, until it reaches the optimal therapeutic effect. The usual maintenance dose to maintain the optimal therapeutic effect is 100-200 mg / day in 1-2 doses. Some patients require a dose of Lamictal 500 mg / day to achieve a therapeutic effect. Children aged 3 to 12 years (Table 2) The initial dose of Lamictal when monotherapy patients with typical absence is 0.3 mg / kg / day in 1 or 2 doses per within 2 weeks followed by increasing the dose to 0.6 mg / kg / day in 1 or 2 doses for 2 weeks. Then the dose should be increased to a maximum of 0.6 mg / kg every 1-2 weeks until the optimum therapeutic effect is achieved. This circumstance allows relatively accurate dosage of the drug in children weighing 40 kg or more. The usual maintenance dose to achieve an optimal therapeutic effect ranges from 1 to 10 g / kg / day in 1 or 2 doses, although some patients with typical absences need higher doses to achieve the desired therapeutic effect. Because of the risk of rash, you should not exceed the initial drug dose and recommended dose titration regimen. As part of combination therapy for epilepsy, adults and children over 12 years old (Table 1) In patients who already receive valproate in combination with other AEDs or without them, the initial and lamotrigine is 25 mg every other day for 2 weeks, further - 25 mg 1 time / day for 2 weeks. Then the dose should be increased to a maximum of 25-50 mg / day every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve the optimal therapeutic effect is 100-200 mg / day in 1 or 2 doses. In such patients who receive concomitant PEP therapy or other drugs that induce lamotrigine glucuronization,in combination with or without other AEDs (with the exception of valproate), the initial dose of Lamictal is 50 mg 1 time / day for 2 weeks, then 100 mg / day in 2 doses for 2 weeks. Then the dose should be increased to a maximum of 100 mg every 1-2 weeks, until it reaches the optimal therapeutic effect. The usual maintenance dose is 200-400 mg / day in 2 divided doses. Some patients may need a dose of 700 mg / day to achieve a therapeutic effect.
Side effects
Adverse reactions identified during clinical studies in patients with epilepsy or bipolar affective disorder were divided into separate sections, specific indications for use. Additional adverse reactions identified during post-registration monitoring for both indications are included in the sub-section Post-registration Monitoring. When considering the general safety profile of Lamictal, you should be familiar with the information contained in all three sections. Epilepsy The following adverse reactions were identified during clinical studies in patients with epilepsy and when determining the general safety profile of Lamictal should be considered together with the adverse reactions identified during clinical studies in patients with bipolar affective disorder and post-registration use of the drug. On the side of the skin and fatty tissue: very often - skin rash; rarely, Stevens-Johnson syndrome, very rarely, toxic epidermal necrolysis. In double-blind, additional clinical studies in adults, skin rash occurred in 10% of patients or less who took Lamictal and in 5% of patients who took placebo. In 2% of patients, the occurrence of skin rash caused the withdrawal of the drug Lamictal. A rash, mainly of maculo-papular nature, usually appears during the first 8 weeks after the start of therapy and disappears after discontinuation of Lamictal. There are rare cases of severe, potentially life-threatening skin rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although in most cases, with the abolition of the drug, the reverse development of symptoms occurred,irreversible scars remained in some patients, and in rare cases deaths associated with taking the drug were reported. The overall risk of rash development is closely associated with high initial doses of Lamictal and excess of the recommended dose when using it; with the concomitant use of valproic acid. There were also reports of rash development in the framework of hypersensitivity syndrome associated with various systemic manifestations (see disorders of the immune system). From the hematopoietic system and lymphatic system: very rarely - hematological disorders (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy. Hematological disorders and lymphadenopathy may or may not be associated with hypersensitivity syndrome (see immune system abnormalities). From the immune system: very rarely - hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, swelling of the face, blood disorders and liver function, DIC, multiple organ failure). The syndrome occurs with varying degrees of clinical severity and may in rare cases lead to the development of DIC and multiple organ dysfunction. It is important to note that early manifestations of hypersensitivity (ie, fever, lymphadenopathy) may be present even in the absence of obvious signs of a rash. With the development of such symptoms, the patient should be immediately examined by a doctor and, unless another reason for the development of symptoms is established, Lamictal should be canceled. On the mental side: often - aggressiveness, irritability; very rarely - tics, hallucinations, confusion. From the nervous system: very often - headache; often - drowsiness, insomnia, dizziness, tremor; infrequently - ataxia; rarely - nystagmus. On the part of the organ of vision: infrequently - diplopia, blurred vision. On the part of the digestive system: often - nausea, vomiting, diarrhea. On the side of the liver and biliary tract: very rarely - increased activity of liver enzymes, impaired liver function, hepatic failure . Liver dysfunction usually develops in conjunction with hypersensitivity reactions,but in isolated cases, there were no obvious signs of hypersensitivity. From the musculoskeletal system: very rarely - lupus-like syndrome. General reactions: often - fatigue. Bipolar affective disorder The following