Convulsan (Tablets) Instructions for Use

ATC Code

N03AX09 (Lamotrigine)

Active Substance

Lamotrigine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Anticonvulsant drug. Lamotrigine is a voltage-gated sodium channel blocker, suppresses the pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), and also inhibits depolarization induced by glutamate.

Pharmacokinetics

Absorption

After oral administration, Lamotrigine is rapidly and completely absorbed from the gastrointestinal tract, undergoing virtually no presystemic metabolism during the first-pass effect. C_max in plasma is reached approximately 2.5 hours after drug administration. The time to reach C_max is slightly increased after food intake, but the extent of absorption remains unchanged. The pharmacokinetics of lamotrigine are linear when administered in a single dose up to 450 mg. Significant interindividual variations in C_max at steady state are observed, but with rare variations in each individual person.

Distribution

The binding of lamotrigine to plasma proteins is approximately 55%. It is unlikely that the release of the drug from protein binding could lead to the development of a toxic effect.

V_d is 0.92-1.22 L/kg.

Metabolism

The enzyme uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase) is involved in the metabolism of lamotrigine. It is metabolized to glucuronides. Lamotrigine slightly increases its own metabolism in a dose-dependent manner.

Excretion

In adults, the clearance of lamotrigine at steady-state concentrations averages 39±14 mL/min. It is excreted in the urine as metabolites, less than 10% of the drug is excreted unchanged in the urine, about 2% is excreted in the feces. Clearance and T_1/2 are dose-independent. T_1/2 in healthy adults averages from 24 hours to 35 hours. The T_1/2 of lamotrigine is significantly influenced by concomitantly administered drugs.

Pharmacokinetics in special clinical cases

In children, the clearance of lamotrigine calculated per body weight is higher than in adults (highest in children under 5 years of age). In children, the T_1/2 of lamotrigine is usually shorter than in adults. Its average value is approximately 7 hours when co-administered with drugs that stimulate glucuronidation, such as carbamazepine and phenytoin, and increases to an average of 45-50 hours when co-administered with valproate.

Clinically significant differences in lamotrigine clearance in elderly patients compared to young patients have not been found.

In patients with Gilbert’s syndrome, a 32% decrease in drug clearance was observed, which, however, did not exceed the normal range for the general population.

Indications

Epilepsy

• As adjunctive or monotherapy for epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaut syndrome) in adults and children over 12 years of age;
• As adjunctive therapy for epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaut syndrome) in children from 2 to 12 years of age (after achieving epilepsy control with combination therapy, concomitant antiepileptic drugs may be discontinued and lamotrigine continued as monotherapy);
• Monotherapy for typical absences.

Bipolar disorders

• For the prevention of mood disorders (depression, mania, hypomania, mixed episodes) in adults with bipolar disorders.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. Convulsan tablets can be chewed, dissolved in a small amount of water (enough to cover the entire tablet), or swallowed whole with a small amount of water.

If the calculated dose of lamotrigine (e.g., when prescribed to children or patients with impaired liver function) cannot be divided into a whole number of tablets, the patient should be prescribed a dose corresponding to the nearest value of a whole tablet in a lower dosage.

Due to the risk of rash, the initial dose of the drug and the recommended dose escalation regimen should not be exceeded.

Epilepsy

Monotherapy in adults and children over 12 years

The initial dose of Convulsan is 25 mg once daily for the first 2 weeks, followed by an increase to 50 mg once daily for the next 2 weeks. The dose should then be increased by 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg/day in 1 or 2 doses. Some patients require Convulsan at a dose of 500 mg/day to achieve a therapeutic effect.

Adjunctive therapy in adults and children over 12 years

When Convulsan is used concomitantly with valproic acid drugs in combination with other antiepileptic drugs (AEDs) or without them the initial dose of lamotrigine is 25 mg every other day for the first 2 weeks; then 25 mg once daily for the next 2 weeks. The dose should then be increased by a maximum of 25-50 mg/day every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg/day in 1 or 2 doses.

