Finlepsin retard, 200 mg 50 pcs

Pharmacotherapeutic group: anti-epileptic drug

ATX code: N03AF01

Pharmacological properties

Pharmacodynamics

Carbamazepine, the active ingredient in Finlepsin^® retard, is a dibenzoazepine derivative. In addition to antiepileptic, the drug also has neurotropic and psychotropic effects.

The mechanism of action of carbamazepine has been only partially explained to date. Carbamazepine stabilizes the membranes of overexcited neurons, suppresses serial discharges of neurons and reduces synaptic transmission of excitatory impulses. Probably the main mechanism of action of carbamazepine is the prevention of reappearance of sodium-dependent action potentials in depolarized neurons by blockade of open potential-dependent sodium channels.

When used as monotherapy in patients with epilepsy (especially in children and adolescents), psychotropic effects of the drug were observed, including a positive effect on symptoms of anxiety and depression, as well as reduction of irritability and aggressiveness. There is no unequivocal information about the effect of the drug on cognitive and psychomotor functions: some studies showed double or negative effect depending on the dose of the drug, other studies showed a positive effect of the drug on attention and memory.

As a neurotropic agent the drug is effective in a number of neurological diseases. For example, in idiopathic and secondary trigeminal neuralgia it prevents the occurrence of paroxysmal pain attacks. In alcohol withdrawal syndrome the drug increases the threshold of seizure readiness, which is usually lowered in this condition, and reduces the severity of clinical manifestations of the syndrome, such as hyperexcitability, tremor, gait disturbances.

In patients with non-sugar diabetes, the drug reduces diuresis and the feeling of thirst. As a psychotropic drug the drug is effective in affective disorders, namely: in the treatment of acute manic states, in the maintenance treatment of bipolar affective (manic-depressive) disorders (both as monotherapy and in combination with neuroleptic agents, antidepressants or lithium drugs), in schizoaffective psychosis attacks, in manic attacks, where it is used in combination with neuroleptics, and in manic-depressive psychosis with rapid cycles. The ability of the drug to suppress manic manifestations may be due to inhibition of dopamine and norepinephrine metabolism.

Pharmacokinetics

absorption

The absorption of carbamazepine is almost complete after oral administration; absorption is relatively slow when the tablet form is taken. After a single dose of carbamazepine the average maximum plasma concentration (Cmax) is reached after 12 hours. After a single oral administration of carbamazepine 400 mg tablet, the mean Cmax of the unchanged active substance is about 4.5 µg/ml. There are no clinically significant differences in the amount of absorbed active substance after administration of different oral dosage forms of carbamazepine.

When using any dosage form of the drug, food intake does not significantly affect the rate and extent of absorption of carbamazepine. Equilibrium concentration of carbamazepine in blood plasma is reached within 1-2 weeks. The time of its achievement is individual and depends on the degree of autoinduction of liver enzyme systems by carbamazepine, heteroinduction by other, simultaneously used medicinal agents, as well as on the patient’s condition before therapy, the drug dose and duration of treatment. There is significant individual variation in the values of equilibrium concentrations in the therapeutic range: in most patients, these values range from 4 to 12 mcg/mL (17-50 μmol/L).

Distribution and binding to plasma proteins

The binding of carbamazepine to plasma proteins is 70-80%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the proportion of the active substance not bound to plasma proteins (20-30%). The concentration of carbamazepine in breast milk is 25-60% of its value in plasma. Carbamazepine penetrates the placental barrier. Taking into account the complete absorption of carbamazepine, the apparent volume of distribution is 0.8-1.9 L/kg.

Metabolism

Carbamazepine is metabolized in the liver. The main biotransformation pathway is the epoxydiol pathway, resulting in the main metabolites: the 10,11-transdiol derivative and its conjugate with glucuronic acid. The conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-transdiol in humans occurs with the microsomal enzyme epoxide hydrolase.

The content of carbamazepine-10,11-epoxide (active metabolite) is approximately 30% of the plasma concentration of carbamazepine. The main isoenzyme that provides biotransformation of carbamazepine to carbamazepine-10,11-epoxide is cytochrome

P4503A4. These metabolic reactions also produce a minor amount of another metabolite, 9-hydroxy-methyl-10-carbamoylacridan.

The other important pathway of carbamazepine metabolism is the formation of various monohydroxylated derivatives under the influence of the UGT2B7 isoenzyme, as well as N-glucuronides.

Elimation

The elimination half-life of unchanged carbamazepine after a single oral administration of the drug is on average about 36 hours, and after repeated administration of the drug – on average 16-24 hours depending on the duration of treatment (due to autoinduction of the liver monooxygenase system). It has been shown that in patients concomitantly taking other drugs inducing microsomal liver enzymes (e.g., phenytoin, phenobarbital) the half-life of carbamazepine is on average 9-10 hours.

