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Active ingredients
Lamotrigine
Release form
Pills
Composition
Lamotrigine 25 mg; Excipients: colloidal anhydrous silicon dioxide, magnesium stearate, povidone, sodium carboxymethyl starch, lactose monohydrate, microcrystalline cellulose.
Pharmacological effect
Antiepileptic drug. Stabilizes potential-dependent sodium channels of cell membranes. Blocks the release of neurotransmitters, mainly glutamine amino acid (which plays a key role in the development of epileptic seizures) .; Pharmacokinetics; Suction; After ingestion, it is rapidly and completely absorbed from the intestine, it is not significantly affected by the effect of "first pass". Cmax is reached 2.5 hours after ingestion. Food intake slows down the process of absorption, but does not affect its effectiveness. Bioavailability - 98%. The pharmacokinetics of the drug after a single dose at a dose not exceeding 450 mg, is linear. The concentration in the equilibrium state is pronounced individual character .; Distribution; Protein binding is 55%. It is unlikely that the elimination of lamotrigine from its association with proteins can cause a toxic effect. Vd is 0.92-1.22 l / kg body weight. It is excreted in breast milk. Concentration in breast milk is 40-60% of the plasma concentration. In some cases, the concentration of the drug in the blood serum of infants whose mothers took the drug during the period of breastfeeding, reaches therapeutic levels .; Metabolism; Biotransformed in the liver under the action of glucuronyl transferase uridine diphosphate. Among the metabolites, N-glucuronides predominate. Lamotrigine induces its own metabolism in a moderate and dose-dependent manner .; Derivation; The average clearance in the equilibrium state in healthy adults is 39 ± 14 ml / min. It is excreted together with urine in the form of a conjugate of glucuronide, less than 10% - in unchanged form, about 2% (in unchanged form and in the form of metabolites) - with feces. Clearance and T1 / 2 do not depend on the dose. T1 / 2 of healthy volunteers is 24-35 hours; Pharmacokinetics in special clinical situations; Clearance, calculated per kg of body weight, in children is higher than in adults, and is highest up to 5 years of age.T1 / 2 in children is usually shorter than in adults .; T1 / 2 in children with simultaneous use of enzymes with inducers is 7 hours, with sodium valproate - 45-60 hours; Lamotrigine clearance in the elderly and younger patients is minimally different from each other.
Indications
Epilepsy; for adults and children over 12 years old; as monotherapy or in combination with other antiepileptic drugs for the treatment of partial and generalized seizures (including tonic-clonic seizures and convulsive seizures with Lennox-Gastaut syndrome); for children from 2 to 12 years; as part of combination therapy for the treatment of partial and generalized seizures (including tonic-clonic seizures and convulsive seizures in Lennox-Gastaut syndrome) .; Bipolar disorders; for adults (18 years and older); for prevention and treatment, mainly episodes of depression.
Contraindications
children up to 2 years; pregnancy; lactation period (breastfeeding); hypersensitivity to lamotrigine or any component of the drug. With caution, the drug should be prescribed to patients with renal insufficiency (due to the possible cumulation of the glucuronide metabolite) .; With caution, prescribe the drug to children as the drug of choice for monotherapy of epilepsy .; Application for violations of liver function; For violations of liver function of moderate degree (class B on the Child-Pugh scale), the initial, increasing and supporting doses should be reduced by approximately 50%, for severe (Class C on the Child-Pugh scale) - 75% . Increasing and maintenance doses should be adjusted depending on the clinical effect.; Use in cases of impaired renal function; Care should be taken when prescribing the drug for patients with renal insufficiency; Contraindication: children up to 2 years.; Use in elderly patients; Correction of the dosing regimen in elderly patients (over 65) is not required (because the pharmacokinetics in this age group is not different from that in adults).
Use during pregnancy and lactation
Lamolep is contraindicated in pregnancy, unless the expected therapeutic benefit to the mother outweighs the potential risk to the fetus.Due to the inhibitory effect of lamotrigine on dihydrofolate reductase, the development of fetal malformations is possible when using the drug during pregnancy, but the data currently available are not enough to determine the degree of safety .; Data on the use of the drug during breastfeeding is limited. In some cases, the concentration of the drug in the blood serum of infants whose mothers took the drug during breastfeeding, reaches therapeutic levels. When using the drug during lactation, you should carefully weigh the benefits of breastfeeding and the likelihood of side effects in a child.