When Convulsan is used concomitantly with antiepileptic drugs or other drugs that stimulate the glucuronidation of lamotrigine, in combination with other AEDs or without them (except for valproic acid drugs) the initial dose of Convulsan is 50 mg once daily for the first 2 weeks, then 100 mg/day in 2 doses for the next 2 weeks. The dose is then increased by a maximum of 100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 200-400 mg/day in 2 doses. Some patients may require a dose of up to 700 mg/day.

When Convulsan is used concomitantly with oxcarbazepine in combination with any other inducers or inhibitors of lamotrigine glucuronidation or without them the initial dose of lamotrigine is 25 mg once daily for the first 2 weeks, then 50 mg/day in one dose for the next 2 weeks. The dose is then increased by a maximum of 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg/day in 1 or 2 doses.

Monotherapy in children aged 2 to 12 years

The initial dose of Convulsan for monotherapy of typical absences is 300 mcg/kg body weight/day in 1 or 2 doses for the first 2 weeks, followed by an increase to 600 mcg/kg/day in 1 or 2 doses for the next 2 weeks. The dose should then be increased by a maximum of 600 mcg/kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is from 1 to 10 mg/kg/day in 1 or 2 doses, although some patients require higher doses.

The titration to a therapeutically effective maintenance dose of Convulsan is carried out with other lamotrigine preparations having an appropriate dosage. When the lamotrigine dose reaches 25 mg or more, a switch to Convulsan can be made.

Selection of a therapeutically effective maintenance dose of Convulsan is carried out using other lamotrigine preparations in the appropriate dosage. When the lamotrigine dose reaches 25 mg or more, a switch to Convulsan can be made.

Adjunctive therapy in children aged 2 to 12 years

When Convulsan and valproic acid drugs are used concomitantly in combination with other AEDs or without them the initial dose of lamotrigine is 150 mcg/kg once daily for the first 2 weeks, then 300 mcg/kg once daily for the next 2 weeks. The dose can then be increased by 300 mcg/kg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 1-5 mg/kg/day in 1 or 2 doses. The maximum daily dose is 200 mg.

When Convulsan is used concomitantly with antiepileptic drugs or other drugs that stimulate the glucuronidation of lamotrigine (phenytoin, carbamazepine, phenobarbital and primidone), in combination with other AEDs or without them (except for valproic acid drugs) the initial dose of lamotrigine is 600 mcg/kg/day in 2 doses for the first 2 weeks, then 1.2 mg/kg/day in 2 doses for the next 2 weeks. The dose should then be increased by a maximum of 1.2 mg/kg/day every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 5-15 mg/kg/day in 2 doses. The maximum daily dose is 400 mg.

When Convulsan is used concomitantly with oxcarbazepine without any other inducers or inhibitors of lamotrigine glucuronidation the initial dose of lamotrigine is 300 mcg/kg/day in 1 or 2 doses for the first 2 weeks, then 600 mcg/kg/day in 1 or 2 doses for the next 2 weeks. The dose is then increased by a maximum of 600 mcg/kg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 1-10 mg/kg/day in 1 or 2 doses. The maximum dose is 200 mg/day.

To ensure that a therapeutic dose is maintained, the child’s body weight should be monitored and the drug dose adjusted if it changes. Children aged 2 to 6 years are most likely to require the highest maintenance doses.

Selection of a therapeutically effective maintenance dose of Convulsan is carried out using other lamotrigine preparations in the appropriate dosage. When the lamotrigine dose reaches 25 mg or more, a switch to Convulsan can be made.

When discontinuing concomitant antiepileptic drugs to switch to Convulsan monotherapy or when prescribing other drugs or AEDs while taking Convulsan, it should be taken into account that this may affect the pharmacokinetics of lamotrigine.

Bipolar disordersin adults (patients over 18 years)

It is necessary to follow the transition dosing regimen, which includes increasing the dose of lamotrigine over 6 weeks to a maintenance stabilizing dose (Table 1), after which other psychotropic and/or antiepileptic drugs can be discontinued if indicated (Table 2).

Table 1. Recommended dose escalation schedule to achieve the maintenance stabilizing daily dose for bipolar disorders in adults.

The maintenance stabilizing dose is adjusted depending on the clinical effect.