When carbamazepine-10,11-epoxide is taken orally, its average half-life is about 6 hours.

After a single oral dose of 400 mg of carbamazepine, 72% of the dose taken is excreted by the kidneys and 28% through the intestines. About 2% of the administered dose is excreted in the urine as unchanged carbamazepine, about 1% as pharmacologically active 10,11-epoxide metabolite. After a single oral administration, 30% of carbamazepine is excreted with the urine as end products of the epoxidiol metabolic pathway. Peculiarities of pharmacokinetics in certain groups of patients

In children, due to the faster elimination of carbamazepine, higher doses of the drug per kilogram of body weight may be required compared to adults.

There is no evidence that the pharmacokinetics of carbamazepine are altered in elderly patients(compared to young adults).

Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function have not been available to date.

Indications

Active ingredient

Composition

How to take, the dosage

Ingestion. The drug may be taken with meals, after meals or between meals. The tablets should be taken with a small amount of liquid.

The drug can be used both as monotherapy and in combination therapy.

With regard to drug interactions with other drugs and pharmacokinetics of antiepileptic drugs, doses of Finlepsin® Retard should be adjusted with caution in elderly patients.

Epilepsy

The drug should be used as monotherapy if possible.

The drug is not used for minor seizures (petit mal, absans) and myoclonic seizures.

The treatment starts with a small daily dose, which is slowly increased over time until optimal effect is achieved. The dose of carbamazepine must be adjusted on an individual basis to achieve adequate seizure control.

The determination of plasma concentrations of the active ingredient is recommended for selection of the optimal dose of the drug. When treating epilepsy, a dose of carbamazepine corresponding to a total plasma carbamazepine concentration of 4-12 µg/ml (17-50 µmol/L) is necessary.

When Finlepsin® retard is added to other antiepileptic drugs taken, the dose of Finlepsin® retard is increased gradually. If necessary, appropriate adjustments are made to the doses of the drugs being taken.

For adults and children over 16 years of age, the initial dose of carbamazepine is 100-200 mg once or twice daily. The dose is then slowly increased until optimal therapeutic effect is achieved; this is usually achieved at a dose of 400 mg 2-3 times daily. Some patients may need to increase the daily dose to 1600 mg or 2000 mg.

Neuralgia of the trigeminal nerve

The starting dose for adults is 200-400 mg daily. It is slowly increased until the pain disappears (usually to a dose of 200 mg 3-4 times a day). Then the dose is gradually reduced to a minimum maintenance dose.

The maximum recommended dose for adults is 1200 mg/day. When pain resolves, therapy with the drug should be gradually discontinued until the next pain attack occurs.

The recommended starting dose for elderly patients is 100 mg 2 times daily, then the dose is slowly increased until pain resolves, which is usually achieved at a dose of 200 mg 3-4 times daily. Then the dose should be gradually reduced to the minimum maintenance dose. In trigeminal neuralgia in this category of patients, the maximum recommended dose is 1200 mg/day. When pain syndrome is resolved, therapy with the drug should be gradually discontinued until the next pain attack occurs.

Alcohol withdrawal syndrome

The average dose is 200 mg 3 times daily. In severe cases during the first few days the dose may be increased (for example, to a dose of 400 mg 3 times a day). In severe manifestations of alcohol withdrawal, treatment is started with the use of the drug in combination with drugs with sedative and hypnotic effects (e.g., clomethiazole, chlordiazepoxide). After resolution of the acute phase, treatment with the drug may be continued as monotherapy.

Acute manic states and maintenance treatment of affective (bipolar) disorders

The daily dose is 400-1600 mg. The average daily dose is 400-600 mg (in 2-3 doses). In acute manic states, the dose should be increased rather quickly. In maintenance therapy of bipolar disorders, in order to ensure optimal tolerability, each subsequent dose increase should be small, the daily dose increasing gradually.

Application in children

The main indication for the use of Finlepsin® retard in children is epilepsy. Children 4 years of age and younger are recommended to take carbamazepine in other dosage forms (syrup).

In children over 4 years of age, treatment may be started with Finlepsin®

retard at a dose of 100 mg/day; the dose is increased gradually, by no more than 100 mg per week.

Supportive doses: for children, set at 10-20 mg/kg body weight per day (in several doses).

Age of child.

Daily dose

4-5 years

200-400 mg per day

6-10 years

400-600 mg per day

11-15 years old

600-1000 mg per day

>15 years

800-1200 mg (as for adults)

Maximal doses: For children aged <6 years is 35 mg/kg/day, 6-15 years is 1000 mg/day, >15 years is 1200 mg/day.

