Lamotrigine

Lamotrin is an anticonvulsant and contains the substance lamotrigine.

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Indications Lamotrina

Among the indications:

• treatment of epilepsy. In children aged 12 years and over and adults: in combination or for monotherapy of generalized or partial forms of epileptic seizures (also of the tonic-clonic type), and along with these seizures that develop against the background of Lennox-Gastaut syndrome. For children aged 2-12 years with the above-mentioned disorders – as an additional drug;
• monotherapy for typical forms of minor epilepsy;
• Treatment of bipolar disorders in adults. Prevention of development of stages of emotional disorders in people with bipolar disorder – mainly prevention of manifestations of depression.

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Release form

Available in tablets of 25, 50 or 100 mg. One blister contains 10 tablets. The package contains 1, 3 or 6 blister strips.

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Pharmacodynamics

Lamotrigine is a phenyltriazine derivative. It is an anticonvulsant that acts on the body by blocking voltage-dependent sodium channels inside presynaptic neuronal walls, as well as by suppressing the excess amount of neurotransmitters with excitatory activity released. This is mainly glutamate, an amino acid that is one of the main causative agents of epileptic seizures.

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Pharmacokinetics

After oral administration, the drug is completely and fairly quickly absorbed in the gastrointestinal tract. The peak plasma concentration of the substance is observed after 2.5 hours. When taking the drug with food, the period of reaching the peak value is extended, but food does not affect the degree of absorption.

Synthesis with plasma protein reaches 55%. The active component undergoes an intensive metabolism process, and the main product of its decay is N-glucuronide. The half-life of the substance in an adult is 29 hours, and in children this period is shorter.

The decay products are mainly excreted through the kidneys (unchanged – less than 10%), and another 2% of the substance is excreted in the feces.

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Dosing and administration

Scheme of administration for the treatment of epilepsy in children from 12 years of age, as well as adults.

Monotherapy:

• 1-2 weeks – 25 mg of medication once a day;
• 3-4 weeks – 50 mg of medication once a day;
• maintenance doses – 100-200 mg per day (once or divided in half). The required dose is achieved by gradually increasing the daily value every 1-2 weeks by 50-100 mg until the desired effect is achieved. Sometimes the size of such a daily dose can reach 500 mg.

In combination with sodium valproate (excluding other additional drugs):

• 1-2 weeks – 25 mg every other day (or 12.5 mg per day);
• 3-4 weeks – 25 mg once a day;
• maintenance treatment – 100-200 mg per day (once or divided in half). The required dose is achieved by increasing it every 1-2 weeks by 25-50 mg.

In combination with carbamazepine, phenytoin, primidone, as well as phenobarbital or other liver enzyme inducers (sodium valproate is not used):

• 1-2 weeks – once 50 mg per day;
• 3-4 weeks – divide the daily dosage of 100 mg into 2 doses;
• maintenance dose - 200-400 mg per day (in 2 doses), achieved with a gradual increase of no more than 100 mg every 1-2 weeks. Some cases required the use of a daily dose of 700 mg.

In combination with other drugs that do not have a significant effect (inhibition/induction) on liver enzymes (sodium valproate is not used):

• 1-2 weeks – once a day, 25 mg;
• 3-4 weeks – 50 mg once a day;
• maintenance treatment – 100-200 mg per day (once or in 2 doses). The required value should be achieved by gradually increasing the dosage after 1-2 weeks by 50-100 mg.

Scheme for eliminating epileptic seizures in children aged 2-12 years.

Monotherapy for typical form of minor seizures:

• 1-2 weeks – 0.3 mg/kg per day (single dose or in 2 doses);
• 3-4 weeks – 0.6 mg/kg per day (single dose or 2 doses);
• maintenance - 1-10 mg/kg per day (single or twice daily). The desired value can be obtained by gradually increasing the amount by 0.6 mg/kg every 1-2 weeks. Sometimes patients need stronger doses. The maximum allowed per day is 200 mg.

In combination with sodium salt (without reference to other additional drugs):

• 1-2 weeks – per day (single dose) 0.15 mg/kg;
• 3-4 weeks – once a day (0.3 mg/kg);
• maintenance treatment – 1-5 mg/kg per day (single or twice daily). This is achieved by gradually increasing the value by 0.3 mg/kg after 1-2 weeks. No more than 200 mg can be taken per day.