For adjunctive therapy in patients receiving AEDs that inhibit lamotrigine glucuronidation (e.g., valproic acid drugs), the initial dose of Convulsan is 25 mg every other day 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. The usual target dose is 100 mg/day in 1-2 doses. The maximum daily dose is 200 mg.

For adjunctive therapy in patients simultaneously receiving AEDs that stimulate lamotrigine glucuronidation (including phenytoin, carbamazepine, phenobarbital, primidone), and not receiving inhibitors of lamotrigine glucuronidation (e.g., valproic acid drugs), the initial dose of Convulsan is 50 mg once daily for 2 weeks, then 100 mg/day in 2 doses for the next 2 weeks, at week 5 the dose should be increased to 200 mg/day in 2 doses. At week 6, the dose may be increased to 300 mg/day, but the usual target dose is 400 mg/day in 2 doses and is prescribed starting from week 7.

For Convulsan monotherapy or for adjunctive therapy in patients receiving lithium, bupropion, olanzapine, oxcarbazepine or other drugs that do not have a significant inducing or inhibitory effect on lamotrigine glucuronidation, the initial dose of Convulsan is 25 mg once daily for the first 2 weeks, then 50 mg/day in 1 or 2 doses for the next 2 weeks. The dose should be increased to 100 mg/day in 1-2 doses at week 5. The usual target dose is 200 mg/day in 1-2 doses.

After reaching the daily maintenance stabilizing dose, other psychotropic drugs may be discontinued (Table 2).

Table 2. Maintenance stabilizing daily dose for the treatment of bipolar disorders after discontinuation of concomitant psychotropic or antiepileptic drugs.

If necessary, the dose can be increased to 400 mg/day.

After discontinuation of adjunctive therapy with inhibitors of lamotrigine glucuronidation (e.g., valproic acid drugs) the initial stabilizing dose of Convulsan is doubled and maintained at this level.

After discontinuation of adjunctive therapy with inducers of lamotrigine glucuronidation (including phenytoin, carbamazepine, phenobarbital, primidone) the dose of Convulsan is gradually reduced over 3 weeks depending on the initial maintenance dose.

After discontinuation of concomitant psychotropic drugs or AEDs that do not have significant pharmacokinetic interaction with lamotrigine (e.g., lithium, bupropion, olanzapine, oxcarbazepine), the target dose of Convulsan achieved during the escalation regimen should be maintained.

Bipolar disorders

There is no clinical experience in adjusting the daily doses of lamotrigine in patients with bipolar disorders after adding other drugs. However, based on drug interaction studies, the following recommendations can be made (Table 3).

Table 3. Adjustment of daily doses of lamotrigine in patients with bipolar disorder after adding other drugs to therapy.

When discontinuing Convulsan therapy in patients with bipolar disorder, Convulsan can be discontinued immediately, without gradual dose reduction.

Re-initiation

If lamotrigine is resumed, the physician should assess the need to increase the maintenance dose in patients who have discontinued the drug for any reason, as high initial doses and exceeding recommended doses are associated with the risk of developing severe rash. The longer the time since the last dose of the drug, the more cautiously the dose should be increased to the maintenance level. If the time since discontinuation exceeds 5 half-lives, the lamotrigine dose should be increased to the maintenance level according to the appropriate schedule.

Lamotrigine therapy should not be resumed in patients whose discontinuation of lamotrigine was associated with the appearance of a rash, unless the potential benefit of such therapy clearly outweighs the possible risk.

Special patient groups

When prescribing Convulsan to women who are already taking hormonal contraceptives, there is no need to adjust the recommended lamotrigine dose escalation regimens.

When prescribing hormonal contraceptives to patients already receiving maintenance doses of Convulsan and not receiving inducers of lamotrigine glucuronidation, an increase in the maintenance dose of lamotrigine may be required, but not more than 2 times, depending on the individual clinical effect.

When discontinuing hormonal contraceptives in patients already receiving maintenance doses of Convulsan and not receiving inducers of lamotrigine glucuronidation, a reduction in the lamotrigine dose by half may be required depending on the individual clinical effect.

No dose regimen adjustment is required for elderly patients (over 65 years old).

In moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, the initial, escalating, and maintenance doses should be reduced by approximately 50% and 75%, respectively. The escalating and maintenance doses should be adjusted based on clinical effect.

Patients with significant renal impairment (serum creatinine ≥ 250 µmol/L) may be recommended to reduce the maintenance dose.

Adverse Reactions

Information on adverse reactions is divided into 2 sections: adverse reactions in patients with epilepsy and adverse reactions in patients with bipolar disorder. However, when considering the overall safety profile of lamotrigine, information from both sections should be taken into account.

Definition of frequency of adverse reactions: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).

In patients with epilepsy

Dermatological reactions: In monotherapy: very common – skin rashes; in other types of clinical use: very common – skin rashes; rare – Stevens-Johnson syndrome; very rare – toxic epidermal necrolysis.

Rash, mainly maculopapular in nature, usually appears within the first 8 weeks after starting therapy and resolves after drug withdrawal.

There are reports of rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome). Although in most cases symptoms resolved after drug withdrawal, some patients had irreversible scarring, and in rare cases, fatal outcomes associated with drug use were reported. The overall risk of developing a rash was largely associated with a high initial dose of lamotrigine and exceeding the recommended rates of lamotrigine dose escalation, with concomitant administration of valproic acid preparations. The development of a rash was also considered as a manifestation of a hypersensitivity syndrome associated with various systemic manifestations.

From the hematopoietic system: very rare – neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis. Hematological disorders may or may not be associated with a hypersensitivity syndrome.

From the immune system: very rare – hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, facial swelling, blood and liver function disorders, DIC syndrome, multiorgan disorders). Rash is also considered part of the hypersensitivity syndrome. It is important to note that early manifestations of hypersensitivity (i.e., fever, lymphadenopathy) may occur even in the absence of obvious signs of a rash. If such symptoms develop, the patient should immediately consult a doctor and, if no other cause for the symptoms is established, Lamotrigine should be discontinued.

From the CNS: In monotherapy: very common – headache; common – irritability, drowsiness, insomnia, dizziness, tremor; uncommon – aggressiveness, ataxia; rare – nystagmus; very rare – tics, hallucinations, confusion; in combination therapy: very common – headache, dizziness; common – nystagmus, tremor, ataxia, drowsiness, insomnia; very rare – aseptic meningitis, agitation, loss of balance, movement disorders, worsening of Parkinson’s disease symptoms, extrapyramidal disorders, choreoathetosis, increased frequency of seizures.

From the sensory organs In monotherapy: uncommon – diplopia, blurred vision; in combination therapy: very common – diplopia, decreased visual acuity; rare – conjunctivitis.

From the digestive system In monotherapy: common – nausea, vomiting, diarrhea; as part of combination therapy: very common – nausea, vomiting; common – diarrhea.

From the hepatobiliary system very rare – increased activity of liver enzymes, impaired liver function, liver failure. Liver function disorders usually develop in combination with symptoms of hyperreactivity, but in isolated cases they were noted in the absence of obvious signs of hypersensitivity.

Other common – fatigue; very rare – lupus-like syndrome.

In patients with bipolar disorder

Dermatological reactions very common – skin rash; rare – Stevens-Johnson syndrome.

From the CNS very common – headache; common – agitation, drowsiness, dizziness.

From the musculoskeletal system common – arthralgia, myalgia, back pain.

From the digestive system: common – dry oral mucosa.

Other common – pain.

Contraindications

• Children under 2 years of age;
• Hypersensitivity to the components of the drug.

Use with caution in chronic renal failure, during pregnancy, during lactation (breastfeeding).

Use in Pregnancy and Lactation

Convulsan should be prescribed during pregnancy only if the expected therapeutic benefit to the mother outweighs the potential risk to the fetus. Physiological changes that develop during pregnancy may affect the level of lamotrigine and/or its therapeutic effect. There are reports of a decrease in lamotrigine concentration during pregnancy. The prescription of lamotrigine to pregnant women should be accompanied by appropriate patient management tactics according to the condition.

