Lamictal,/dispersible 5 mg 30 pcs.

Antioepileptic drug. Lamotrigine is a blocker of potential-dependent sodium channels. In neuronal culture it causes potential-dependent blockade of continuously repetitive impulsation and inhibits pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), as well as inhibits glutamate-induced depolarization.

The efficacy of Lamictal in preventing mood disorders in patients with bipolar disorder has been demonstrated in two basic clinical studies.

A combined analysis of the findings found that the duration of remission, defined as the time before the first episode of depression and before the first episode of mania/hypomania/mixed post-stabilization, was longer in the lamotrigine group compared to placebo. Duration of remission was more pronounced for depression.

Indications

Epilepsy

for adults and children over 12 years old

Epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaud syndrome) as part of combination therapy or monotherapy.

For children from 2 to 12 years of age

– Epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in Lennox-Gastaud syndrome) as part of combined therapy (after achieving epilepsy control with combined therapy, concomitant antiepileptic drugs may be discontinued and lamotrigine may be continued in monotherapy);

– monotherapy of typical absences.

Bipolar disorders

for adults (18 years and older)

– for prevention of mood disorders (depression, mania, hypomania, mixed episodes).

Active ingredient

Composition

1 tablet – lamotrigine* 5 mg

Supplementary substances:

calcium carbonate,

hydroxypropyl cellulose low substituted,

aluminum-magnesium silicate,

/p>

sodium starch glycolate (type A),

povidone K30,

sodium saccharin,

blackcurrant flavoring 502.009/AP 0551,

magnesium stearate.

* The generic international name recommended by the WHO is lamotrigine.

How to take, the dosage

Epilepsy

Adults and children over 12 years of age

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

In combination therapy when Lamictal is coadministered with valproic acid in combination with or without other antiepileptic drugs (AEDs), the starting dose of Lamictal is 25 mg daily for the first 2 weeks; thereafter, 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 to 2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose to maintain optimal therapeutic effect is 100-200 mg/day in 1-2 doses.

. As part of combined therapy with concomitant therapy with PEP or other drugs inducing glucuronidation of lamotrigine (phenytoin, carbamazepine, phenobarbital and primidone) in combination or without other PEP (except valproic acid preparations), the initial dose of Lamictal is 50 mg once daily during the first 2 weeks, further during the next 2 weeks – 100 mg/day in 2 doses. Then the dose is increased by 100 mg every 1-2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose is 200-400 mg/day in 2 doses. Some patients may require a dose of 700 mg/day to achieve therapeutic effect.

In combination therapy with oxcarbazepine in combination with or without any other inducers or glucuronidation inhibitors of lamotrigine the initial dose of Lamictal is 25 mg once daily for the first 2 weeks, subsequently – 50 mg/day at 1 visit for the next 2 weeks. Thereafter, the dose is increased by a maximum of 50-100 mg every 1 to 2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg daily at 1 or 2 doses.

Because of the risk of rash, the starting dose of the drug and the recommended dosage escalation regimen should not be exceeded.

Children 2 to 12 years of age

It should be noted that accurate initial therapy with Lamictal 5 mg tablets using the suggested dosing regimen is not possible if the child’s body weight is less than 17 kg. It is likely that children between the ages of 2 and 6 years will need the highest maintenance doses.

The starting dose of Lamictal for monotherapy of typical absences is 0.3 mg/kg body weight/day in 1 or 2 doses for the first 2 weeks, followed by increasing the dose to 0.6 mg/kg/day in 1 or 2 doses for the next 2 weeks. The dose should then be increased by a maximum of 0.6 mg/kg every 1 or 2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 1 to 10 mg/kg/day in 1 or 2 doses, although some patients with typical absences require higher doses to achieve therapeutic effect.

In combination therapy when Lamictal is used with or without valproic acid in combination with other PEPs, the starting dose of Lamictal is 0.15 mg/kg body weight once/day for the first 2 weeks, followed by 0.3 mg/kg once/day for the next 2 weeks. The dose should then be increased by 0.3 mg/kg every 1 to 2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose in this case is 1-5 mg/kg/day in 1-2 doses. Maximum daily dose is 200 mg.