In combination with phenobarbital, phenytoin, primidone and carbamazepine or other liver enzyme inducers (without using the sodium salt):

• 1-2 weeks – twice daily administration of the drug in the amount of 0.6 mg/kg;
• 3-4 weeks – 1.2 mg/kg per day (twice a day);
• maintenance dosage – 5-15 mg/kg per day (2 times a day). This value can be obtained by gradually increasing the dose after 1-2 weeks by 1.2 mg/kg. No more than 400 mg of the drug is allowed per day.

In combination with other drugs that do not have a noticeable effect (by inhibition/induction) on liver enzymes (without sodium salt):

• 1-2 weeks – single or double dose of 0.3 mg/kg of medication per day;
• 3-4 weeks – 0.6 mg/kg per day (1-2 doses);
• maintenance value – 1-10 mg/kg per day (1-2 times a day). It can be obtained by gradually increasing the daily dose (after 1-2 weeks) by 0.6 mg/kg. No more than 200 mg of the drug is allowed per day.

(For people taking anticonvulsants with unknown interactions with lamotrigine, a treatment regimen suitable for combination with valproate is recommended.)

The following dosage escalation schedule of Lamotrine is recommended to achieve a stabilizing daily dose during treatment of adults with bipolar disorder.

As an additional agent together with liver enzyme inhibitors, as well as with valproate:

• 1-2 weeks – 25 mg every other day;
• 3-4 weeks – 25 mg daily (once);
• 5th week – 50 mg daily (1-2 doses);
• Week 6 (stabilizing dosage) – 100 mg (single or twice daily). Maximum per day – 200 mg.

As an adjunctive drug with liver enzyme inducers (without combination with valproates and other inhibitors) such as primidone, carbamazepine, phenytoin, as well as phenobarbital or other inducers of lamotrigine glucuronidation processes:

• 1-2 weeks – once a day, 50 mg;
• 3-4 weeks – 100 mg (in 2 doses) per day;
• 5th week – 200 mg per day (2 doses);
• Week 6 (stabilizing) – 300 mg per day in 2 doses (week 6), with a possible increase, if necessary, to 400 mg (week 7), also taken in 2 doses.

For monotherapy or in combination with drugs that do not have a significant effect (induction or inhibition) on the function of liver enzymes:

• 1-2 weeks – 25 mg once a day;
• 3-4 weeks – 50 mg (1-2 doses);
• 5th week – 100 mg per day (once or in 2 doses);
• Week 6 (stabilizing) – 200 mg per day (in 1 dose or divided in half). Doses in the range of 100-400 mg were also noted.

(In this case, the stabilizing value may change depending on the medicinal effect provided).

The size of the stabilizing dosage of drugs in the treatment of bipolar disorders with subsequent discontinuation of additionally used anticonvulsants or psychotropic drugs.

When subsequently discontinuing the use of liver enzyme inhibitors (eg, valproates):

• 1st week – increase the stabilizing value by two times, but not more than 100 mg per week (for example, increase from 100 to 200 mg per day per week);
• 2-3 weeks – maintaining this value (200 mg per day; if necessary, the dose can be increased to 400 mg) with consumption in 2 doses.

Upon subsequent discontinuation of liver enzyme inducers (dose-dependent regimens) – carbamazepine, primidone, as well as phenytoin with phenobarbital, etc.:

• Dosage for the 1st week – 400 mg; 2nd week – 300 mg; 3rd week – 200 mg;
• Dosage for the 1st week – 300 mg; 2nd week – 225 mg; 3rd week – 150 mg;
• Dosage for the 1st week – 200 mg; 2nd week – 150 mg; 3rd week – 100 mg.

With subsequent withdrawal of other drugs that do not have a noticeable effect on the process of glucuronidation of the active substance (suppression/induction):

• For the entire period of therapy (3 weeks), the maintenance daily dosage is 200 mg (twice a day). This value may fluctuate within 100-400 mg.

Changing the dose size of a drug for people with bipolar disorder when combined with other drugs.

In combination with liver enzyme inhibitors (valproates); the dosage of lamotrigine is taken into account:

• maintenance value: 200 mg per day; 1st week – 100 mg per day; 2nd and from the 3rd week – maintaining the value set in the 1st week (100 mg/day);
• maintenance value 300 mg per day; in the 1st week – 150 mg per day; in the 2nd and from the 3rd week the dosage of the first week is maintained (150 mg/day);
• maintenance value: 400 mg per day; in the 1st week – 200 mg per day; in the 2nd and from the 3rd week it is necessary to maintain the dose of the first week (200 mg per day).

