Do lamictal side effects go away

Treatment of epilepsy involves long-term use of antiepileptic drugs (AEDs), but sometimes, after some time after the start of treatment, the previously prescribed AED has to be replaced with another one. One of the important reasons for the forced replacement of the drug is its side effects.

Distinguish between acute and chronic toxic effects that antiepileptic drugs have [1]. Among them, non-specific dose-dependent, specific pharmacodynamic effects for a given drug and rare, but potentially life-threatening idiosyncratic reactions are distinguished. The first two types of reactions can usually be diagnosed and prevented in a timely manner. The latter type of reactions, as a rule, is unpredictable and develops very quickly, which practically does not allow diagnostics at the preclinical stage [2-5]. The main serious side effects of this type include hepatitis, pancreatitis, bone marrow suppression, and exfoliative dermatitis. These effects, if not recognized in time, can lead to the death of the patient [6], and the reaction does not depend on the dose of the drug and is unique in each case [1]. nine0007

Potentially life-threatening idiosyncratic reactions are listed in Table 1.

Idiosyncratic reactions usually develop within the first 6 months after starting the drug. Their frequency is approximately 1:30,000 - 1:50,000. This risk is higher for the development of Stevens-Johnson syndrome for lamotrigine - about 1:1000 [7], aplastic anemia for felbamate - about 1:5000 [8] and liver damage in young children with polytherapy with the inclusion of valproic acid preparations - about 1:500 [9].

Hypersensitivity syndrome to AED is observed at 2-8 weeks of treatment with aromatic AED.

Hypersensitivity syndrome to AED is observed at 2-8 weeks of treatment with aromatic AED. Symptoms are rash, fever, and eosinophilia. Lymphadenopathy and potentially life-threatening necrotic changes in the liver may also occur [10]. More severe reactions include exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis [11], which is presumably based on the pharmacogenetic features of biotransformation [12]. nine0007

When prescribing any AED that is at risk of developing Stevens-Johnson and Lyell syndrome or anticonvulsant hypersensitivity syndrome [13], the patient (parents or caregivers) should be warned of the risk of rash and the need for daily skin examination. The patient should be instructed on what action to take if a rash is detected. The doctor should plan in advance a possible reserve AED, which has two properties: no risk of developing skin complications and the possibility of prescribing a therapeutic dose from the first day (valproate, levetiracetam). nine0007

There are currently no reliable ways to prevent idiosyncratic reactions.

Currently, there are no reliable ways to prevent idiosyncratic reactions. Taking into account the proposed mechanism of immediate type hypersensitivity [14], it is proposed to use a mast cell degranulation test before prescribing a drug or a lymphocyte transformation reaction, taking into account the alleged role of epoxide hydrolase deficiency (a component of the cytochrome oxidase system) in the pathogenesis of these conditions [12,15]. nine0007

Neurotoxic effects in the form of drowsiness, dizziness, affective changes (depression, agitation), impaired memory, attention, performance when using AED are quite common [1,16]. Tracking these effects is especially necessary in the early stages of treatment, because. over time, the patient forgets his "normal" state - the one that was before the appointment of the drug. A few months after the appointment of AED, the patient himself and his relatives begin to perceive the "new" state as "normal". And only after discontinuation of the drug, patients often notice that the world around them began to be perceived brighter, the level of cognitive functioning increased, and working capacity increased. Thus, the so-called. the phenomenon of "adaptation to the drug" does not mean that the neurotoxic effect disappears over time, the patient simply forgets how he felt before treatment [4]. In the early stages of therapy, it is especially important to ask the patient about his well-being, to try to accurately identify neurotoxic symptoms (for example, drowsiness with carbamazepine or slow thinking with topiramate). Comparison of the results of simple non-labor-intensive tests to assess the level of attention, working capacity, short-term memory and psychomotor tests before treatment and in the first months after its start reveals the appearance of neurotoxic effects of the drug. We suggest conducting such testing before prescribing the drug, and then, in the absence of complaints, after 1 month from the start of taking the drug and then 1 time in 3 months in the first year of treatment and 1 time in 6 months thereafter. In children, it is advisable not to compare individual indicators during treatment in "raw" scores, but to conduct a centile assessment of test performance, because standards change with age. nine0007

When taking AEDs, more pronounced neurotoxic effects may also be observed: tremor, diplopia, sometimes dysarthria, ataxia [1,16].