In combination therapy with concomitant therapy with PEPs or other drugs that induce glucuronidation of lamotrigine (phenytoin, carbamazepine, phenobarbital and primidone) in combination with or without other PEPs (except valproic acid drugs), the starting dose of Lamictal is 0.6 mg/kg/day in 2 doses for the first 2 weeks, thereafter 1.2 mg/kg/day in 2 doses for the next 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg/day every 1-2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose at which maximum therapeutic effect is achieved is 5-15 mg/kg/day in 2 doses. The maximum daily dose is 400 mg.

In combination therapy with oxcarbazepine without any other inducers or glucuronidation inhibitors of lamotrigine the initial dose of Lamictal is 0.3 mg/kg body weight 1 or 2 times/day during the first 2 weeks, later on – 0.6 mg/kg/day in 1 or 2 doses during the next 2 weeks. Then the dose is increased by max 0.6 mg/kg every 1 or 2 weeks until 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 be sure that the therapeutic dose is maintained, the child’s body weight should be monitored and the dose adjusted if there are changes.

Because of the risk of rash, the starting dose of the drug and the recommended dosage escalation regimen should not be exceeded.

There is insufficient information on the use of Lamictal in children younger than 2 years of age.

When withdrawing concomitant antiepileptic drugs to switch to Lamictal monotherapy or when other medications or PEPs are prescribed with Lamictal, consideration should be given that this may affect the pharmacokinetics of lamotrigine.

Bipolar disorders

Adult patients over 18 years of age

Because of the risk of rash, the initial dose of the drug and the subsequent regimen of increasing doses should not be exceeded.

A transitional dosing regimen should be followed, which includes increasing the lamotrigine dose to a maintenance stabilizing dose for 6 weeks, after which other psychotropic and/or antiepileptic medications may be discontinued if indicated.

The maintenance stabilizing dose varies depending on the clinical effect.

In combination therapy when Lamictal and other PEPs that inhibit hepatic enzymes (e.g., valproic acid drugs) are used together, Lamictal is prescribed at a dose of 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. The stabilizing dose at week 6 is 100 mg/day in 1-2 doses; however, it may be increased to a maximum daily dose of 200 mg depending on the clinical effect.

In combination therapy when Lamictal and other PEDs that induce hepatic enzymes (e.g., carbamazepine, phenobarbital) are used together in patients not receiving valproic acid drugs, Lamictal is administered at a dose of 50 mg once daily for the first 2 weeks, 100 mg/d in 2 doses at weeks 3-4, 200 mg/d in 2 doses at week 5. At week 6, the dose may be increased to 300 mg/day, but the stabilizing dose for optimal therapeutic effect is 400 mg/day in 2 doses, and is prescribed starting at week 7.

In Lamictal monotherapy or in combination therapy when Lamictal is coadministered with lithium, bupropion, olanzapine, oxcarbazepine, without lamotrigine inducers or glucuronidation inhibitors, Lamictal is prescribed at a dose of 25 mg once daily for first 2 weeks, 50 mg/day at 3-4 weeks in 1-2 doses, 100 mg/day at 5 weeks in 1-2 doses. The stabilizing dose at week 6 is 200 mg/day in 1-2 doses. However, doses ranging from 100 to 400 mg have been used in clinical trials.

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

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

After withdrawal of additional therapy with lamotrigine glucuronidation inhibitors (e.g., valproic acid preparations), the initial stabilizing dose of lamotrigine is doubled and maintained at this level.

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

After withdrawal of concomitant psychotropic or antiepileptic drugs with no significant pharmacokinetic interactions with lamotrigine (e.g., lithium drugs, bupropion, olanzapine, oxcarbazepine) the stabilizing dose of Lamictal achieved during the upregulation should be maintained.

There is no clinical experience with adjusting daily lamotrigine doses in patients with bipolar disorders after the addition of other medications.

In clinical trials of Lamictal in bipolar disorders, abrupt withdrawal of lamotrigine did not increase the frequency, severity, or change the nature of adverse reactions compared with placebo. Thus, Lamictal can be withdrawn immediately, without gradual dose reduction.