Since there is insufficient reliable information about its use for other indications in children, it is recommended to choose the dosing regimen according to the age and weight of the child, not exceeding the dosages stated in the table.

Cessation of the drug

The sudden discontinuation of the drug may provoke epileptic seizures, so carbamazepine should be withdrawn gradually over 6 months or more. If it is necessary to withdraw the drug in a patient with epilepsy, switching to another antiepileptic drug should be done under the cover of the drug indicated in such cases.

Interaction

Carbamazepine is not recommended for use concomitantly with monoamine oxidase inhibitors (MAOIs). MAO inhibitors should be discontinued at least 2 weeks before using the drug or, if the clinical situation allows, even longer.

Cytochrome P4503A4 (CYP3A4) is the main isoenzyme responsible for the formation of carbamazepine-10,11-epoxide (active metabolite). Concomitant use of CYP3A4 isoenzyme inhibitors with the drug may increase the concentration of carbamazepine in blood plasma, which, in turn, may cause adverse reactions. Concomitant use of CYP3A4 isoenzyme inducers may lead to accelerated metabolism of carbamazepine and thus to a possible decrease in its plasma concentration and, consequently, to a possible reduction in the severity of therapeutic effect of the drug. Cancellation of simultaneously taken inducers of CYP3A4 isoenzyme may decrease the rate of biotransformation of carbamazepine, and, consequently, lead to increased plasma concentrations of carbamazepine.

Carbamazepine is a potent inducer of CYP3A4 isoenzyme and other enzymatic hepatic systems of the first and second phase of drug metabolism and when used concomitantly with drugs metabolized by CYP3A4 isoenzyme, may cause induction of metabolism and decrease their plasma concentrations.

Because the conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-transdiol occurs via microsomal epoxide hydrolase, use of carbamazepine concomitantly with microsomal epoxide hydrolase inhibitors may lead to increased plasma concentration of carbamazepine-10,11-epoxide.

Drugs that may increase plasma concentrations of carbamazepine:

Because increased plasma concentrations of carbamazepine may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), in these situations the drug dose should be adjusted and/or plasma concentrations of carbamazepine should be determined regularly.

The drugs that may increase plasma concentrations of carbamazepine-10,11-epoxide are: loxapine, quetiapine, primidone, progabide, valproic acid, valnoktamide, and valpromide.

Because increased plasma concentrations of carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), in these situations the drug dose should be adjusted and/or plasma concentrations of carbamazepine-10,11-epoxide should be determined regularly. Drugs that may decrease plasma concentrations of carbamazepine:

The dose of carbamazepine may need to be adjusted if used concomitantly with the above drugs.

Influence of carbamazepine on plasma concentrations of drugs used as concomitant therapy

Concomitant use with carbamazepine may decrease plasma concentrations and decrease or even completely stop the effect of some drugs.

In concomitant use with carbamazepine doses of the following drugs may need to be adjusted:

“slow” calcium channel blockers of the dihydropyridine group (felodipine); simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine;

Combinations to consider

When carbamazepine is used concomitantly with levetiracetam, an increase in the toxic effects of carbamazepine has occasionally been noted.

Isoniazid-induced hepatotoxicity has been reported to be increased when used concomitantly with carbamazepine.

The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptic agents (haloperidol, thioridazine) may increase the frequency of adverse neurological reactions (in the latter combination – even at therapeutic plasma concentrations of active substances).

The concomitant use of carbamazepine with some diuretics (hydrochlorothiazide, furosemide) may lead to hyponatremia accompanied by clinical manifestations.

Carbamazepine may antagonize the action of nondepolarizing myorelaxants (e.g., pancuronium bromide). If this combination of drugs is used, it may be necessary to increase the dose of these myorelaxants; patients should be closely monitored, as the effects of the myorelaxants may be discontinued sooner than expected.

The occurrence of bleeding between menstrual periods has been reported in women when hormonal contraceptives have been used concomitantly. The drug

may decrease the effect of hormonal contraceptives due to induction of microsomal liver enzymes.

Carbamazepine, as well as other psychotropic drugs, may decrease alcohol tolerance. In this regard, it is recommended that the patient refrain from drinking alcohol.

The concomitant use of carbamazepine and oral direct anticoagulants (e.g., rivaroxaban, dabigatran, apixaban, edoxaban) may lead to decreased plasma concentrations of the oral direct anticoagulant, which leads to a risk of thrombosis. Thus, caution should be exercised with respect to signs and symptoms of thrombosis if concomitant use of these drugs is necessary.

Influence on serological studies

Carbamazepine may lead to false positive results of determining the concentration of perphenazine by high-performance liquid chromatography.

Carbamazepine and 10,11-epoxide carbamazepine may cause false-positive tricyclic antidepressant concentrations by polarization fluorescence immunoassay.