Dosage and administration
Epilepsy; In adults and children over 12 years of age for monotherapy, the initial dose of Lamolep is 25 mg 1 time per day for the first 2 weeks; in the next 2 weeks - 50 mg 1 time / day. In the future, every 1-2 weeks, it is possible to increase the dose by 50-100 mg, until the optimal therapeutic effect is achieved. Maintenance dose to maintain the optimal therapeutic effect is usually 100-200 mg / day in 1-2 doses. In rare cases, in order to achieve a therapeutic effect, the drug should be prescribed in a dose of 500 mg / day; In combination therapy with or without valproic acid in combination with other antiepileptic drugs or without it, the initial dose of Lamolep within the first 2 weeks is 25 mg every other day; in the future - daily 25 mg 1 time / day for the next 2 weeks. In the future, every 1-2 weeks it is possible to increase the dose by 25-50 mg, until the optimal therapeutic effect is achieved. Maintenance dose is usually 100-200 mg / day in 1-2 doses. When using Lamolep in combination therapy with drugs that induce glucuronization of lamotrigine (phenytoin, carbamazepine, phenobarbital, primidone), with or without other antiepileptic drugs (but not taking valproic acid) for the first 2 weeks, the initial dose is 50 mg 1 time / day, further in the next 2 weeks - 100 mg / day in 2 divided doses. In the future, every 1-2 weeks, a dose increase of 100 mg is possible until the optimal therapeutic effect is achieved. Maintenance dose is usually 200-400 mg / day in 1-2 doses.In isolated cases, a dose of 700 mg / day may be required; When used in combination with an antiepileptic drug, the pharmacokinetic interaction of which with lamotrigine has not been established, the dose of Lamolep should be increased gradually (and to a lesser extent) according to the scheme described for combination therapy with sodium valproate .; Table 1. Recommended dosing regimen in the treatment of epilepsy in adults and children over 12 years old .; Treatment option Week 1-2 Week 3-4 Maintenance dose; Monotherapy 25 mg 1 time / day 50 mg; 1 time / day 100-200 mg 1 or 2 times / day; to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks; Combination therapy with Lamolep and valproic acid preparations, regardless of other concomitant therapy, 12.5 mg (or 25 mg every other day) 25 mg; 1 time / day 100- 200 mg (in 1 or 2 doses); to achieve a therapeutic effect, the dose may be increased by 25-50 mg every 1-2 weeks; Combination therapy without valproic acid (with phenytoin, carbamazepine, phenobarbital, primidone, or other lamotrigine glucuronidation inductors) 50 mg 1 time / day 100 mg (in 2 receptions) 200-400 mg (in 2 receptions); to achieve a therapeutic effect, the dose is increased by 100 mg every 1-2 weeks; In combination therapy with antiepileptic drugs, the pharmacokinetic interaction of which with lamotrigine is currently unknown, you should use the regimen recommended for prescribing lamotrigine in combination with valproic acid drugs; age from 2 to 12 years as part of combination therapy with valproic acid drugs in combination with other antiepileptic drugs or without them Lamolepa-lingual dose for the first 2 weeks was 0.15 mg / kg body weight 1 times / day for the next 2 weeks - 0.3 mg / kg 1 time / day. Then every 1-2 weeks the dose should be increased by 0.3 mg / kg until the optimal therapeutic effect is achieved. The maintenance dose on average is 1-5 mg / kg / day in 1-2 doses. The maximum daily dose is 200 mg. As part of combination therapy with other antiepileptic drugs or other drugs that induce lamotrigine glucuronidation (phenytoin, carbamazepine, phenobarbital, and primidone), in combination with other AEDs (or without valproic acid), the initial dose of Lamolepa during the first 2 weeks is 0.6 mg / kg / day in 2 doses, later in the next 2 weeks - 1.2 mg / kg / day in 2 doses.Then every 1-2 weeks the dose should be increased to a maximum of 1.2 mg / kg / day, until the optimum therapeutic effect is achieved. The maintenance dose averages 5-15 mg / kg / day in 2 doses. The maximum daily dose is 400 mg. When used in combination with an antiepileptic drug, the pharmacokinetic interaction of which with lamotrigine has not been established, the dose of Lamolep should be increased gradually (and to a lesser extent) according to the scheme described for combination therapy with sodium valproate .; Table 2. Recommended dosing regimen in the treatment of