Lamotrigine is not indicated for bipolar disorder in children and adolescents under 18 years of age. The safety and effectiveness of lamotrigine in bipolar disorder in patients in this age group has not been evaluated.

When Lamictal is administered to women already taking hormonal contraceptives, no specific lamotrigine dose escalation regimens have been developed (despite the fact that hormonal contraceptives increase lamotrigine clearance). Dose escalation regimens should follow recommended guidelines depending on whether lamotrigine is prescribed with valproic acid (a lamotrigine glucuronidation inhibitor) or a lamotrigine glucuronidation inducer; or lamotrigine is prescribed in the absence of valproic acid or lamotrigine glucuronidation inducers.

When prescribing hormonal contraceptives in patients already taking maintenance doses of Lamictal and not taking lamotrigine glucuronidation inducers, an increase in lamotrigine dose is required in most cases, but no more than 2-fold. If hormonal contraceptives are prescribed, it is recommended that the dose of lamotrigine be increased by 50 to 100 mg/day each week depending on the clinical picture. It is not recommended to exceed these figures if the clinical condition of the patient does not require further increase in lamotrigine dose.

When discontinuing hormonal contraceptives in patients already taking maintenance doses of Lamictal and not taking lamotrigine glucuronidation inducers, a 2-fold reduction in lamotrigine dose is required in most cases. A gradual reduction in the daily dose of lamotrigia by 50-100 mg each week (reduction of no more than 25% of the daily dose per week) over 3 weeks is recommended, depending on the clinical picture.

Despite the fact that plasma lamotrigine concentrations were decreased with atazanavir/ritonavir co-administration, the recommended dose increase of lamotrigine with atazanavir/ritonavir is not required. Dose escalation of lamotrigine should be based on recommendations based on whether lamotrigine is added to valproic acid (lamotrigine glucuronide inhibitor) or lamotrigine glucuronide inducer therapy, or whether lamotrigine is used in the absence of valproic acid or lamotrigine glucuronide inducer.

In patients already taking maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers, the dose of lamotrigine may need to be increased when atazanavir/ritonavir is prescribed, and the dose of lamotrigine may need to be reduced when atazanavir/ritonavir is withdrawn.

There is no need to adjust the dosing regimen in elderly patients (over 65 years of age) (because the pharmacokinetics in this age group are the same as in adults).

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

In patients with terminal renal failure, the initial dose of lamotrigine is calculated according to the standard antiepileptic drug regimen. For patients with a significant decrease in renal function, reduction of the maintenance dose may be recommended.

The chewable/dissolvable Lamictal tablets may be chewed, dissolved in a small volume of water (enough to cover the entire tablet) or swallowed whole with a small volume of water.

If the calculated dose of lamotrigine (e.g., when administered to children or patients with impaired liver function) cannot be divided into a whole number of lower-dose tablets, the patient should be given a dose that corresponds to the nearest whole value of the lower-dose tablet.

If lamotrigine is resumed, the physician should evaluate the need to increase the maintenance dose in patients who have discontinued the drug for any reason, since high starting doses and exceeding recommended doses are associated with a risk of developing a severe rash. The longer the time since the last dose, the more caution should be exercised in increasing the dose to a maintenance dose. If the time since discontinuation exceeds 5 half-lives, the lamotrigine dose should be increased to maintenance according to an appropriate regimen.

Lamotrigine therapy should not be resumed in patients whose discontinuation of lamotrigine treatment has been associated with the appearance of a rash unless the potential benefit of such therapy clearly exceeds the possible risk.

Interaction

There are no data on the ability of lamotrigine to cause clinically significant induction or inhibition of microsomal liver enzymes. In this regard, interactions between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes are unlikely. Lamotrigine may induce its own metabolism, but this effect is moderate and of no clinical significance.

Table Effect of other drugs on glucuronidation of lamotrigine.

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

The valproic acid, which inhibits glucuronidation of lamotrigine, reduces its metabolic rate and prolongs its mean T1/2 by almost 2-fold.

Some antiepileptic drugs (such as phenytoin, carbamazepine, phenabarbital and primidone), which induce hepatic microsomal enzymes, accelerate glucuronidation of lamotrigine and its metabolism. Adverse CNS events have been reported, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started carbamazepine therapy with lamotrigine. These symptoms usually disappeared after reducing the dose of carbamazepine. A similar effect was observed when lamotrigine and oxcarbazepine were administered to healthy volunteers; the effect of dose reduction has not been studied.