Special Instructions

The drug should only be taken under medical supervision.

Patients with mixed forms of epileptic seizures including absans and myoclonic seizures.

The drug is generally ineffective in absences (petit mal) and myoclonic seizures. In patients with mixed forms of epileptic seizures the drug should be used with caution and only under condition of regular medical supervision (because of possible seizure aggravation). In case of seizures worsening Finlepsin® retard should be stopped.

Decrease in platelet and leukocyte counts

Transient or persistent decreases in platelet or leukocyte counts have been noted with varying frequency during carbamazepine use. However, in most cases these phenomena are transient and are not usually precursors to the onset of aplastic anemia or agranulocytosis. Clinical blood counts, including platelet counts and possibly reticulocyte counts, as well as determination of serum iron concentration should be performed before initiating treatment, and periodically during treatment.

The patient should be made aware of the early signs of toxicity associated with likely hematologic abnormalities, as well as skin and liver symptoms. Patients should be advised to seek medical attention immediately if they have adverse reactions such as fever, sore throat, rash, oral ulcers, or hemorrhages without cause, such as petechiae or purpura.

In cases where low (or decreasing) leukocyte or platelet counts have been noted during treatment, the patient’s condition and the scores on a complete clinical blood count should be monitored closely.

If signs of significant bone marrow depression are found, Finlepsin® retard should be discontinued.

Dermatological reactions

Severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome), have very rarely been reported with carbamazepine. Finlepsin® retard should be immediately stopped and an alternative therapy should be chosen if signs and symptoms are observed that are suspected of severe dermatological reactions, such as Stevens-Johnson syndrome or Lyell syndrome. If severe (in some cases life-threatening) skin reactions develop, the patient must be hospitalized. In most cases, Stevens-Johnson syndrome and Lyell’s syndrome developed in the first months of therapy with the drug. These reactions developed in approximately 1-6 cases per 10,000 first-time users of the drug in countries with predominantly Caucasian populations.

The retrospective analysis in Japanese and Northern European patients demonstrated an association between severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, DRESS syndrome, acute generalized exanthematous pustulosis, and blotchy-knot rash) in carriers of the HLA-A*3101 human leukocyte antigen (HLA) allele and carbamazepine use.

The frequency of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene can vary in different ethnic groups: about 2-5% in the European population and about 10% in the Japanese population. The frequency of this allele is less than 5% in most populations in Australia, Asia, Africa, and North America, with exceptions ranging from 5% to 12%. Frequencies greater than 15% are found in some ethnic groups in South America

(Argentina and Brazil), indigenous people in North America (Navajo and Siocs tribes, in Mexico – Sanora Seri), South India (Tamil Nadu), and 10-15% among other indigenous people in these regions.

When using carbamazepine in possible carriers of the HLA-A*3101 allele (e.g., Japanese, Caucasian, Native American, Hispanic, South Indian, and Arab patients), genotyping for this allele is recommended. Use in carriers of this allele only if the benefit of therapy outweighs the possible risk.

Patients already receiving carbamazepine should not be genotyped for this allele because severe skin reactions were seen in most cases in the first months of use (regardless of the presence of HLA-A*3101).

A retrospective analysis of carbamazepine use in Chinese and Thai patients showed a correlation between the incidence of Stevens-Johnson syndrome and Lyell syndrome and the presence of the HLA- B*1502 allele of the human leukocyte antigen (HLA) gene in the patient’s genome. The frequency of this allele in Chinese patients is 2-12%, and in Thai patients it is about 8%.

The use of carbamazepine in patients in Asian countries (Taiwan, Malaysia, Philippines), where there is a high prevalence of the HLA-B*1502 allele, has been found to increase the frequency of development (from “very rare” to “rare”) of Stevens-Johnson syndrome. The frequency of HLA-B*1502 allele prevalence is: in the Philippines and among some populations in Malaysia – more than 15%. The prevalence of the HLA-B*1502 allele in Korea and India is 2% and 6%, respectively. The prevalence of this allele in persons of Caucasoid, Negroid, Hispanic, Native American and Japanese races is insignificant (< 1%).

The frequencies of these alleles represent the percentage of chromosomes in certain populations that carry the allele. This means that the percentage of patients carrying a copy of the allele in at least one of her two chromosomes is almost twice the frequency of the allele. Thus, the percentage of patients at risk is almost twice the frequency of the allele.

When using carbamazepine in possible carriers of the HLA-B*1502 allele, genotyping for this allele is recommended. The drug should only be used in carriers of this allele if the benefit of therapy is greater than the possible risk. Genotyping is not recommended in ethnicities with a low incidence of this allele in their populations.