adverse reactions were identified in clinical studies in patients with bipolar affective disorder and in determining the overall safety profile of the drug Lamictal should be considered in conjunction with adverse reactions identified during clinical trials in patients with epilepsy and post-registration observation. From the side of the skin and subcutaneous fat: very often - skin rash; rarely - Stevens-Johnson syndrome. In evaluating all studies (controlled and uncontrolled) for Lamictal in patients with bipolar affective disorder, skin rash occurred in 12% of all patients receiving Lamictal, while skin rash in controlled clinical studies in patients with bipolar affective disorder occurred in 8% of patients receiving Lamictal, and in 6% of patients receiving placebo. For the nervous system: very often - headache; often - agitation, drowsiness, dizziness. From the musculoskeletal system: often - arthralgia. General reactions: often - pain, back pain. Post-registration observation This section includes unwanted reactions detected during post-registration observation for both indications. In determining the overall safety profile of Lamictal, these adverse reactions should be considered in conjunction with adverse reactions identified in clinical studies in patients with epilepsy and bipolar affective disorder. On the side of the skin and subcutaneous fat: rarely - alopecia. Mental disorders: very rarely nightmares. On the nervous system: very often - drowsiness, ataxia, headache, dizziness; often - nystagmus, tremor, insomnia; rarely, aseptic meningitis; very rarely - agitation, instability of gait, movement disorders, worsening of symptoms of Parkinson's disease, extrapyramidal disorders, choreoathetosis.There are reports that the drug Lamictal may worsen parkinsonism symptoms in patients with Parkinson's disease and in isolated cases cause the extrapyramidal symptoms of choreoathetosis in patients without prior disorders. On the part of the organ of vision: very often - diplopia, fuzzy vision; rarely - conjunctivitis. From the digestive system: very often - nausea, vomiting; often - diarrhea. Only with epilepsy. From the nervous system: very rarely - an increase in the frequency of convulsive seizures.
Overdose
It was reported about a single dose, exceeding the maximum therapeutic 10-20 times. Overdose was manifested by the following symptoms: nystagmus, ataxia, impaired consciousness, and coma. Treatment: hospitalization and maintenance therapy is recommended in accordance with the clinical picture or recommendations of the National Toxicological Center.
Interaction with other drugs
DF-glucuronyltransferase is the main enzyme that metabolizes lamotrigine. There is no evidence of the ability of lamotrigine to cause a clinically significant induction or inhibition of microsomal liver enzymes. In this regard, the interaction between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes is unlikely. Lamotrigine can induce its own metabolism, but this effect is mild and has no clinical significance. Interaction with PEP-Valproic acid, which inhibits lamotrigine glucuronization, reduces its metabolic rate and extends its average T1 / 2 almost 2 times. Some antiepileptic drugs (such as phenytoin, carbamazepine, fenabarbital and primidone), which induce microsomal liver enzymes, accelerate lamotrigine glucuronidation and its metabolism. It was reported on the development of adverse events on the part of the central nervous system, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who began taking carbamazepine during lamotrigine therapy. These symptoms usually subsided after lowering the dose of carbamazepine. A similar effect was observed when lamotrigine and oxcarbazepine were taken by healthy volunteers, the result of dose reduction was not studied. When lamotrigine was administered simultaneously at a dose of 200 mg and oxcarbazepine at a dose of 1200 mg,Neither oxcarbazepine nor lamotrigine disrupt each other's metabolism. The combined use of felbamate at a dose of 1,200 mg 2 times / day and lamotrigine 100 mg 2 times / day did not lead to clinically significant changes in the pharmacokinetics of lamotrigine. The possible drug interactions of levetiracetam and lamotrigine were investigated in assessing the serum concentrations of both drugs in placebo-controlled clinical trials. These data show that lamotrigine and levetiracetam do not affect each other's pharmacokinetics. There was no effect of pregabalin at a dose of 200 mg 3 times / day on equilibrium concentrations of lamotrigine, i.e. pregabalin and lamotrigine do not interact pharmacokinetically with each other. The use of topiramate did not lead to a change in the concentration of lamotrigine in the plasma. However, taking lamotrigine increased the concentration of topiramate by 15%. Taking zonisamide (at a dose of 200-400 mg / day) during the clinical program together with lamotrigine (at a dose of 150-500 mg / day) did not lead to a change in pharmacokinetic parameters of lamotrigine. Studies showed that lamotrigine does not affect plasma concentrations of other antiepileptic drugs. Results of in vitro studies have shown that lamotrigine does not force other antiepileptic drugs out of association with plasma proteins. When used with other psychotropic drugs Lamotrigine at a dose of 100 mg / day does not cause a violation of the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times / day for 6 days) when administered together. Repeated administration of bupropion orally does not have a statistically significant effect on the pharmacokinetics of a single dose Lamotrigine and causes a slight increase in AUC of lamotrigine glucuronide. Olanzapine in a dose of 15 mg reduces the AUC and Cmax of lamotrigine on average by 24% and 20%, respectively, which is clinically insignificant. Lamotrigine at a dose of 200 mg does not alter the pharmacokinetics of olanzapine. Repeated intake of lamotrigine at a dose of 400 mg / day did