When lamotrigine at a dose of 200 mg and oxcarbazepine at a dose of 1200 mg are administered concomitantly, neither oxcarbazepine nor lamotrigine interfere with each other’s metabolism.

The combined use of felbamate at a dose of 1200 mg 2 times/day and lamotrigine 100 mg 2 times/day did not result in clinically significant changes in lamotrigine pharmacokinetics.

The apparent clearance of lamotrigine was not altered when lamotrigine and gabapentin were used together.

Possible drug interactions between levetiracetam and lamotrigine have been investigated when assessing 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 alter plasma lamotrigine concentrations. However, lamotrigine administration resulted in a 15% increase in topiramate concentrations.

The administration of 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 changes in the pharmacokinetic parameters of lamotrigine.

Studies have shown that lamotrigine does not affect plasma concentrations of other antiepileptic drugs.

The results of in vitro studies have shown that lamotrigine does not displace other antiepileptic drugs from binding to plasma proteins.

Lamotrigine at a dose of 100 mg/day does not disrupt the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times/day for 6 days) when prescribed together.

Multiple oral administration of bupropion has no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC of lamotrigine glucuronide.

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

Multiple administration of lamotrigine at a dose of 400 mg/day had no clinically significant effect on the pharmacokinetics of risperidone after a single dose of 2 mg in healthy volunteers. However, drowsiness was observed in 12 of 14 patients when lamotrigine and risperidone were combined; in 1 of 20 patients when risperidone alone was administered; in none of the patients when lamotrigine alone was administered.

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

Studies of bufuralol metabolism by microsomal liver enzymes isolated in humans suggest that lamotrigine does not decrease the clearance of drugs metabolized primarily by CYP2D6 isoenzymes. In vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

The administration of combined oral contraceptives containing 30 µg ethinylestradiol and 150 µg levonorgestrel causes approximately twice the clearance of lamotrigine (after oral administration), resulting in an average 52% and 39% decrease in AUC and Cmax of lamotrigine, respectively. During the week free of active drug administration, there is an increase in plasma lamotrigine concentrations, with lamotrigine concentrations measured at the end of that week before administration of the next dose being on average 2 times higher than during active therapy.

At equilibrium concentrations, lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinylestradiol, a component of the combined oral contraceptive. There is a slight increase in clearance of the second component of the oral contraceptive, levonorgestrel, resulting in a 19% and 12% decrease in AUC and Cmax of levonorgestrel, respectively. Measurement of serum FSH, LH, and estradiol levels during this study revealed a slight decrease in ovarian hormonal suppression in some women, although measurement of plasma progesterone levels in none of the 16 women showed hormonal evidence of ovulation. No effect of a moderate increase in levonorgestrel clearance and changes in plasma FSH and LH concentrations on ovarian ovarian activity was found. The effects of other doses of lamotrigine (other than 300 mg/day) have not been studied and studies including other hormonal agents have not been conducted.

Rifampicin increases lamotrigine clearance and decreases its T1/2 due to induction of hepatic microsomal enzymes responsible for glucuronidation. In patients taking rifampicin as concomitant therapy, the regimen of lamotrigine should follow the regimen recommended when lamotrigine and glucuronidation-inducing agents are prescribed together.

With lopinavir/ritonavir, a decrease of approximately 50% in plasma lamotrigine concentrations has been observed, possibly due to induction of glucuronidation. In patients receiving concomitant treatment with lopinavir/ritonavir, a dosing regimen of lamotrigine with concomitant glucuronidation inducers should be recommended.

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

Special Instructions

There are data on the development of skin rashes, which have usually been reported within the first 8 weeks of starting Lamictal treatment. In most cases, skin rashes are mild and go away on their own, but there have been occasional serious cases requiring hospitalization and withdrawal of Lamictal (e.g., Stevens-Johnson syndrome and Lyell’s syndrome).