Patients already receiving carbamazepine should not be genotyped for this allele because severe skin reactions were seen in most cases in the first months of use (regardless of the presence of HLA-B*1502).

It has been shown that identifying patients with the HLA-B*1502 allele and not using carbamazepine in these patients reduces the incidence of carbamazepine-induced Stevens-Johnson syndrome or Lyell syndrome.

However, the results of genotyping should not affect the degree to which the patient is monitored and the physician’s alertness to severe skin reactions. The development of severe skin lesions is possible in patients who are negative for these alleles. Also, in many cases, patients who are positive for HLA-B*1502 or HLA-A*3101 alleles have not developed severe skin syndromes when using carbamazepine.

The effect of other factors-such as anticonvulsant medication dose, patient compliance, concurrent therapy with other medications, comorbidities, or level of dermatologic reaction control- on the incidence and prevalence of severe skin reactions has not been established.

Mild skin reactions, such as isolated maculopapular or maculopapular exanthema, are in most cases transient and not severe, usually resolving within a few days or weeks with continued treatment or after reduction of the drug dose. However, since differential diagnosis between early manifestations of severe skin reactions and mild transient skin rashes may be difficult, the patient should be kept under medical supervision if any skin reactions develop (with the goal of discontinuing therapy in a timely fashion if the patient’s condition worsens).

There is an association between the HLA-A*3101 allele in the genome and the development of less severe skin reactions (such as hypersensitivity to antiepileptic drugs or non-serious maculopapular exanthema); this relationship has not been established for the HLA-B*1502 allele.

Hypersensitivity reactions

. When patients develop hypersensitivity to carbamazepine, various reactions may occur, including DRESS syndrome, delayed multi-organ manifestations of hypersensitivity with the development of fever, skin rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in liver function parameters and bile duct destruction syndrome with decreased number, which may occur in any combination. Other internal organs (including lungs, kidneys, pancreas, myocardium, colon) may also be affected.

In case of signs and symptoms of hypersensitivity to Finlepsin® retard, the drug should be stopped immediately.

Patients with known hypersensitivity to carbamazepine should be informed of the possibility of 25-30% of cases of hypersensitivity reactions to oxcarbazepine.

The development of cross-sensitivity reactions between carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, pyrimidone and phenobarbital) is possible.

Hyponatremia

The development of hyponatremia is associated with the use of carbamazepine. In patients with pre-existing renal impairment associated with low serum sodium content, or in patients receiving concomitant medicines which reduce sodium content (e.g. diuretics, medicines which affect antidiuretic hormone secretion), serum sodium content should be determined before starting carbamazepine therapy. Thereafter, sodium content should be determined after about two weeks and then monthly for the first three months of therapy, or as clinically necessary. These risk factors are particularly common in elderly patients. In the presence of hyponatremia, fluid restriction is important to determine the condition if clinically indicated.

Hypothyroidism

Carbamazepine may decrease serum thyroid hormone concentrations by induction of hepatic microsomal enzymes, requiring an increase in the dose of drugs used for replacement therapy in patients with hypothyroidism. In this category of patients it is necessary to monitor thyroid function to select the dose of drugs of substitution therapy.

Hepatic disorders

Before using Finlepsin® retard and during treatment, liver function should be investigated, especially in patients with a history of liver disease and in elderly patients. Finlepsin® retard should be discontinued immediately if pre-existing liver function abnormalities worsen or if active liver disease develops.

Renal dysfunction

Before starting treatment with the drug and periodically during therapy, urinalysis and determination of blood urea concentration are recommended.

M-choline-blocking activity

The drug has weak m-choline-blocking activity, so patients with elevated intraocular pressure, prostatic hyperplasia, and urinary retention should be closely monitored when these drugs are used concomitantly.

Psychiatric disorders

As latent psychiatric disorders may worsen with the use of the drug, elderly patients should be monitored for symptoms such as confusion and psychomotor agitation. Suicidal behavior or intentions

Suicidal behavior or intentions have been reported in patients receiving anticonvulsants for several indications. Results of a meta-analysis of randomized placebo-controlled trials showed a small increase in the risk of suicidal behavior in patients receiving anticonvulsants. The mechanism of increased suicidal behavior in this patient population has not been established. Therefore, careful monitoring of suicidal behavior and intentional symptoms and decision making about appropriate treatment is necessary. Patients (and their caregivers) should be strongly encouraged to seek medical attention if symptoms of suicidal behavior or intentions occur.

Endocrinological disorders

Due to induction of microsomal liver enzymes, carbamazepine may impair the therapeutic effect of oral contraceptives containing estrogens and/or progesterone. Patients with preserved reproductive potential should be advised to use alternative methods of contraception during therapy with

the drug. The occurrence of bleeding from the vagina between menstruations has been reported with concomitant use of the drug with hormonal contraceptives (breakthrough bleeding).