In combination with liver enzyme inducers (carbamazepine, phenytoin, primidone, phenobarbital or other drugs from this category) without the use of valproates; the dose of Lamotrin is taken into account:

• maintenance value: 200 mg per day; in the 1st week – 200 mg; in the 2nd week – 300 mg; starting from the 3rd week – 400 mg;
• maintenance dose: 150 mg/day; in the 1st week – 150 mg; in the 2nd week – 225 mg; starting from the 3rd week – 300 mg;
• maintenance dose: 100 mg/day; in the 1st week – 100 mg; in the 2nd week – 150 mg; starting from the 3rd week – 200 mg.

In combination with drugs that do not have a significant inhibitory or inducing effect on liver enzymes:

• During the entire course, the dosage should be maintained at 200 mg per day.

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Use Lamotrina during pregnancy

Existing post-marketing data from several notable registries of 2000+ pregnant women (1 trimester) receiving lamotrigine monotherapy have shown that there is no significant increase in the incidence of many birth defects. However, there are also limited registries that have shown that there is a high incidence of isolated oral clefts.

Current information from controlled trials does not show an increased risk of developing oral clefts compared with other birth defects after using lamotrigine. If treatment with the drug cannot be avoided, it is recommended to take it at the lowest effective dose.

There is currently little information about the use of lamotrigine in combination with other drugs during pregnancy, so it is not possible to determine whether this substance affects the likelihood of birth defects associated with other drugs.

Like other drugs, Lamotrine is prescribed to pregnant women only when the likelihood of a beneficial effect for the woman exceeds the possibility of negative reactions in the fetus.

Since lamotrigine has a weak inhibitory effect on dihydrofolate reductase and can reduce folic acid levels, it can theoretically increase the likelihood of developing disorders in embryonic development. Therefore, it is necessary to consider the need for folic acid intake during pregnancy planning or in its early stages.

Contraindications

Contraindications include intolerance to lamotrigine or other substances contained in the drug, and also children under 2 years of age.

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Side effects Lamotrina

As a result of using the drug, the following side effects may develop:

• subcutaneous tissues and skin: itching, skin rashes, Lyell's or Stevens-Johnson syndromes;
• lymph and hematopoiesis: pancyto-, neutro-, thrombocyto- or leukopenia, agranulocytosis, anemia (or its aplastic form), as well as lymphadenopathy;
• organs of the immune system: swelling of the face, disorders of hematopoietic or liver function, hypersensitivity syndrome (also a state of fever), multiple organ failure, and in addition, DIC syndrome;
• mental disorders: feelings of aggression or irritability, the appearance of hallucinations or tics, as well as confusion;
• organs of the nervous system: dizziness and headaches, a feeling of insomnia or drowsiness, development of ataxia, tremor, nystagmus. In addition, also serous meningitis, loss of balance, agitation with a feeling of anxiety, movement disorders, exacerbated motor paralysis, extrapyramidal syndromes, increased frequency of seizures and choreoathetosis;
• visual organs: development of conjunctivitis or diplopia, as well as the appearance of a veil before the eyes;
• digestive system: diarrhea, vomiting, dry mouth and nausea;
• liver: liver dysfunction, increased liver function tests, and liver failure;
• connective tissues, as well as the structure of bones and muscles: development of arthralgia or the appearance of signs of SLE;
• other disorders: back pain, increased fatigue.

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Overdose

There is information about acute overdose due to the use of drugs in amounts that exceed the maximum permissible level by 10-20 times (including fatal outcomes).

The symptoms are headaches with dizziness, nystagmus, vomiting, a feeling of drowsiness, and the development of ataxia. In addition, there is a disorder of consciousness, a state of coma, severe epileptic seizures, and also widening of the teeth inside the QRS complex (a delay in conduction begins inside the cardiac ventricles).

To reduce the absorption of the drug, gastric lavage should be performed, and then enterosorbents should be given to the patient. After this, hospitalization for intensive care is required to conduct the necessary supportive and symptomatic treatment.

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Interactions with other drugs

It has been revealed that UDFGT is an enzyme involved in the metabolism of the substance lamotrigine. There are no reliable facts that the active component of Lamotrin is capable of inhibiting or stimulating oxidative liver enzymes, which are involved in drug metabolism processes, in medicinally significant limits. There is also a low probability of its interaction with drugs, the metabolism of which is carried out with the help of hemoprotein 450 enzymes. At the same time, lamotrigine is capable of independently inducing its own metabolism, although this effect is quite weak and does not have a noticeable clinical significance.

Combination with anticonvulsants.