Serious skin reactions in adults taking Lamictal according to generally accepted guidelines develop at a rate of about 1 in 500 epileptic patients. Stevens-Johnson syndrome is reported in about half of these cases (1 in 1,000). In patients with bipolar disorders, the incidence of severe skin rashes, according to clinical studies, is approximately 1 per 1,000 patients.

Children have a higher risk of severe skin rashes than adults. The incidence of skin rashes that required hospitalization in children with epilepsy has been reported to be between 1 in 300 and 1 in 100 children.

In children, the initial rash may be mistaken for an infection, so we must consider the possibility of children reacting to the drug with a rash and fever during the first 8 weeks of therapy.

In addition, the cumulative risk of rash is significantly associated with a high starting dose of Lamictal and exceeding its recommended rate of increase, as well as with concomitant use with valproate medications.

Caution is necessary when prescribing to patients with a history of allergic reactions or rash in response to administration of other antiepileptic drugs because the incidence of rash (not classified as severe) in patients with such a history was 3 times greater with lamotrigine administration than in patients with an unweighted history.

All patients (adults and children) should be seen by a physician immediately if a rash is detected. Administration of lamotrigine should be stopped immediately unless it is obvious that the development of the rash is not related to taking the drug. It is not recommended to resume lamotrigine administration in cases where its previous prescription was discontinued due to the development of a skin reaction, unless the expected therapeutic effect of the drug exceeds the risk of side effects.

It has been reported that rash may be part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial swelling, and blood and liver disorders. The severity of the syndrome varies widely, and in rare cases may lead to the development of DIC and multiple organ failure. It should be noted that early manifestations of hypersensitivity syndrome (i.e., fever, lymphadenopathy) may be observed even if there are no obvious manifestations of rash. If such symptoms develop, the patient should be seen immediately by a physician and, if no other cause of the symptoms is identified, lamotrigine should be withdrawn.

If patients start or stop taking hormonal contraceptives while on Lamictal, the dose of lamotrigine may need to be adjusted.

The combined drug ethinylestradiol/levonorgestrel (30 mcg/150 mcg) has been shown to increase lamotrigine clearance by approximately 2-fold, resulting in lower plasma levels. When prescribing it, maintenance doses of lamotrigine should be increased to achieve maximum therapeutic effect, but by no more than a factor of 2. In women who are not already taking lamotrigine glucuronidation inducers and who are taking hormonal contraceptives, whose regimen includes a week of inactive drug (or a one-week break in taking contraceptives), a gradual transient increase in lamotrigine concentration will be observed during this period of time. The concentration increase will be more pronounced if another increase in lamotrigine dose is taken immediately before or during the period of inactive medication.

Other oral contraceptives and hormonal replacement therapy have not been studied, although they may similarly affect the pharmacokinetic parameters of lamotrigine.

In addition, coadministration of lamotrigine and a combined hormonal contraceptive (ethinylestradiol/levonorgestrel) results in a moderate increase in levonorgestrel clearance and changes in FSH and LH concentrations. The effect of these changes on ovarian ovulatory activity is unknown. However, the possibility cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives, these changes may cause a decrease in contraceptive efficacy. Patients should be informed about the need to immediately report changes in the pattern of the menstrual cycle, i.e., sudden bleeding.

Lamotrigine is a weak dihydrofolate reductase inhibitor, and therefore the drug may affect folate metabolism with long-term therapy. However, even with long-term use, lamotrigine has not been shown to cause major changes in hemoglobin, mean erythrocyte volume, or folate concentration in serum (when used for up to 1 year) or erythrocytes (when used for up to 5 years).

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

If a patient is receiving any other drug containing lamotrigine, he should not take Lamictal without consulting his physician.

Abrupt discontinuation of Lamictal, as with other PEPs, can provoke seizures. If abrupt discontinuation is not a safety requirement (e.g., if a rash occurs), the lamotrigine dose should be reduced gradually over 2 weeks.

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

Symptoms of depression and/or bipolar disorder may occur in patients with epilepsy. Patients with epilepsy and concomitant bipolar disorder are at high risk for suicide. 25-50% of patients with bipolar disorder have had at least one suicide attempt; these patients may have worsening suicidal ideation and suicidal behavior (suicidality) while taking bipolar medications, including lamotrigine, as well as without treatment.