Pregnancy and patients with preserved reproductive potential

The use of the drug during pregnancy may be associated with a risk to the fetus (see section “Use in pregnancy and lactation”). The use of the drug in pregnancy is possible only if the expected benefits justify the potential risks.

Pregnant patients and patients with preserved reproductive potential should be fully informed about the risks to the fetus associated with the potential teratogenic effects of carbamazepine (see section “Use in pregnancy and breastfeeding”).

Patients with preserved reproductive potential should use reliable contraception during therapy and for 2 weeks after the last dose of the drug (see “Endocrinologic Disorders” as well as “Interaction with Other Drugs” and “Use in Pregnancy and Breastfeeding”).

Determination of plasma carbamazepine concentration

Although there is little relationship between drug dose, plasma carbamazepine concentration, clinical efficacy, or tolerability, regular determination of carbamazepine concentration may be appropriate in the following situations if there is a sudden increase in seizure frequency, in order to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if carbamazepine absorption disorders are suspected; if toxic reactions are suspected if the patient is taking more than one medication.

Falls

The drug therapy may be accompanied by ataxia, dizziness, somnolence, hypotension, confusion, sedation (see section “Side effects”), which may lead to falls and, consequently, fractures or other injuries. In patients with concomitant diseases, conditions, or receiving concomitant drug therapy with drugs that may exacerbate the above effects, the risk of falls during long-term therapy with the drug should be regularly evaluated.

Influence on driving, operating machinery

The ability of a patient taking Finlepsin® retard may be impaired, particularly at the beginning of therapy or during dose adjustment, both by the disease itself) and by adverse events such as dizziness, somnolence, ataxia, diplopia, accommodation disorder, and visual disturbances. The patient should use caution when driving vehicles and operating machinery.

Synopsis

Contraindications

With caution

. In patients with a history of heart disease (including decompensated chronic heart failure), liver disease (including hepatic failure), renal disease (including renal failure), adverse hematological reactions to other medications, or when previously treated with carbamazepine are discontinued, Finlepsin® retard should be administered only after careful consideration of the relationship between expected treatment effects and possible risks of therapy and with careful and regular monitoring of patients.

The drug should be prescribed with caution:

Side effects

Certain types of adverse reactions, such as CNS reactions (dizziness, headache, ataxia, somnolence, fatigue, diplopia), gastrointestinal reactions (nausea, vomiting), and allergic skin reactions are very common or frequent, especially at the beginning of drug treatment or when using excessively high initial drug doses or when treating older patients.

Dose-dependent adverse reactions usually go away within a few days, either spontaneously or after temporary reduction of the drug dose. The development of adverse reactions on the CNS side may be a consequence of relative overdose of the drug or significant fluctuations in plasma concentrations of the active substance. In such cases it is recommended to monitor the plasma concentration of the active substance.

The undesired drug reactions are grouped according to the MedDRA classification of organs and organ systems, within each group are listed in decreasing order of frequency of occurrence. Within each group, the frequencies of adverse drug reactions are listed in decreasing order of importance.

The following gradations were used to estimate the frequency of various adverse reactions: “very common” – ≥1/10, “common” – ≥1/100 – < 1/10, “infrequent” – ≥1/1000 –

< 1/100, “rare” – ≥1/10000 – < 1/1000, “very rare” – < 1/10000, including individual reports.

Psychiatric disorders: rarely – hallucinations (visual or auditory), depression, aggression, anxiety, agitation, confusion; very rarely – activation of psychosis.

Nervous system disorders: very common – ataxia, dizziness, somnolence; common – diplopia, headache; infrequent – abnormal involuntary movements (e.g., tremor, “fluttering” tremor (asterixis), muscular dystonia, tics), nystagmus; rarely – dyskinesia, oculomotor disorders, speech disorders (e.g., dysarthria, slurred speech), choreoathetosis, peripheral neuropathy, paresthesias, paresis; very rarely – malignant neuroleptic syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Skin and subcutaneous tissue disorders: very often – urticaria, which can be significantly pronounced, allergic dermatitis; infrequently – exfoliative dermatitis; rarely – systemic lupus erythematosus, skin itching; very rare – Stevens-Johnson syndrome (classified as “rare” in some Asian countries), toxic epidermal necrolysis (Lyell syndrome), photosensitization reactions, erythema multiforme, erythema nodosa, skin pigmentation disorders, purpura, acne, hyperhidrosis, alopecia, hirsutism.