Neurotoxic effects can be pharmacokinetic and pharmacodynamic [17]. Therefore, when neurotoxic effects appear, it is necessary to determine the level of the drug in the blood to exclude the pharmacokinetic mechanism of their occurrence. With a high content of the drug in the blood, it is enough to reduce its dose, which will eliminate the side effect of the treatment. However, the presence of a dose-independent neurotoxic (pharmacodynamic) effect, as a rule, requires discontinuation of the drug. nine0007

Protocols for monitoring the presence of chronic specific adverse effects of AED are currently not published [4]. Most authors recommend conducting a preliminary examination, during which a risk group is identified in relation to the development of undesirable effects of the use of AEDs [4,17]. This group consists of patients with changes in biochemical parameters, neurodegenerative diseases, concomitant somatic diseases, and a history of severe idiosyncratic reactions [17]. The observation plan for the timely detection of the occurrence of undesirable effects depends on the specific clinical situation (type and doses of the drug used, risk factors). Table 2 lists the major serious adverse effects of AEDs. nine0007

Below are descriptions of the main side effects of AEDs presented on the Russian pharmaceutical market.

Barbiturates commonly cause behavioral problems in children (hyperactivity, irritability) and drowsiness in adults. Attention disturbances, thought disorders, and depression may be both dose-dependent and independent of plasma concentrations of the drug in sensitive patients [18]. Dose-dependent neurotoxic effects include nystagmus, ataxia, dyskinesia, and disruption of sleep patterns. nine0007

Idiosyncratic reactions include allergic dermatitis, Stevens-Johnson syndrome, serum sickness (serum sickness, the term is used in the English literature and for non-protein drugs) and liver damage, agranulocytosis and aplastic anemia [5]. Exacerbation of porphyria may be noted [17].

Being inducers of microsomal enzymes, barbiturates alter the metabolism of vitamin D, which leads to the development of osteoporosis, especially in childhood. nine0007

Being inducers of microsomal enzymes, barbiturates change the metabolism of vitamin D, which leads to the development of osteoporosis, especially in childhood and immobilized patients [17]. In addition, barbiturates impair absorption and accelerate the metabolism of vitamin K. In this regard, newborns from mothers receiving barbiturates need to be given vitamin K to prevent hemorrhagic disease of the newborn. The pregnant woman should receive vitamin K during the last month of pregnancy, at the beginning of the birth process, and the child should be given vitamin K immediately after delivery [17]. nine0007

Barbiturates interfere with absorption and accelerate the metabolism of vitamin K, therefore, newborns from mothers receiving barbiturates need vitamin K to prevent hemorrhagic disease of the newborn.

With chronic use of barbiturates, changes in the connective tissue can be observed with the development of coarsening of facial features, Dupuytren's contracture, plantar fibromatosis and stiffness of the shoulder joint [17].

Phenytoin is characterized by non-linear pharmacokinetics and a narrow therapeutic range, which often leads to the development of dose-dependent adverse effects (nystagmus, ataxia, dyskinesia and cognitive impairment) not only at the beginning of treatment due to drug accumulation [5]. Children may sometimes be irritable or hyperactive. The combination of anorexia, vomiting and weight loss are characteristic of phenytoin intoxication in childhood [17]. There are also a number of dose-independent effects. With prolonged use of the drug, there is a coarsening of facial features, a change in the texture and color of the hair, gum hyperplasia, the appearance of acne, the development of osteoporosis and lymphadenopathy. Folic acid deficiency with phenytoin can lead to megaloblastic anemia and transient encephalopathy. nine0007

Folic acid deficiency with phenytoin can lead to megaloblastic anemia and transient encephalopathy.

Long-term elevated plasma levels of phenytoin can lead to cerebellar atrophy. Potentially life-threatening idiosyncratic reactions include allergic skin reactions, hepatopathy, serum sickness-type reaction, and aplastic anemia [5]. The development of a systemic drug reaction in the form of lupus erythematosus has also been described [17]. nine0007

Ethosuximide in a high single dose causes vomiting, abdominal pain. These phenomena can be reduced by taking the drug during meals and by reducing the single dose by increasing the frequency of taking the drug. Rare idiosyncratic effects include skin rashes, leukopenia, pancytopenia, and aplastic anemia [10]. Neurotoxic effects include headaches, which can be very intense, as well as drowsiness, agitation, aggressiveness, depression, and memory impairment. Mental disorders are associated with the phenomenon of forced normalization of the EEG. In children, the development of a systemic drug reaction similar to lupus has also been described [17]. nine0007