Suicidal thoughts and suicidal behavior have been reported in patients taking PEPs for several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized placebo-controlled trials of PEPs (including lamotrigine) showed a small increase in suicidal risk. The mechanism of this effect is unknown, and the available data do not rule out the possibility of an increased risk of suicide with lamotrigine. Thus, patients should be closely monitored for suicidal ideation and behavior. Patients and caregivers should be informed of the need for medical consultation if such symptoms occur.

Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behaviors in children and adolescents under 18 years of age with major depression and other psychiatric disorders.

In patients with bipolar disorder receiving lamotrigine, the symptoms of clinical deterioration, including the appearance of new symptoms, and suicidality should be closely monitored, particularly at the start of treatment and at the time of dose changes. Patients who have a history of suicidal thoughts or suicidal behavior, young patients, and patients who were found to have significant suicidal thoughts before therapy are at high risk for suicidal thoughts or suicidal behavior, and such patients should be closely monitored during treatment.

Patients and caregivers should be warned to monitor for any deterioration in patients, including the appearance of new symptoms, and/or the appearance of suicidal thoughts/behavior or thoughts of self-harm and to seek medical attention immediately if these symptoms are present. In doing so, assess the situation and make appropriate changes to the therapy regimen, including the possibility of withdrawing the drug in patients who have clinical deterioration, including the appearance of new symptoms, and/or the appearance of suicidal thoughts/behavior, especially if these symptoms are severe, with a sudden onset and have not been previously noted.

Patients with bipolar disorder may experience worsening symptoms of depression and/or the appearance of suicidal thoughts and behaviors whether or not they are taking bipolar medications. When monitoring such patients, the symptoms of clinical deterioration (including the appearance of new symptoms) and suicidality should be carefully monitored, especially at the beginning of treatment and at the time of dose changes.

High-risk patients (those with a history of suicidal thoughts or behaviors, younger patients, patients with increasing suicidal ideation compared to the start of therapy, patients at risk for suicidal thoughts and suicide attempts) should be monitored closely during treatment.

Patients and caregivers should be warned to monitor for any deterioration in patients, including the appearance of new symptoms, and/or the appearance of suicidal ideation/behavior or thoughts of self-harm and to seek medical attention immediately if these symptoms are present.

In doing so, the situation should be evaluated and appropriate changes made to the therapy regimen, including the possibility of withdrawing the drug in patients who experience clinical deterioration, including the appearance of new symptoms, and/or the appearance of suicidal thoughts/behavior, especially if these symptoms are severe, sudden onset and have not previously occurred.

A decision should be made to modify the dosing regimen, including possible withdrawal of the drug in patients who experience clinical deterioration, including the appearance of new symptoms, and/or the appearance of suicidal thoughts/behavior, particularly if these symptoms are severe, sudden onset, or were not previously present.

In clinical studies involving patients with bipolar disorder, the incidence of suicidal thoughts/behavior was numerically higher in those taking lamotrigine compared to those taking placebo, but the differences were not statistically significant. When generalized data were analyzed in patients taking lamotrigine for psychiatric indications, this indicator was most common in the first month of therapy. Suicidal behavior was observed in a greater number of cases in male patients. In patients with epilepsy, there were no statistically significant differences between the incidence of suicidal ideation/behavior in the lamotrigine and placebo groups. The overall incidence of suicidal thoughts/behavior in both compared groups was very small.

The effect on driving and operating ability

Two studies conducted, with healthy volunteers, showed that the effects of lamotrigine on precise visual-motor coordination, eye movements, and subjective sedation were not different from placebo. There have been reports of neurological side effects of lamotrigine, such as dizziness and diplopia. Therefore, the patient’s individual response to Lamictal administration should be evaluated before engaging in work requiring increased attention and rapid psychomotor reactions.

Contraindications

Side effects

The undesired phenomena presented below are listed according to anatomico-physiological classification and frequency of occurrence. The frequency is defined as follows: very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10 000, < 1/1000), very rare (< 1/10 000, including individual cases). Frequency categories were formed based on clinical studies of the drug and post-marketing surveillance.

In patients with epilepsy

Skin and subcutaneous fatty tissue: very common – skin rash; rare – Stevens-Johnson syndrome, very rare – toxic epidermal necrolysis.

