Lamolep, tablets 50 mg 30 pcs

A anticonvulsant (antiepileptic) drug. Stabilizes potential-dependent sodium channels of cell membranes. It also blocks release of neurotransmitters, mainly glutamic amino acid (which plays key role in development of epileptic seizures).

Pharmacokinetics

Intake

After oral administration it is quickly and completely absorbed from the intestine, significantly not subject to the “first pass” effect. C_max reached 2.5 h after oral administration. Food intake slows down the process of absorption, but does not affect its effectiveness. Bioavailability is 98%. Pharmacokinetics of the drug after a single dose not exceeding 450 mg is linear. The concentration in equilibrium is sharply pronounced individual character.

Distribution

Protein binding is 55%. It is unlikely that displacement of lamotrigine from protein binding can cause toxic effects. V_d is 0.92-1.22 L/kg body weight. It is excreted with breast milk. The concentration in breast milk is 40-60% of the plasma concentration. In some cases, the drug concentration in the serum of infants whose mothers took the drug while breastfeeding reaches therapeutic levels.

Metabolism

The drug is biotransformed in the liver under the action of uridine diphosphate glucuronyl transferase. Among the metabolites, N -glucuronides predominate. Lamotrigine moderately and dose-dependently induces its own metabolism.

The mean equilibrium clearance in healthy adults is 39±14 mL/min. It is excreted with urine as glucuronide conjugate, less than 10% – unchanged, about 2% (unchanged and as metabolites) – with feces. Clearance and T_1/2 are not dose dependent.T_1/2 of healthy volunteers is 24-35 h.

Pharmacokinetics in Special Clinical Cases

Clearance, converted to kg body weight, is higher in children than in adults and is highest until age 5 years. T_1/2 in children is usually shorter than in adults.

T_1/2 in children when concomitantly used with enzyme inducers is 7 h, with sodium valproate 45-60 h.

Lamotrigine clearance in elderly and younger patients is minimally different.

Indications

Epilepsy

for adults and children over 12 years

for children aged 2-12 years

Bipolar disorder

for adults (18 years and older)

Active ingredient

How to take, the dosage

Epilepsy

In adults and children over 12 years of age for monotherapy, the initial dose of Lamolep is 25 mg once daily for the first 2 weeks; in the following 2 weeks, 50 mg once daily. Further, every 1-2 weeks the dose may be increased by 50-100 mg until the optimal therapeutic effect is achieved. Maintenance dose for maintenance of optimal therapeutic effect is usually 100-200 mg/day in 1-2 doses. In single cases, to achieve therapeutic effect, administration of the drug in a dose of 500 mg/day is required.

In combination therapy in concurrent use with valproic acid in combination with other antiepileptic agents or without them the initial dose of Lamolep during the first 2 weeks is 25 mg daily; further 25 mg 1 time per day for the next 2 weeks. Thereafter, every 1-2 weeks the dose may be increased by 25-50 mg until the optimal therapeutic effect is achieved. The maintenance dose is usually 100-200 mg/day in 1-2 doses.

. When using Lamolep in combination therapy with drugs inducing lamotrigine glucuronization (phenytoin, carbamazepine, phenobarbital, primidone) in combination or without other antiepileptic agents (but not taking valproic acid) during first 2 weeks the initial dose is 50 mg once a day, further during next 2 weeks – 100 mg/day in 2 doses. Thereafter, every 1-2 weeks the dose may be increased by 100 mg until the optimal therapeutic effect is achieved. Maintenance dose is usually 200-400 mg/day in 1-2 receipts. A dose of 700 mg/day may be required in isolated cases.

When used in combination with an antiepileptic drug whose pharmacokinetic interaction with lamotrigine has not been established, the dose of Lamolep should be increased gradually (and to a lesser degree) according to the scheme described for combination therapy with sodium valproate.

Table 1. Recommended dosing regimen for the treatment of epilepsy in adults and children over 12 years of age.