Lamotrigine is excreted in breast milk and is detected in breast milk, according to preliminary data, in concentrations amounting to 40-60% of its concentration in maternal plasma. Plasma concentrations of lamotrigine in breastfed infants may reach values at which a pharmacological effect develops. If it is necessary to prescribe Convulsan during lactation, the potential benefits of breastfeeding and the potential risk of side effects in the child should be weighed.

Use in Hepatic Impairment

In moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, the initial, escalating, and maintenance doses should be reduced by approximately 50% and 75%, respectively. The escalating and maintenance doses should be adjusted based on clinical effect.

Use in Renal Impairment

Use with caution in renal failure.

Patients with significant renal impairment may be recommended to reduce the maintenance dose.

Pediatric Use

Contraindicated in children under 2 years of age.

Special Precautions

Skin rash

In adults with epilepsy who received the drug at recommended doses in clinical trials, the frequency of severe forms of skin reactions was 1:500. Among them, Stevens-Johnson syndrome was observed in half of the cases (1:1000).

The risk of developing severe skin rashes is higher in children than in adults. According to available data, the frequency of skin rashes requiring hospitalization in children with epilepsy ranged from 1 in 300 to 1 in 100 children.

In children, the initial manifestations of a rash may be mistaken for an infection, so the possibility of a child’s reaction to the drug, manifested by the development of a rash and fever in the first 8 weeks of therapy, should be taken into account.

In addition, the overall risk of developing a rash is largely associated with a high initial dose of Convulsan and exceeding the recommended rate of its escalation, as well as with concomitant use with valproic acid preparations.

Caution is necessary when prescribing lamotrigine to patients with a history of allergic reactions or rash in response to taking other antiepileptic drugs, since the frequency of rash (not classified as serious) in patients with such a history was observed 3 times more often when prescribing lamotrigine than in patients with an unburdened history.

If a rash is detected, all patients (adults and children) should be immediately examined by a doctor. Lamotrigine should be discontinued immediately unless it is obvious that the rash is not related to the drug. It is not recommended to resume taking lamotrigine in cases where its previous prescription was discontinued due to the development of a skin reaction, unless the expected therapeutic effect of using the drug outweighs the risk of side effects.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, and therefore the drug may affect folate metabolism during long-term therapy. However, it has been shown that Lamotrigine did not cause significant changes in hemoglobin content, mean erythrocyte volume, serum folate concentration (with use up to 1 year) or erythrocyte folate concentration (with use up to 5 years).

Hormonal contraceptives

If patients start or stop taking hormonal contraceptives while using Convulsan, dose adjustment of lamotrigine may be required.

It has been shown that the combined drug ethinylestradiol/levonorgestrel (30 mcg/150 mcg) approximately doubles the clearance of lamotrigine, leading to a decrease in its plasma level. When prescribing it, to achieve the maximum therapeutic effect, an increase in the maintenance doses of lamotrigine is necessary, but not more than 2 times. In women who are not taking inducers of lamotrigine glucuronidation and are taking hormonal contraceptives according to a regimen that includes a week of taking an inactive drug (or a week-long break in taking the contraceptive), a gradual transient increase in lamotrigine concentration will be observed during this period. The increase in concentration will be more pronounced if the next dose increase of lamotrigine is carried out immediately before or during the period of taking the inactive drug. Other oral contraceptives and hormone replacement therapy have not been studied, although they may similarly affect the pharmacokinetic parameters of lamotrigine.

In addition, the combined administration of lamotrigine and a combined hormonal contraceptive (ethinylestradiol/levonorgestrel) leads to a moderate increase in the clearance of levonorgestrel and changes in the concentration of FSH and LH. The effect of these changes on ovarian ovulatory activity is unknown. However, it cannot be ruled out that in some patients taking Lamotrigine and hormonal contraceptives, these changes may cause a decrease in the effectiveness of contraception. Patients should be informed of the need to immediately inform the doctor about changes in the nature of the menstrual cycle, i.e., about sudden bleeding.

Impaired liver and kidney function

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

Lamotrigine should be prescribed with caution to patients with renal failure. In end-stage renal failure, with a single dose of lamotrigine, its plasma concentration does not change significantly, but accumulation of the lamotrigine glucuronide metabolite is possible.