children with epilepsy aged 2 to 12 years (total daily dose in mg / kg body weight) .; Administration regimen Week 1-2 Week 3-4 Maintenance dose; Combination therapy with valproic acid, regardless of other concomitant therapy 0.15 mg / kg 1 time / day 0.3 mg / kg 1 time / day * Dose increase by 0.3 mg / kg every 1-2 weeks before reaching a maintenance dose of 1-5 mg / kg / day (in 1-2 doses) up to a maximum dose of 200 mg / day; Combination therapy without valproic acid drugs with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization 0.6 mg / kg (in 2 doses) 1.2 mg / kg (in 2 doses) Increase dose of 1.2 mg / kg every 1-2 weeks until a maintenance dose of 5-15 mg / kg / day is reached (in 1-2 doses) up to a maximum dose of 400 mg / day; In patients taking antiepileptic drugs, the pharmacokinetic interaction with which Lamotrigine is currently unknown, it is necessary to use the regimen recommended for prescribing lamotrigine in combination with valproic acid preparations; * the dose is increased in whole pills .; Bipolar disorder; When treating bipolar disorders, Lamolep is prescribed to prevent episodes of depression. However, during short-term therapy, the maintenance dose of lamotrigine should be increased gradually, over a period of 6 weeks, until the patient’s condition stabilizes. Then, with the appropriate clinical picture of the disease, the administration of a psychotropic or other antiepileptic drug can be stopped .; For the prevention of episodes of mania may require adjuvant therapy, because the effectiveness of lamotrigine in mania and manic states is ambiguous .; Table 3.The recommended scheme for the selection of a supporting daily dose for adults (over 18 years) for bipolar disorders .; Dosage regimen Weeks 1-2 Weeks 3-4 Week 5 Maintenance stabilizing dose (week 6); Combination therapy with valproic acid) 12.5 mg (25 mg every other day) 25 mg 1 time / day 50 mg / day (1-2 reception) 100 mg / day (1-2 doses), the maximum daily dose of 200 mg; Combination therapy with inducers of lamotrigine glucuronidation (without taking valproic acid) 50 mg 1 time / day 100 mg / day (2 doses) 200 mg / day (in 2 doses) 300 mg on the 6th week of therapy, if necessary, increase the dose to 400 mg on the 7th week of therapy (in 2 doses); with drugs that do not interact with lamotrigine 25 mg 1 time / day 50 mg / day (in 1-2 doses) 100 mg / day (in 1-2 doses) 200 mg (from 100 mg to 400 mg) in 1 or 2 in patients taking antiepileptic drugs, the pharmacokinetic interaction of which with lamotrigine has not been studied, it is necessary to use the regimen recommended for prescribing lamotrigine in combination with valproic acid preparations; As part of combination therapy with other antiepileptic drugs inhibiting hepatic enzymes (for example, proevoy acid) for the first 2 weeks Lamolepa initial dose is 25 mg every other day, and then for a further 2 weeks - 1 25 mg once / day. At week 5, the dose should be increased to 50 mg / day in 1-2 doses. To achieve the optimal therapeutic effect, a dose of 100 mg / day is required in 1-2 doses; maintenance daily dose is 1-5 mg / kg body weight in 1-2 doses. The maximum daily dose is 200 mg. As part of a combination therapy with antiepileptic drugs that induce hepatic enzymes (for example, carbamazepine, phenobarbital) in patients not receiving valproic acid, for the first 2 weeks the initial dose is 50 mg 1 time / day, then for the next 2 weeks - 100 mg / day in 2 doses, at 5 weeks the dose is increased to 200 mg / day in 2 doses. At week 6, the dose may be increased to 300 mg / day. At week 7, the daily dose can reach 400 mg in 2 doses. In monotherapy or in combination therapy with drugs, the pharmacokinetic interaction of which with lamotrigine is unknown or possible, during the first 2 weeks the initial dose of Lamolep is 25 mg 1 time / day, then over the next 2 weeks - 50 mg / day in 1-2 doses , at week 5, the dose is increased to 100 mg / day in 1-2 doses.To achieve the optimal therapeutic effect, a dose of 200 mg / day is required in 1-2 doses. The maximum daily dose is 400 mg / day in 2 doses. After reaching a daily maintenance stabilizing dose, other psychotropic drugs may be canceled .; Table 4. Supportive stabilizing total daily dose for the treatment of bipolar disorders after discontinuation of concomitant psychotropic or antiepileptic drugs .; Additional therapy Week 1 Week 2 Week 3 and further (max. Dose 400 mg / day); After discontinuation