Disorders of the blood and lymphatic system: very often – leukopenia; often

Agranulocytosis and aplastic anemia may develop while taking the drug. However, because these conditions occur very rarely, it is difficult to quantify their risk. It is known that the cumulative risk of developing agranulocytosis in the general untreated population is 4.7 cases per 1 million population per year and aplastic anemia is 2.0 cases per 1 million population per year.

Gastrointestinal tract disorders: very common – nausea, vomiting; common – dry mouth; infrequent – diarrhea, constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

Hepatic and biliary tract disorders: rarely – hepatitis of cholestatic, parenchymatous (hepatocellular) or mixed type, destruction of intrahepatic bile ducts with decreased number, jaundice; very rarely – liver failure, granulomatous liver damage.

Disorders of the immune system: rare – delayed-type multiple organ hypersensitivity with fever, skin rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered parameters of liver function and destruction of intrahepatic bile ducts with a decrease in their number (these manifestations occur in various combinations), other organs can also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon); very rarely – anaphylactic reaction, angioedema, hypogammaglobulinemia. In case of the above reactions of hypersensitivity the drug should be discontinued.

Cardiac disorders: rare – intracardiac conduction disorders; very rare – arrhythmia, atrioventricular block with syncope, bradycardia, chronic heart failure, exacerbation of coronary heart disease.

vascular disorders: rare – arterial hypertension or hypotension; very rare – circulatory collapse, thrombophlebitis, thromboemboli (e.g., pulmonary embolism).

Endocrine system disorders: Frequent – edema, fluid retention, increased body weight, hyponatremia and decreased blood osmolarity due to an effect similar to that of antidiuretic hormone, which in rare cases leads to water intoxication (dilution hyponatremia), accompanied by lethargy, vomiting, headache, disorientation and neurological disorders; very rare – galactorrhea, gynecomastia.

Disorders of metabolism and nutrition: rarely – folic acid deficiency, decreased appetite; very rarely – acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria).

Repnal and urinary tract disorders: very rare – tubulointerstitial nephritis, renal failure, impaired renal function

(e.g., albuminuria, hematuria, oliguria, increased urea/azotemia), urinary retention, rapid urination.

Gender and mammary gland disorders: very rarely – disorders of sexual function/ erectile dysfunction, disorders of spermatogenesis (decreased sperm count and motility).

VIight organ disorders: often – accommodation disorders (including blurred vision); very rare – blurred lens, conjunctivitis.

Hearing and labyrinth disorders: very rare – hearing disorders, including tinnitus, hyperacusis, hypoacusis, changes in pitch perception.

Muscular and connective tissue disorders: rare – muscle weakness; very rare – disorders of bone metabolism (decrease of calcium and 25-hydroxycholecalciferol in plasma, leading to osteomalacia/osteoporosis), arthralgia, myalgia and muscle cramps.

Disorders of the respiratory system, chest and mediastinum organs: very rare – hypersensitivity reactions characterized by fever, shortness of breath, pneumonitis or pneumonia.

General disorders and disorders at the site of administration: very often – increased fatigue.

Laboratory and instrumental findings: very often – increased activity of gamma-glutamyltransferase (due to induction of this enzyme in the liver), which usually has no clinical significance; often – increased activity of blood alkaline phosphatase; infrequently – increased activity of transaminases; very rarely – increase of intraocular pressure, increased concentration of cholesterol, including high density lipoprotein cholesterol, and triglycerides, changes of thyroid function parameters – decrease of thyroxine concentration (free and bound fraction) and triiodothyronine and increase of thyroid hormone concentration, which usually are not accompanied with clinical manifestations, increased concentration of prolactin in blood serum.

An adverse event detected in the post-registration period (reports were obtained from a population of uncertain size, so the frequency of occurrence cannot be determined, “frequency unknown”)

Infectious and parasitic diseases: Reactivation of herpes simplex virus type 6. Disorders of the blood and lymphatic system: bone marrow insufficiency.

Injuries, intoxications and complications of manipulations: falls (associated with ataxia, dizziness, somnolence, arterial hypotension, confusion, sedation caused by taking the drug).

Nervous system disorders: sedation, memory impairment.

Gastrointestinal tract disorders: colitis.

Immune system disorders: drug rash with eosinophilia and systemic manifestations (DRESS syndrome).

Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis, lichenoid keratosis, onychomadesis.

Muscular and connective tissue disorders: bone fractures.

Laboratory and instrumental findings: decreased bone density.

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Overdose is usually manifested by CNS, cardiovascular and respiratory system symptoms, as well as the phenomena described under “Side effects”.

In overdose, the following symptoms and complaints are possible:

Central nervous system: Depression of CNS functions; impaired consciousness, disorientation, somnolence, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (initially), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Respiratory system: respiratory depression, pulmonary edema.