Drug withdrawal in patients with epilepsy

Abrupt withdrawal of Convulsan, like other AEDs, can provoke the development of seizures. Unless abrupt discontinuation of therapy is a safety requirement (e.g., in case of rash), the dose of lamotrigine should be reduced gradually over 2 weeks.

There are reports that severe seizures, including status epilepticus, can lead to the development of rhabdomyolysis, multiorgan disorders and DIC syndrome, sometimes with fatal outcome. Similar cases have been observed during treatment with Convulsan.

Suicidal risk in bipolar disorders

In patients with bipolar disorders, an increase in depressive symptoms and/or the emergence of suicidal thoughts and behavior is possible, regardless of whether they are taking drugs for the treatment of bipolar disorders or not. When monitoring such patients, it is necessary to carefully control symptoms of clinical worsening (including the emergence of new symptoms) and suicidal behavior, especially at the beginning of the course of treatment and at the time of dose change.

Patients at increased risk (with a history of suicidal thoughts or behavior, young patients, patients with an increase in suicidal ideas compared to the start of therapy, patients at risk of acting on suicidal thoughts and suicide attempts) should be under close observation during treatment.

Patients (and patient caregivers) should be warned about the need to monitor for any worsening of the condition (including the emergence of new symptoms) and/or the emergence of suicidal ideas/behavior or thoughts of self-harm and seek medical help immediately if these symptoms are present.

The physician should decide to change the dosing regimen, including possible drug discontinuation, in patients who experience clinical worsening (including the emergence of new symptoms) and/or the emergence of suicidal thoughts/actions, especially if these symptoms are severe, occur suddenly, or were not present before treatment.

If the patient is taking any other drug containing Lamotrigine, then they should not take Convulsan without consulting a doctor.

Effect on ability to drive vehicles and machinery

It is not recommended to engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions during the period of drug use.

Overdose

There have been reports of single use of Convulsan in a dose exceeding the maximum therapeutic dose by 10-20 times . The following symptoms were observed: nystagmus, ataxia, impaired consciousness and coma.

Treatment: gastric lavage in case of recent drug intake (less than 2 hours), hospitalization and symptomatic therapy.

Drug Interactions

The mean T_1/2 decreases to approximately 14 hours when co-administered with drugs that stimulate glucuronidation, such as carbamazepine and phenytoin, and increases to an average of 70 hours in adults and 45-55 hours in children when co-administered with valproic acid.

UDP-glucuronyltransferase is the main enzyme involved in the metabolism of lamotrigine. There are no data on the ability of lamotrigine to cause clinically significant induction or inhibition of hepatic oxidative enzymes. In this regard, interaction between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes is unlikely. Lamotrigine may stimulate its own metabolism, but this effect is moderate and has no clinically significant consequences.

Table 4. Effect of other drugs on lamotrigine glucuronidation.

The effect of other oral contraceptives and hormone replacement therapy drugs has not been studied, although they may have a similar effect on the pharmacokinetic parameters of lamotrigine.

Interaction with AEDs

Valproic acid, which inhibits lamotrigine glucuronidation, reduces its metabolic rate and prolongs its mean T_1/2 by almost 2 times.

Certain antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which stimulate the system of metabolizing liver enzymes, accelerate the glucuronidation of lamotrigine and its metabolism. The development of adverse effects from the CNS, including dizziness, ataxia, diplopia, blurred vision, and nausea, has been reported in patients who started taking carbamazepine while on Convulsan therapy. These symptoms usually resolved after reducing the dose of carbamazepine. A similar effect was observed when lamotrigine and oxcarbazepine were administered to healthy volunteers; the result of dose reduction was not studied.

When lamotrigine 200 mg and oxcarbazepine 1200 mg were taken simultaneously, neither oxcarbazepine nor Lamotrigine disrupted each other’s metabolism.

Concomitant use of felbamate 1200 mg twice daily and lamotrigine 100 mg twice daily did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

When lamotrigine and gabapentin were used together, the apparent clearance of lamotrigine did not change.

No effect on the pharmacokinetics of levetiracetam and lamotrigine was identified when these drugs were used together.