In children aged 2 to 12 years in combination therapy with valproic acid drugs, in combination with or without other antiepileptic agents, the initial daily dose of Lamolep for the first 2 weeks is 015 mg/kg body weight once daily, for the next 2 weeks it is 0.3 mg/kg once daily. Then every 1-2 weeks the dose should be increased by 0.3 mg/kg until optimal therapeutic effect is achieved. The maintenance dose averages 1-5 mg/kg/day in 1-2 doses. The maximum daily dose is 200 mg.

In combination therapy with other antiepileptic agents or other drugs that induce glucuronidation of lamotrigine (phenytoin, carbamazepine, phenobarbital and primidone), in combination with other PEP or without them (except valproic acid drugs)the initial dose of Lamolep for the first 2 weeks is 06 mg/kg/day in 2 doses, then 1.2 mg/kg/day in 2 doses for the next 2 weeks. Then every 1-2 weeks the dose should be increased by maximum 1.2 mg/kg/day until optimal 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 whose pharmacokinetic interaction 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 for the treatment of children with epilepsy aged 2 to 12 years (total daily dose in mg/kg body weight).

*Dose escalation is performed in whole tablets.

Bipolar disorders

In the treatment of bipolar disorders, Lamolep is prescribed to prevent episodes of depression. In this case, in short-term therapy, the maintenance dose of lamotrigine should be increased gradually, over 6 weeks, until the patient’s condition stabilizes. Thereafter, the psychotropic or other antiepileptic medication may be discontinued if the clinical picture is appropriate.

Adjuvant therapy may be necessary to prevent episodes of mania, because the efficacy of lamotrigine in mania and manic states is controversial.

Table 3: Recommended daily maintenance dosage regimen for adults (over 18 years of age) with bipolar disorders.

In combination therapy with other antiepileptic agents that inhibit hepatic enzymes (e.g., valproic acid agents), the initial dose of Lamolep is 25 mg daily for the first 2 weeks, then 25 mg once daily for the next 2 weeks. At week 5, the dose should be increased to 50 mg/day in 1-2 doses. To achieve optimal therapeutic effect, a dose of 100 mg/day in 1-2 doses is required; the maintenance daily dose is 1-5 mg/kg body weight in 1-2 doses. The maximum daily dose is 200 mg.

In combined therapy with antiepileptic agents which induce liver enzymes (e.g., carbamazepine, phenobarbital) in patients who do not receive valproic acid agents the first 2 weeks the starting dose is 50 mg once daily, then during the next 2 weeks – 100 mg/day in 2 doses, at week 5 the dose is increased to 200 mg/day in 2 doses. In week 6, the dose may be increased to 300 mg/day. At week 7, the daily dose can reach 400 mg in two doses.

In monotherapy or in combination therapy with drugs whose pharmacokinetic interaction with lamotrigine is unknown or possible, during the first 2 weeks the initial dose of Lamolep is 25 mg once daily, then during 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 optimal therapeutic effect, a dose of 200 mg/day in 1-2 doses is required. The maximum daily dose is 400 mg/day in 2 doses.

After achieving a daily maintenance stabilizing dose, other psychotropic medications may be discontinued.

Table 4: Maintenance stabilizing total daily dose for treatment of bipolar disorder after withdrawal of concomitant psychotropic or antiepileptic drugs.

In moderate hepatic impairment (Child-Pugh class B), the initial, increasing and maintenance doses should be reduced by approximately 50%; in severe hepatic impairment (Child-Pugh class C), the dose should be reduced by 75%. Increasing and maintenance doses should be adjusted according to clinical effect.

Caution should be exercised when prescribing the drug in patients with renal insufficiency. In end-stage renal failure, the initial dose of lamotrigine is dependent on the dosing regimen of the other antiepileptic drug. For patients with a significant decrease in renal function, reduction of the maintenance dose may be recommended.

Interaction

When used concomitantly, valproic acid drugs competitively block hepatic enzymes and interfere with lamotrigine metabolism, nearly doubling its mean T1/2, prolonging it to 70 h.