of inhibitors of lamotrigine glucuronization, (for example, valproic acid drugs), the dose is increased 2 times, not more than 100 mg / week, t. e. at 1 week, the dose should be 200 mg / day. Save the dose at 200 mg / day in 2 divided doses; After discontinuation of the inducers of lamotrigine glucuronization (for example, carbamazepine), depending on the initial dose. 400 mg 300 mg 200 mg; 300 mg 225 mg 150 mg; 200 mg 150 mg 100 mg; After discontinuation of other psychotropic or antiepileptic drugs in patients not taking inducers or inhibitors of lamotrigine glucuronization (for example, lithium preparations, bupropion) The adjusted dose should be prescribed 200 mg / day (recommended dose in the range from 100 mg to 400 mg); After discontinuation of an antiepileptic agent that does not interact with lamotrigine, it is recommended to increase the dose of Lamolep according to the regimen recommended when taking lamotrigine with Valpro after withdrawal of additional therapy with lamotrigine glucuronidation inhibitors (for example, with valproic acid preparations), the initial stabilizing dose of lamotrigine doubles and remains at this level after discontinuation of valproic acid preparations .; After the additional therapy is discontinued by inducers of lamotrigine glucuronidation (for example, carbamazepine), the dose of lamotrigine is gradually reduced over 3 weeks .; After discontinuation of concomitant psychotropic or antiepileptic drugs that do not have significant pharmacokinetic interaction with lamotrigine (for example, lithium preparations, bupropion), lamotrigine is continued to be used at a dose selected in the process of the regimen; There is no clinical experience in the correction of daily doses of lamotrigine in patients with bipolar disorders after the addition of other drugs.However, based on drug interaction studies, the following recommendations can be given. Table 5. Correction of daily doses of lamotrigine in patients with bipolar disorder after joining other drugs to therapy .; Additional therapy Initial dose of Lamolep (mg / day) Week 1 Week 2 Week 3 and further; After discontinuation of inhibitors of lamotrigine glucuronization, (for example, valproic acid drugs) depending on the initial dose of Lamolep 200 mg 100 mg Save dose 100 mg / day; 300 mg 150 mg Save a dose of 150 mg / day; 400 mg 200 mg Save a dose of 200 mg / day; Adherence of lamotrigine glucuronidation inducers (for example, carbamazepine) to patients not receiving valproic acid, depending on the initial dose of Lamolep 200 mg 200 mg 300 mg 400 mg; 150 mg 150 mg 225 mg 3 00 mg; 100 mg 100 mg 150 mg 200 mg; Adding other psychotropic or antiepileptic drugs with unknown pharmacokinetic interaction with lamotrigine (for example, lithium preparations, bupropion) Dose achieved during the regimen of increase (200 mg / day); dose range from 100 mg to 400 mg; Patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is not currently known, recommended dosing regimen used when taking lamotrigine with valproic acid preparations; Lamolepa withdrawal in bipolar disorder does not require a gradual dose reduction ; The safety and efficacy of lamotrigine in bipolar disorder of infants and adolescents under 18 years of age have not been evaluated, therefore, there are no recommendations on the dosing regimen .; Tablets should be taken orally without chewing and with a small amount of water .; If the calculated dose of lamotrigine cannot be divided into a whole number of pills of a lower dosage, then the patient should be assigned such a dose that corresponds to the nearest value of the whole tablet in a lower dosage .; Correction of the dosing regimen in elderly patients (over 65 years old) is not required (since the pharmacokinetics in this age group is not different from that in adults) .; In case of impaired liver function (class B on the Child-Pugh scale), the initial, increasing and maintenance doses should be reduced by approximately 50%, and in severe cases (Class C on the Child-Pugh scale) - by 75%.Increasing and supporting doses should be adjusted depending on the clinical effect .; Caution should be exercised in the appointment of the drug to patients with renal insufficiency. In end-stage renal disease, the initial dose of lamotrigine depends on the dosing regimen of another antiepileptic drug. For patients with a significant reduction in renal function, a reduction in maintenance dose may be recommended.