Valproate, which significantly inhibits microsomal liver enzymes, inhibits the metabolism of lamotrigine and also prolongs its half-life by approximately two times.

Anticonvulsants such as primidone, phenobarbital, and carbamazepine with phenytoin, which induce microsomal liver enzymes, increase the rate of metabolism of lamotrigine.

There is information about the development of negative reactions from the central nervous system, including diplopia, nausea, dizziness, ataxia and blurred vision when combining the drug with carbamazepine. After reducing the dosage of the latter, the symptoms of the disorder usually disappear. A similar effect was observed when testing a combination of Lamotrin with oxcarbazepine (a drug that does not induce or inhibit liver enzymes), although according to existing information, neither has any effect on the metabolism of the other.

Anticonvulsants such as levetiracetam, zonisamide with gabapentin, and also felbamate with tomiramate and preagabalin, which do not have an inducing or depressing effect on liver enzymes, do not affect the pharmacokinetic properties of lamotrigine. It, in turn, does not affect the pharmacokinetic characteristics of pregabalin with levetiracetam. When combined with lamotrigine, topiramate indicators increase (by 15%).

Although there are reports of changes in plasma levels of other anticonvulsants, the information provided by testing demonstrates that lamotrigine does not affect the plasma levels of concomitant anticonvulsants. In vitro testing has shown that the active substance of lamotrin does not affect the synthesis of other anticonvulsants with plasma protein.

Combination with other psychotropic drugs.

Interactions with substances that do not induce or inhibit liver enzymes (such as aripiprazole, olanzapine, and bupropion with lithium).

In the treatment of bipolar disorders, the combination of lamotrigine with aripiprazole resulted in a decrease in peak and AUC values (about 10%) of the former. However, such an effect is not expected to have a significant clinical effect.

Concomitant use with olanzapine reduces the peak level and AUC of lamotrigine by 20% and 24% (mean value), respectively. An effect of such magnitude is very rare in clinical practice. Lamotrigine does not affect the pharmacokinetic properties of olanzapine.

With repeated oral administration of bupropion, no noticeable medicinal effect on the properties of lamotrigine is observed, only a slight increase in lamotrigine glucuronide levels is possible.

In the case of a combination of the active substance with lithium gluconate, the properties of the latter remain unchanged.

Multiple oral doses of lamotrigine have no significant clinical effect on the performance of risperidone. Concomitant use of these drugs may cause drowsiness.

In vitro testing has shown that the formation of the primary breakdown product of the active component of the drug – N-glucuronide – is only slightly affected by substances such as bupropion, fluoxetine, amitriptyline, as well as haloperidol with lorazepam.

A study of the processes of bufuralol metabolism in liver microsomes revealed that lamotrigine does not reduce the clearance rate of drugs that are mainly metabolized with the participation of the CYP 2D6 element. In vitro tests suggest that substances such as phenelzine, trazodone, as well as sertraline with risperidone and clozapine do not affect the clearance rate of lamotrigine.

Combination with hormonal contraception.

There is information that ethinyl estradiol (30 mcg dose) and levonorgestrel (150 mcg dose) used in combination, which cause a pronounced induction of liver enzymes, are capable of approximately doubling the excretion of lamotrigine. Because of this, the indicator of the latter decreases, and with a weekly interval in the use of contraceptives, it begins to increase again (temporarily and gradually).

In combination with oral contraception, lamotrigine does not affect ethinyl estradiol levels and slightly reduces plasma levonorgestrel levels. There is no information on how these changes affect the ovulation process.

Combination with other drugs.

Medicines that significantly induce liver enzymes (such as rifampicin and also lopinavir with ritonavir, as well as atazanavir with ritonavir).

In combination with rifampicin, excretion rates increase and the half-life of lamotrigine decreases, as there is an induction of liver enzymes responsible for the glucuronidation process.

Lopinavir with ritonavir approximately halve the plasma levels of lamotrigine due to the induction of glucuronidation.

People taking lopinavir with ritonavir and rifampin should use a regimen that is appropriate for concomitant administration of lamotrigine with appropriate glucuronidation-inducing drugs.

Combination with atazanavir and ritonavir (at doses of 300 and 100 mg) reduces the peak level and AUC of lamotrigine in plasma (dosage of 100 mg) by 6% and 32% (on average), respectively.

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Storage conditions

The medicine is stored in standard conditions for medicines, inaccessible to children. Temperature values are no more than 25°C.

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Shelf life

Lamotrin is permitted to be used for 3 years from the date of release of the drug.

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