not have a clinically significant effect on the pharmacokinetics of risperidone after a single dose of 2 mg by healthy volunteers.At the same time, drowsiness was noted: in 12 of 14 patients with combined intake of lamotrigine and risperidone; in 1 out of 20 patients with risperidone alone; none of the patients taking lamotrigine. Inhibition of the action of lamotrigine by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has a minimal effect on the formation of the 2-N-glucuronide primary metabolite. Investigation of the metabolism of buroralol by microsomaltoraltomaltomaltomaltomaltomaltomalolumine 2-N-glucuronide metabolism. Investigation of the metabolism of buroralol by microsomaltomaltomaltomaltomaltomalolumine 2-N-glucuronide metabolism. the conclusion that lamotrigine does not reduce the clearance of drugs that are metabolized predominantly by CYP2D6 isoenzymes. In vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance. Interaction with hormonal contraceptives1. The effect of hormonal contraceptives on lamotrigine pharmacokinetics. Taking combined oral contraceptives containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel causes a twofold increase in lamotrigine clearance (after ingestion), which leads to a decrease in AUC and Cmax of lamotrigine by an average of 52% and 39%, respectively. During the week free from taking the active drug, an increase in the plasma concentration of lamotrigine is observed, while the concentration of lamotrigine, measured at the end of this week before the next dose, is on average 2 times higher than during the period of active therapy.2. The effect of lamotrigine on the pharmacokinetics of hormonal contraceptives. During equilibrium concentrations of lamotrigine at a dose of 300 mg, it does not affect the pharmacokinetics of ethinyl estradiol, a component of the combined oral contraceptive. There is a slight increase in clearance of the second component of the oral contraceptive, levonorgestrel, which leads to a decrease in the AUC and Cmax of levonorgestrel by 19% and 12%, respectively. Measurement of serum levels of FSH, LH and estradiol during this study revealed a slight decrease in the suppression of the hormonal activity of the ovaries in some women, although the measurement of the plasma level of progesterone did not reveal any hormonal evidence of ovulation in 16 women.The effect of a moderate increase in the clearance of levonorgestrel and changes in plasma concentrations of FSH and LH on the ovulation activity of the ovaries has not been established. The effect of other doses of lamotrigine (except 300 mg / day) has not been studied and studies with the inclusion of other hormonal drugs have not been conducted. Interaction with other drugsRifampicin increases the clearance of lamotrigine and reduces its T1 / 2 due to the induction of liver microsomal enzymes responsible for glucuronization. In patients taking rifampicin as concomitant therapy, the regimen of lamotrigine should follow the regimen recommended for co-administration of lamotrigine and drugs that induce glucuronization. When using lopinavir / ritonavir, a decrease in plasma concentration of lamotrigine was observed, possibly due to the induction of glucuronization. In patients taking concomitant treatment with lopinavir / ritonavir, a lamotrigine dosing regimen with concomitant glucuronization inducers should be recommended. In a study of healthy volunteers, atazanavir / ritonavir (300 mg / 100 mg) resulted in a decrease in lamotrigine AUC and Cmax (100 mg in a single dose) ) by about 32% and 6%, respectively. The results of in vitro studies have shown that it is lamotrigine that is an inhibitor of cationic carriers of organic substrates in potentially clinically significant concentrations. These data show that lamotrigine is a more potent inhibitor (half of the inhibitory concentration (IC50) varies from 53.8 nmol / l to 186 nmol / l, respectively) than cimetidine. Interaction, including laboratory indicators Lamotrigine, is reported to affect the performance of some rapid methods urinalysis to identify prohibited drugs that can lead to false-positive results, especially in the detection of phencyclidine (dissociative anesthetic). To confirm a positive result, a more specific alternative chemical method should be used.
special instructions
Skin rash There are data on the development of skin rashes, which were usually observed during the first 8 weeks after the start of treatment with Lamictal. In most cases, skin eruptions are slightly pronounced and pass on their own,but, at the same time, serious cases have been noted that require hospitalization of the patient and cancellation of Lamictal (for example, Stevens-Johnson syndrome and Lyell's syndrome). Severe skin reactions in adults taking Lamictal according to generally accepted recommendations develop with a frequency of approximately 1 in 500 epileptic patients . In about half of these cases, Stevens-Johnson syndrome (1 in 1000) was recorded. In patients with bipolar disorders, the incidence of severe skin rashes according to clinical studies is approximately 1 per 1000 patients. In children, the risk of developing severe skin rashes is higher than in adults. According to available data, the frequency of skin eruptions that required hospitalization in children with epilepsy ranged from 1 to 300 to 1 per 100 children. In children, the initial manifestations of the rash can be mistaken for an infection, so you should consider the possibility of children's reactions to the drug, manifested by the development of rash and fever in the first 8 weeks of therapy. In addition, the overall risk of developing rash is largely associated with a high initial dose of Lamictal and an excess of the recommended rate of increase, as well as with combined use with drugs HAND valproatami.Ostorozhnost required when administered to patients having a history of rash or allergic reactions in response to the reception of other