Side effects
Undesirable reactions are presented for each indication separately, using the following conditional classification of the frequency of undesirable reactions: very often (> 1/10), often (> 1 / 100.1 / 1000, <1/100), rarely (> 1/10 000 In patients with epilepsy; On the part of the hemopoietic system: very rarely - neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis; Allergic reactions: very often - in the first 8 weeks of treatment skin rash (maculo-papular), which disappears after the abolition of lamotrigine; rarely - Stevens-Joe syndrome Nsona, very rarely - hypersensitivity syndrome (including such symptoms as fever, lymphadenopathy, swelling of the face, blood and liver function disorders, DIC, multiorgan disorders), toxic epidermal necrolysis (Lyell syndrome, in some cases recovery with scar formation) .; CNS: very often - headache; often - irritability, drowsiness, insomnia, dizziness, tremor, nystagmus, ataxia, anxiety; sometimes aggressiveness; very rarely - increased excitability, hallucinations, confusion, imbalance, worsening of the course of Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased frequency of convulsive seizures .; From the organ of vision: very often - diplopia, blurred vision; rarely conjunctivitis .; On the part of the digestive system: often - nausea, vomiting; very rarely - increased levels of liver enzymes, impaired liver function, liver failure .; Other: often - increased fatigue; very rarely - lupus-like syndrome .; In patients with bipolar disorders; In addition to the above symptoms, the following phenomena are also possible .; On the part of the musculoskeletal system: often - arthralgia, myalgia, back pain.
Overdose
Symptoms: nystagmus, ataxia, headache, vomiting, drowsiness, impaired consciousness, even coma .; Treatment: admission to hospital and appropriate supportive and symptomatic therapy; if necessary, gastric lavage and the introduction of activated carbon.
Interaction with other drugs
With simultaneous use, valproic acid preparations competitively block liver enzymes and interfere with lamotrigine metabolism, almost doubling its average T1 / 2, extending it to 70 hours; Antiepileptic drugs-inducers of liver enzymes (such as phenytoin, carbamazepine, fenabarbital and primidon), as well as paracetamol, stimulate lamotrigine metabolism and reduce its T1 / 2 by 2 times, to 14 h (phenytoin, carbamazepine). In patients taking carbamazepine, administration of lamotrigine may cause undesirable effects on the CNS, including dizziness, ataxia, diplopia, decreased visual acuity and nausea. Reducing the dose of carbamazepine usually leads to the disappearance of these phenomena .; With simultaneous use of lamotrigine does not affect the concentration of other antiepileptic drugs in the plasma, as well as the concentration of ethinyl estradiol and levonorgestrel (included in the simultaneous oral contraceptives) .; With simultaneous use of lamotrigine does not reduce the clearance of drugs, the metabolism of which is involved CYP2D6 .; With simultaneous use of clozapine, phenelzine, risperidone, sertalin and trazodone, apparently, do not affect the clearance of lamotrigine .; There are no data on the effect of lamotrigine on the pharmacokinetics of other antiepileptic drugs and on drug interactions between it and drugs metabolized with the participation of isoenzymes of the cytochrome P450 system .; Perhaps combined use with sedatives, antiepileptic and anxiolytic agents.