In double-blind clinical trials in adults where lamotrigine was used as combination therapy, the incidence of skin rash in patients taking lamotrigine was 10% and in patients taking placebo – 5%. In 2% of cases, the occurrence of skin rash was the reason for withdrawal of lamotrigine. The rash, mostly maculopapular in nature, usually appears within the first 8 weeks of starting therapy and subsides after drug withdrawal.

There have been reports of rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome). Although most cases reversed symptoms upon drug withdrawal, some patients were left with irreversible scarring, and in rare cases deaths associated with the drug have been reported.

The overall risk of rash development was significantly associated with a high initial dose of lamotrigine and exceeding the recommended rate of lamotrigine dose escalation, with concomitant administration of valproic acid. The development of rash was also seen as a manifestation of a hypersensitivity syndrome associated with various systemic manifestations.

Hematological disorders (neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphoadenopathy are very rare. Hematological disorders and lymphoadenopathy may or may not be associated with hypersensitivity syndrome.

Immune system disorders: very rarely – hypersensitivity syndrome (including such symptoms as fever, lymphadenopathy, facial edema, disorders of blood and liver function, DIC, multiple organ failure). Rash is also considered part of hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial edema, blood and liver disorders. The syndrome has varying degrees of severity and may rarely lead to the development of DIC syndrome and multiple organ failure. It is important to note that early manifestations of hypersensitivity (i.e., fever, lymphadenopathy) may occur even in the absence of obvious signs of rash. If such symptoms develop, the patient should be seen immediately by a physician and, unless another cause for the symptoms is identified, lamotrigine should be withdrawn.

Psychiatric disorders: often – aggressiveness, irritability; very rarely – tics, hallucinations, confusion.

CNS disorders: in monotherapy: very common – headache; common – somnolence, insomnia, dizziness, tremor; infrequent – ataxia; rare – nystagmus. As part of combined therapy: very common – somnolence, ataxia, headache, dizziness; common – nystagmus, tremor, insomnia; very rare – aseptic meningitis, agitation, unsteady gait, motor disorders, worsening of Parkinson’s disease symptoms, extrapyramidal disorders, choreoathetosis, increased frequency of seizures. There are reports that lamotrigine may worsen extrapyramidal parkinsonian symptoms in patients with concomitant Parkinson’s disease and, in isolated cases, cause extrapyramidal symptoms and choreathetosis in patients without preexisting disorders.

Senses: in monotherapy: infrequent – diplopia, blurred vision; in combined therapy: very common – diplopia, blurred vision; rarely – conjunctivitis.

The digestive system: in monotherapy: frequently – nausea, vomiting, diarrhea; in combined therapy: very frequently – nausea, vomiting; frequently – diarrhea; very rarely – increase of liver enzymes activity, liver dysfunction, liver failure. Liver function abnormalities usually develop in combination with symptoms of hypersensitivity, but in single cases there were also observed the absence of obvious signs of hypersensitivity.

Muscular and connective tissue disorders: very rare – lupus-like syndrome.

Others: common – fatigue;

In patients with bipolar affective disorder

To assess the overall safety profile of lamotrigine, the following adverse events should be taken into account along with those specific to epilepsy.

Skin and subcutaneous fat: very common – skin rash; rarely – Stevens-Johnson syndrome. In an evaluation of all studies (controlled and uncontrolled) examining the use of Lamictal in patients with bipolar affective disorder, skin rash occurred in 12% of all patients receiving lamotrigine, whereas the incidence of skin rash in controlled studies alone was 8% in patients receiving Lamictal and 6% in patients receiving placebo.

CNS disorders: very common – headache; common – agitation, somnolence, dizziness.

Muscular and connective tissue: often – arthralgia.

Digestive system disorders: often – dryness of the oral mucosa.

Others: often – pain, back pain.

Overdose

Single administration of Lamictal at a dose 10-20 times the maximum therapeutic has been reported. The following symptoms have been observed: nystagmus, ataxia, impaired consciousness and coma.

Treatment: hospitalization and supportive therapy in accordance with the clinical picture or the recommendations of the national poison center are recommended.

Similarities