Carbamazepine causes a moderate dose-dependent neurotoxic effect. At the beginning of treatment, transient symptoms may occur in the form of nausea, drowsiness, dizziness, ataxia and blurred speech, which regress within a week without changing the dose of the drug. Diplopia, tremor and headache occur with an increase in plasma concentrations of the drug and can serve as a clinical marker during dose titration [16]. Occasionally, nausea, vomiting, diarrhea, and abdominal pain may occur. Hyponatremia is common but rarely reaches a clinically significant level. These dose-dependent effects are less pronounced when using prolonged forms of the drug [17]. nine0007

Skin rashes occur in 5-8% of patients, but exfoliative dermatitis and bullous-type reactions (eg, Stevens-Johnson syndrome) are rare [16]. Hematological changes occur quite often - leukopenia is noted in 10-12% of patients.

Leukopenia occurs in 10-12% of patients receiving carbamazepines.

However, fatal reactions such as aplastic anemia are rare, with a mortality rate of about 1.1:500,000 treated with carbamazepine per year. Despite the fact that this opinion is not shared by all authors [4,17], we consider it appropriate to conduct hematological control to exclude the progressive nature of leukopenia. As suggested by the Canadian Association of Child Neurologists [19], we perform a clinical blood test with platelet count before starting treatment. Then, taking into account the life span of cytopopulations, it is advisable to carry out hematological control after 5-6, 14-16 and 30 days from the start of taking the drug (or increasing its dose). In the future, in the first year of treatment, hematological control is carried out 1 time in 3 months, with a longer use of the drug - 1 time in 6 months. Taking into account the possible hepatotoxic effect [16], we suggest monitoring the activity of liver enzymes within 1 month from the start of taking the drug, then once every 6 months and according to indications. Since the drug can lead to the development of atrioventricular blockade [16], it is desirable to monitor the ECG (1 month after the start of the drug or increasing its dose, in the future - 1 time in 6 months). nine0007

Valproates can cause gastrointestinal symptoms - nausea, vomiting, abdominal pain, diarrhea, which in most patients disappear when prolonged forms of the drug are prescribed and taken with food. Tremor during stress and at rest depends on the dose of the drug and, possibly, the age of the patient, because. in children, this symptom is less common. An increase in body weight due to an increase in appetite is observed in 20-54% of patients, which in some cases requires discontinuation of the drug. Hair loss is another common unwanted effect. The effect is transient. Hair becomes brittle, and newly growing hair changes its structure, becoming more curly. The use of multivitamins containing folic acid and zinc can reduce this undesirable phenomenon. The development of thrombocytopenia, which usually does not reach a clinically significant level, depends on the dose of the drug and requires a dose reduction, and in the presence of clinical symptoms (appearance of petechiae, ecchymosis) - and its cancellation [17, 20]. For timely diagnosis of thrombocytopenia, we determine the number of platelets after 14-16 and 30 days from the start of taking the drug (or increasing its dose). In the future, in the first year of treatment, control is carried out 1 time in 3 months, with a longer use of the drug - 1 time in 6 months. nine0007

There is evidence of the possibility of developing polycystic ovaries during treatment with valproate.

There is evidence of the possibility of developing polycystic ovaries during treatment with valproate [21]. In this regard, it is recommended that girls and women undergo pelvic ultrasound with the determination of the volume of the ovaries before the start of treatment, followed by control once a year.

Idiosyncratic reactions include acute encephalopathy and coma, which may occur early in treatment. In a laboratory study, pronounced acidosis and increased excretion of organic acids are revealed. It is assumed that this complication occurs in patients with a previously compensated defect in mitochondrial beta-oxidases [22,23]. Allergic skin reactions are extremely rare, but can be quite severe [24]. Acute hemorrhagic pancreatitis can be fatal, and therefore in patients with abdominal pain during treatment with valproate, it is necessary to determine the level of lipase and amylase [17]. nine0007