special instructions
Data confirming the clinically significant inducing and inhibitory effects of lamotrigine on oxidative enzymes in the liver are not available. The ability of the drug to induce its own metabolism is small and probably has no clinical significance .; Lamolep should not be given at the same time as others containing lamotriginedrugs .; If Lamolep provides good control of epilepsy attacks, other antiepileptic drugs can be stopped. An objective criterion for the effectiveness of treatment is the ability to reduce the frequency of peaks on the EEG by 78-98%; In the first 8 weeks of treatment, skin reactions may develop. Skin rashes are usually of mild severity and disappear spontaneously. Perhaps the development of severe forms that require hospitalization and cessation of lamotrigine therapy (for example, Stevens-Johnson syndrome and toxic epidermal necrolysis). The use of the drug in high initial doses and the acceleration of the recommended rate of increase in the dose of lamotrigine, as well as the simultaneous administration of valproic acid drugs contribute to the appearance of a skin rash. To reduce the likelihood of such dermatological reactions, the indicated doses and rates of their increase should be strictly observed .; Children are more prone to the development of severe forms of skin reactions (the incidence of cases requiring hospitalization of children is 1 / 300–1 / 100) .; The early symptoms of an allergic rash are easily confused with an infectious rash, so if a fever and a rash occur in the first 8 weeks of treatment, a drug reaction should be assumed .; It is important to remember that early manifestations of hypersensitivity reactions (eg, high fever, lymphadenopathy) can occur without a rash. If a rash appears (regardless of the patient's age), a thorough examination of the patient should be carried out immediately and lamotrigine therapy should be stopped if the development of dermatological symptoms cannot be explained by another reason .; The appearance of a rash may be accompanied by various systemic manifestations of hypersensitivity (high body temperature, lymphadenopathy, swelling of the face, reactions from the liver and the hematopoietic system). The severity of hypersensitivity reactions can be different, sometimes it is possible the development of disseminated intravascular coagulopathy and polyorgan functional insufficiency. It should be borne in mind that early signs of hypersensitivity (for example, high body temperature, lymphadenopathy) are not always accompanied by a skin rash .; Liver dysfunction is usually part of hypersensitivity syndrome, but is not always accompanied by other symptoms .; Long-term treatment with lamotrigine can change the metabolism of folic acid, because Lamotrigine is a weak inhibitor of dihydrofolate reductase.At the same time, long-term, 12-month treatment with lamotrigine does not significantly affect the level of hemoglobin, the average volume of red blood cells, the concentration of folic acid in plasma and red blood cells, and after 5 years of treatment - the concentration of folic acid .; In case of lactose intolerance, it should be borne in mind that pills containing 25 mg of lamotrigine contain 16.35 mg of lactose monohydrate, containing 50 mg - 32.5 mg, 100 mg - 65 mg. Despite the fact that when taking oral contraceptives, lamotrigine does not affect the concentration of ethinyl estradiol and levonorgestrel, menstrual disorders during lamotrigine therapy in patients taking oral contraceptives require close attention of the attending physician .; When treating patients with renal failure on hemodialysis, it should be borne in mind that on average during 4-hour hemodialysis, 20% of lamotrigine is eliminated from the body .; Abrupt cessation of lamotrigine treatment provokes epileptic seizures, up to epileptic status. Therefore, with the exception of special cases (for example, the appearance of a skin rash) requiring immediate cessation of therapy, drug withdrawal should be carried out gradually with a gradual decrease in dose over a period of 2 weeks .; Severe seizures and status epilepticus can lead to the development of rhabdomyolysis, organ organ failure, and disseminated intravascular coagulopathy, sometimes fatal. Similar cases have occurred in connection with the use of lamotrigine .; Bipolar disorders are prone to suicide, so when prescribing a drug to patients with a tendency to suicide, careful monitoring of patients is required .; Influence on ability to drive motor transport and control mechanisms; During treatment, it is prohibited to drive a car and engage in activities that require increased concentration of attention and quickness of psychomotor reactions.