The antiepileptic hepatic enzyme inducers (such as phenytoin, carbamazepine, phenabarbital, and primidone) and paracetamol stimulate lamotrigine metabolism and decrease its T1/2 by 2 times, to 14 h (phenytoin, carbamazepine). In patients taking carbamazepine, administration of lamotrigine may cause CNS adverse effects including dizziness, ataxia, diplopia, decreased visual acuity and nausea. Decreasing the dose of carbamazepine usually results in the disappearance of these phenomena.

When used concomitantly lamotrigine has no effect on the plasma concentrations of other antiepileptic drugs and concentrations of ethinylestradiol and levonorgestrel (part of concomitantly used oral contraceptives).

Concomitant use of lamotrigine does not decrease clearance of drugs metabolized by CYP2D6.

When used concomitantly, clozapine, phenelzine, risperidone, sertraline and trazodone do not appear to affect lamotrigine clearance.

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 cytochrome P450 isoenzymes.

Possible co-administration with sedatives, antiepileptics and anxiolytics.

Special Instructions

There are no data confirming clinically significant inducing and inhibitory effects of lamotrigine on oxidative enzymes in the liver. The ability of the drug to induce its own metabolism is small and probably has no clinical relevance.

Lamotrigine should not be administered concomitantly with other drugs containing lamotrigine.

If Lamolep provides good control of epileptic seizures, other antiepileptic drugs may be discontinued.

The ability to reduce EEG peak frequency by 78-98% is an objective criterion of treatment effectiveness.

In the first 8 weeks of treatment it is possible to develop skin reactions. Skin rashes are usually mild in severity and disappear spontaneously. Severe forms requiring hospitalization and discontinuation of lamotrigine therapy (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may develop. The use of the drug in high initial doses and accelerating the recommended rates of increasing the dose of lamotrigine, as well as concomitant use of valproic acid drugs contribute to the appearance of skin rash. To reduce the likelihood of such dermatological reactions, the indicated doses and rates of dose escalation should be strictly adhered to.

Children are more prone to develop severe skin reactions (the frequency of cases requiring hospitalization in children is 1/300-1/100).

The early symptoms of an allergic rash are easily confused with an infectious rash, so if fever and rash occur within the first 8 weeks of treatment, a drug reaction should be suspected.

It is important to remember that early manifestations of hypersensitivity reactions (e.g., fever, lymphadenopathy) can occur without a rash. If a rash occurs (regardless of the patient’s age), a thorough evaluation of the patient should be performed immediately and therapy with lamotrigine should be discontinued if the development of dermatologic symptoms cannot be explained by another cause.

The appearance of rash may be accompanied by various systemic manifestations of hypersensitivity (high body temperature, lymphadenopathy, facial edema, liver and hematopoietic reactions). The severity of hypersensitivity reactions may vary, sometimes the development of disseminated intravascular coagulopathy and multiple organ failure. Note that early signs of hypersensitivity (e.g., high body temperature, lymphadenopathy) are not always accompanied by a skin rash.

Liver function abnormalities are usually part of the hypersensitivity syndrome, but are not always accompanied by other symptoms.

Long-term treatment with lamotrigine may alter folic acid metabolism because lamotrigine is a weak dihydrofolate reductase inhibitor. However, long-term, 12-month treatment with lamotrigine has no significant effect on hemoglobin levels, mean erythrocyte volume, plasma and erythrocyte folic acid concentrations, and after 5 years of treatment, folic acid concentrations.

In case of lactose intolerance, note that tablets containing 25 mg of lamotrigine contain 16.35 mg of lactose monohydrate, those containing 50 mg contain 32.5 mg, 100 mg contains 65 mg.

While lamotrigine has no effect on ethinylestradiol and levonorgestrel concentrations when taking oral contraceptives, menstrual irregularities during lamotrigine therapy in patients taking oral contraceptives require the close attention of the treating physician.

When treating patients with renal impairment who are on hemodialysis, it should be kept in mind that an average of 20% of lamotrigine is eliminated from the body during 4 hours of hemodialysis.