No effect of pregabalin 200 mg three times daily on the C_ss of lamotrigine was observed, i.e., pregabalin and Lamotrigine do not interact pharmacokinetically with each other.

The use of topiramate did not lead to a change in lamotrigine plasma concentration. However, taking lamotrigine led to a 15% increase in topiramate concentration.

Administration of zonisamide (at doses from 200-400 mg/day) during the clinical program together with lamotrigine (at doses of 150-500 mg/day) did not lead to changes in the pharmacokinetic parameters of lamotrigine.

Studies have shown that Lamotrigine does not affect the plasma concentration of other concurrently taken antiepileptic drugs. In vitro studies, Lamotrigine does not displace other AEDs from their binding to plasma proteins.

Interaction with other psychotropic drugs

Lamotrigine at a dose of 100 mg/day does not cause impairment of the pharmacokinetics of lithium gluconate anhydrous (2 g twice daily for 6 days) when used together.

Repeated oral administration of bupropion does not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC of lamotrigine glucuronide.

Olanzapine 15 mg reduces the AUC and C_max of lamotrigine by an average of 24% and 20%, respectively, which is clinically insignificant. Lamotrigine 200 mg does not alter the pharmacokinetics of olanzapine.

Repeated administration of lamotrigine 400 mg/day did not have a clinically significant effect on the pharmacokinetics of risperidone after a single 2 mg dose in healthy volunteers. At the same time, drowsiness was noted in 12 out of 14 patients with concomitant use of lamotrigine and risperidone; whereas only in 1 out of 20 patients taking risperidone alone, and in none taking lamotrigine alone.

Inhibition of lamotrigine by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam has minimal effect on the formation of the primary metabolite of lamotrigine, 2-N-glucuronide.

A study of bufuralol metabolism by human liver microsomal enzymes leads to the conclusion that Lamotrigine does not reduce the clearance of drugs metabolized primarily by CYP2D6 isoenzymes. Results of in vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect the clearance of lamotrigine.

Interaction with hormonal contraceptives

Taking combined oral contraceptives containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel causes an approximately two-fold increase in the clearance of lamotrigine (after oral administration), leading to a decrease in the AUC and C_max of lamotrigine by an average of 52% and 39%, respectively. During the week free of active drug intake, an increase in lamotrigine plasma concentration is observed, with the lamotrigine concentration measured at the end of this week before the next dose administration being on average 2 times higher than during the active therapy period.

At steady-state concentrations, Lamotrigine 300 mg does not affect the pharmacokinetics of ethinyl estradiol, a component of the combined oral contraceptive. A slight increase in the clearance of the second component of the oral contraceptive, levonorgestrel, is noted, leading to a decrease in the AUC and C_max of levonorgestrel by 19% and 12%, respectively. Measurement of serum FSH, LH, and estradiol levels during this study revealed a slight decrease in the suppression of ovarian hormonal activity in some women, although measurement of plasma progesterone levels in none of the 16 women revealed hormonal confirmation of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in plasma FSH and LH levels on ovarian ovulatory activity has not been established. The effect of other doses of lamotrigine (other than 300 mg/day) has not been studied, and studies involving other hormonal preparations have not been conducted.

Interaction with other drugs

Rifampicin increases the clearance of lamotrigine and reduces its T_1/2 due to stimulation of liver enzymes responsible for glucuronidation (UDP-glucuronosyltransferase). In patients receiving rifampicin as concomitant therapy, the lamotrigine dosing regimen should correspond to the scheme recommended for concomitant use of lamotrigine and agents that stimulate glucuronidation.

When lopinavir/ritonavir was used, an approximately 2-fold decrease in lamotrigine plasma concentration was observed, possibly due to induction of glucuronidation. Patients receiving concomitant therapy with lopinavir/ritonavir should be recommended a lamotrigine dosing regimen with concomitant inducers of glucuronidation.

In a study in healthy volunteers, administration of atazanavir/ritonavir (300 mg/100 mg) led to a decrease in the AUC and C_max values of lamotrigine (in a single 100 mg dose) by approximately 32% and 6%, respectively.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.