The most severe idiosyncratic reaction associated with this drug is fulminant irreversible liver damage. Most often, this complication occurs against the background of polytherapy in children under the age of 2 years, with severe epilepsy, mental retardation, and signs of organic brain damage [9]. Routine laboratory tests do not allow to identify a risk group and catch the initial signs of liver damage: in many patients with advanced liver damage, laboratory data remained within the normal range, while in other patients there is often a change in liver tests without evidence of clinically significant liver damage [23] . The combination of nausea, vomiting and anorexia was observed in 82% of cases of fulminant hepatopathy, and drowsiness, decreased level of consciousness and coma - in 40% [9]. Most often, this complication develops in the first 6 months of treatment, but can also be observed within 2 years after taking valproates [9]. Specific disorders associated with an increased risk of developing acute hepatopathy include: urea cycle disorders, organic aciduria, multiple carboxylase deficiencies, mitochondrial or respiratory chain dysfunction, cytochrome aa3 deficiency in muscle tissue, pyruvate carboxylase deficiency, and insufficiency of the hepatic pyruvate dehydrogenase complex [25 ], gangliosidosis type 2 GM1, spinocerebellar degeneration, Friedreich's ataxia, Lafort's disease, Alper's disease, MERRF syndrome [26]. nine0007

Gabapentin causes mild neurotoxic manifestations, but severe behavioral disorders (aggression, hyperactivity) may occur in mentally retarded children. In addition, there may be an increase in body weight and peripheral edema with a normal content of protein and albumin in the blood plasma [27].

Lamotrigine may cause neurotoxic effects such as fatigue, drowsiness and confusion [28]. A feature of the beginning of treatment with lamotrigine is the need for a slow dose titration. This is due to the risk of developing skin rashes in the first 8 weeks of therapy, in rare cases, up to the development of Stevens-Johnson and Lyell syndromes. nine0007

The risk of rash when lamotrigine 5-10% is used with valproate increases to 14%.

The risk of developing a rash when lamotrigine 5-10% is used together with valproate increases to 14%. Predictors of the development of a rash are: a rash against the background of another AED in history; children under 13 years of age; combined use with valproate [29]. Currently, slow titration of the dose of lamotrigine is considered mandatory. Strict adherence to this rule reduces the risk of developing severe, life-threatening rashes without reducing the overall risk of developing benign rashes. nine0007

Pregabalin may cause neurotoxic effects (dizziness, ataxia, drowsiness) and weight gain [30].

Levetiracetam may cause headache, irritability, drowsiness and anorexia [31]. Significant behavioral disorders and psychoses have been described in childhood [32].

Topiramate causes dose-dependent neurotoxic effects (ataxia, dizziness, paresthesia, impaired concentration, impaired thinking, fatigue, drowsiness, confusion, psychosis) [33]. Slow titration of the drug reduces the risk of these effects. Other serious complications in the treatment of this drug are weight loss, skin rashes. Acute secondary glaucoma may also occur, and therefore the patient should be warned about the need to immediately contact a specialist in case of pain in the eyes and visual impairment [34]. Another serious adverse effect associated with carbonic anhydrase inhibition is nephrolithiasis, which occurs in 1% of patients receiving topiramate [21], which requires monitoring of urine tests and periodic renal ultrasound for the detection of calculi. Increased fluid intake can reduce the risk of this complication. Children may develop hypohidrosis and hyperthermia; which is especially important in hot weather and during outdoor games. Parents need to be informed about this, because. a child with this complication needs additional cooling due to impaired heat transfer by convection [35]. nine0007

Oxcarbazepine is a derivative of carbamazepine, which is rapidly converted to the active metabolite 10,11-dihydro-10-hydroxycarbamazepine, due to which its toxic effects are less pronounced compared to carbamazepine. Dose-dependent neurotoxic effects (dizziness, drowsiness, fatigue) may occur. Hyponatremia can be quite pronounced. Skin rashes, Stevens-Johnson syndrome, and exfoliative dermatitis are rare with oxcarbazepine [36]. nine0007

Thus, the prescription of any AED carries the risk of side effects. It is necessary to identify groups of patients where this risk may be increased. The patient (or his parents, guardian) must be warned about the occurrence of possible undesirable effects. During the treatment of epilepsy, it is necessary to carry out clinical and laboratory monitoring according to an individually drawn up observation plan for the earliest possible detection of possible side effects, especially in the first six months of treatment with the drug. If signs of undesirable effects appear, the patient should contact the attending physician to resolve the issue of correcting antiepileptic therapy. nine0007