The abrupt discontinuation of lamotrigine treatment provokes epileptic seizures, up to and including epileptic status. Therefore, except in special cases (e.g., the appearance of a skin rash) requiring immediate discontinuation of therapy, withdrawal of the drug is carried out gradually, with a gradual, over 2 weeks, reduction of the dose.

Severe seizures and status epilepticus may lead to the development of rhabdomyolysis, multiple organ failure, and disseminated intravascular coagulopathy, sometimes with fatal outcome. Similar cases have occurred with lamotrigine.

Bipolar disorders are characterized by suicidal tendencies, so close monitoring of patients with suicidal tendencies is required when prescribing the drug.

Impact on driving and operating machinery

During treatment, it is prohibited to drive a vehicle and engage in activities requiring increased concentration and rapid psychomotor reaction.

Contraindications

Patients with renal impairment should use the drug with caution (because of possible cumulation of the glucuronide metabolite).

With caution, children should be prescribed as the drug of choice in epilepsy monotherapy.

Hepatic impairment use

In moderate hepatic impairment (Child-Pugh class B), the initial, increasing and maintenance doses should be reduced by approximately 50%; in severe hepatic impairment (Child-Pugh class C), by 75%. Increasing and maintenance doses should be adjusted according to clinical effect.

The use in renal dysfunction

Patients with renal impairment should be treated with caution when prescribing the drug.

Periatric use

There is no need for dosing adjustment in elderly patients (>65 years) (because the pharmacokinetics are the same as in adults in this age group).

Side effects

Adverse reactions are presented separately for each indication, using the following conditional classification of the frequency of adverse reactions: very common (>1/10), common (>1/100,1/1000, <1/100), rare (>1/10,000,

In patients with epilepsy

Hematopoietic system: very rare – neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis.

Allergic reactions: very common – in the first 8 weeks of therapy, skin rash (maculopapular), which disappears after withdrawal of lamotrigine; rare – Stevens-Johnson syndrome, very rare – hypersensitivity syndrome (including such symptoms as fever, lymphadenopathy, facial edema, blood and liver function disorders, DIC syndrome, multi-organ disorders), toxic epidermal necrolysis (Lyell syndrome, in some cases recovery with formation of scars).

CNS disorders: very commonly – headache; frequently – irritability, somnolence, insomnia, dizziness, tremor, nystagmus, ataxia, anxiety; sometimes – aggressiveness; very rarely – hyperexcitability, hallucinations, mental confusion, loss of balance, worsening of Parkinson disease course, extrapyramidal disorders, choreoathetosis, increased frequency of seizures.

An organ of vision: very common – diplopia, blurred vision; rarely – conjunctivitis.

The digestive system: frequently – nausea, vomiting; very rare – increased liver enzymes levels, liver dysfunction, liver failure.

Others: common – increased fatigue; very rare – lupus-like syndrome.

In patients with bipolar disorders

In addition to the above symptoms, the following phenomena are also possible.

Muscular system disorders: often – arthralgia, myalgia, back pain.

Overdose

Symptoms: nystagmus, ataxia, headache, vomiting, drowsiness, impaired consciousness up to coma.

Treatment: hospitalization and appropriate supportive and symptomatic therapy; if necessary, gastric lavage and administration of activated charcoal.

Pregnancy use

Lamolet is contraindicated in pregnancy unless the expected therapeutic benefit to the mother exceeds the potential risk to the fetus. Due to the inhibitory effect of lamotrigine on dihydrofolate reductase, fetal malformations are likely to develop when using the drug in pregnancy; however, the data currently available are insufficient to determine the degree of safety.

There are limited data on the use of the drug during breastfeeding. In some cases the drug concentration in the serum of infants whose mothers took the drug during breastfeeding reaches the therapeutic level. When using the drug during lactation the benefits of breastfeeding and the possibility of side effects in the baby should be carefully weighed.

Pediatric use

With caution, the drug is prescribed in children as the drug of choice in epilepsy monotherapy. Contraindication: children under 2 years of age.

Similarities