Table 1. Serious side effects of AEP (according to Schmidt D. [13])

reactions	OXC	PB	PHT
142 Osteoporosis x x 9000 CBZ - CBAMZ ESC, ethosuximide; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; TPM - Topamax VPA - Valproic Acid. Table 2. The most common specific side effects of AEDs (Fountain N.B., 2007 [37]) 989; 345-348. Camfield CS, Camfield PR, Smith E. Asymptomatic children with epilepsy: little benefit from screening for anticonvulsant induced liver, blood or renal damage. //Neurology. ? 1986; 36:838-841. Fenichel FM. Valproat hepatotoxicity; two new cases, a summary of others and recommendations. //Pediatr Neurol ? 1985; 1:109-113. Camfield PR, Camfield CS. Monitoring for adverse effects of antiepileptic drugs. // Epilepsy. ? 2006; 47 (suppl. 1): 31-34. nine0500 Plaa GI, Willmore LJ. General principles: toxicology. /In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. // New York, Raven Press. ? 1998: 51-60. You can request a complete list of references in the editorial office Source: Journal "Medical Council" No. 9-10 (2008) Author: S. R. BOLDYREVA, A.Yu. .Sci., Children's City Hospital No. 1, St. Petersburg, Federal State Institution "Moscow Research Institute of Pediatrics and Pediatric Surgery of Rosmedtekhnologii"

How to take antiepileptic drugs (AEDs)

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How to take antiepileptic drugs (AEDs)

General

Antiepileptic drugs (AEP) reduce the excessive excitability of brain cells, preventing the development of epileptic seizures. The effect of AEDs depends on their concentration in the blood, so the drugs should be taken daily. Most modern AEDs must be taken twice a day (morning and evening) to keep their blood levels stable. nine0007

How to increase the dose of the drug?

The slower the dose is increased, the lower the risk of side effects. Usually start with ½ or 1 tablet in the evening, after a few days add ½ or 1 tablet in the morning and so on, bringing the dose to therapeutic.

What if I miss a dose?

For such cases, drugs have been developed that must be taken 2 times a day. If you forgot to drink your morning dose and remembered about it a few hours later, feel free to take it. If you remembered the forgotten dose only in the evening, you should not drink the morning + evening dose. Drink only the evening drink and do not forget to take the drug again. nine0007

How do I remember to take my medication?

It is necessary to "attach" the drug intake to regular events in life, for example: after breakfast and after dinner, after morning and evening walks with the dog, after morning and evening washing. You can use reminders on your mobile phone. If the patient suffers from impaired memory and thinking, relatives should monitor the medication. We recommend that you keep a diary of seizures every day and record each medication in it.

How to take medicines: before or after meals?

For modern drugs, this is not important. However, some of the AEDs can irritate the stomach, so we generally recommend taking it after a meal.

How do I change from one drug to another?

The most important rule is to do everything gradually. In most cases, the dose of the "new" drug is gradually increased first, then the dose of the "old" drug is also gradually reduced.

How to replace the drug with its analogue from another manufacturer (after all, the active substance is the same there)? nine0542

The universal rule is that if the body is accustomed to a certain drug of a certain company, then it is better not to change it. However, if there is no other choice (they stopped giving the drug for free and offer its substitute, but there is no money to buy the old drug), then it is necessary to gradually replace the “old” pills with the “new” ones. If you abruptly quit the “old” ones and start drinking the “new” ones, the risk of developing seizures and side effects is higher.

How dangerous are AEDs to health?

Unfortunately, absolutely safe drugs do not exist. In the world, 80% of patients taking AEDs report some side effects. The more modern the drug, the more side effects are indicated in its instructions for use (the manufacturer indicates them so that it cannot be sued). Side effects can be divided into 3 groups: nine0007

A) Idiosyncratic reactions (individual intolerance). They develop in the first months from the start of the medication. Most often - skin rash, jaundice, severe abdominal pain, bleeding, severe vomiting (there may be other manifestations). Idiosyncrasy appears suddenly, it cannot be predicted in advance. At risk are patients who have previously had severe adverse reactions to any drugs. If after the start of taking the medicine there are any serious disorders, you should immediately stop taking it and consult a doctor. nine0007

B) Dose-dependent side effects (they are not on small doses, but they appear on large ones). Typical examples: drowsiness, double vision, unsteadiness when walking, lethargy, trembling in the hands, etc.

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