Cardiovascular system: tachycardia, arterial hypotension or in some cases arterial hypertension, conduction disorders with enlarged QRS complex; cardiac arrest and fainting caused by cardiac arrest.

Gastrointestinal tract: vomiting, delayed evacuation of food from the stomach, decreased motility of the colon.

Mineral system: urinary retention, oliguria or anuria; fluid retention; water intoxication (dilutional hyponatremia) due to the effect of carbamazepine similar to that of antidiuretic hormone.

Skeletal and muscular system: there are reports of rhabdomyolysis associated with carbamazepine use.

Changes in laboratory parameters: hyponatremia, possible metabolic acidosis, possible hyperglycemia, increased activity of muscle fraction of creatine phosphokinase.

Treatment

There is no specific antidote. Initial treatment should be based on the clinical condition of the patient; hospitalization is indicated. Plasma concentrations of carbamazepine are determined to confirm poisoning from this agent and assess the degree of overdose.

Gastric evacuation, gastric lavage, and activated charcoal are performed. Late evacuation of gastric contents may lead to delayed absorption and reappearance of intoxication symptoms during recovery. Symptomatic supportive treatment in the intensive care unit, monitoring of cardiac function, careful correction of water-electrolyte balance disorders are used.

Hemosorption with carbon sorbents is recommended. Hemodialysis is an effective method of treatment in carbamazepine overdose.

The symptoms of overdose may worsen again on the 2nd and 3rd day after its onset due to delayed absorption of carbamazepine.

Pregnancy use

Pregnancy Risk Summary

Carbamazepine rapidly crosses the blood-placental barrier and is found in high concentrations in fetal tissues, especially in the liver and kidneys.

Children of patients with epilepsy are more likely than others to be predisposed to developmental abnormalities, including birth defects. Despite the lack of conclusive data from controlled trials about a causal association of these disorders with carbamazepine monotherapy in mothers, there have been reports of cases of congenital diseases and malformations, including non-compaction of vertebral arches (spina bifida) and other congenital anomalies: defects of craniofacial structures, cardiovascular and other organ systems, hypospadias, during use of the drug.

According to the North American Pregnancy Registry, the incidence of gross malformations related to structural anomalies requiring surgical, medical or cosmetic correction diagnosed within 12 weeks of birth was 3.0% in mothers who had taken carbamazepine as monotherapy in the first trimester and 1.1% in mothers who had not taken any anti-epileptic drugs.

Clinical significance

Finlepsin® retard should be used with particular caution in pregnant women with epilepsy.

If it is necessary to use the drug in pregnant women, and if pregnancy is diagnosed during the use of the drug, or if the patient plans to become pregnant, the balance of expected benefits and possible risks should be carefully evaluated, especially in the first trimester of pregnancy.

When clinically effective in patients with preserved reproductive potential, Finlepsin® retard should be used in monotherapy because the incidence of congenital fetal abnormalities is higher with combined antiepileptic therapy than with monotherapy with these drugs. Depending on the drugs in combination therapy, the risk of birth defects may increase, especially when valproate is added to therapy.

Finlepsin® retard should be used at the lowest effective dose. Regular monitoring of plasma concentrations of the active substance is recommended. With effective anticonvulsant control in pregnant women, minimal plasma concentrations of carbamazepine (therapeutic range 4-12 mcg/ml) should be maintained because there are reports of possible dose-dependent risk of birth defects (for example, the incidence of birth defects was lower when using a dose less than 400 mg per day than when using higher doses).

Patients should be advised of the possibility of increased risk of malformations and the need for antenatal diagnostics for this reason.

The effective antiepileptic treatment should not be interrupted during pregnancy, because the progression of the disease can have adverse effects on the mother and the fetus.

Control and prevention

Folio acid deficiency is known to develop during pregnancy. Antiepileptic drugs have been reported to exacerbate this deficiency. This may contribute to an increased incidence of birth defects in children born to women taking antiepileptic drugs. Because of the above, additional folic acid supplementation is recommended before and during pregnancy.

In order to prevent increased bleeding in newborns, women in the last weeks of pregnancy as well as newborns are recommended to use vitamin K1.

Newborns

There have been several reported cases of epileptic seizures and/or respiratory depression in newborns whose mothers took carbamazepine concomitantly with other anticonvulsants. In addition, several cases of vomiting, diarrhea, and/or hypotrophy have also been reported in newborns whose mothers received carbamazepine. It is possible that these reactions are manifestations of “withdrawal” syndrome in newborns.

Doclinical data

The various preclinical studies in animals (mice, rats, rabbits) have summarized that carbamazepine has little or no teratogenic potential when used in doses consistent with those used in humans. However, data from preclinical studies were insufficient to rule out a teratogenic effect of carbamazepine. In a study of reproductive toxicity, a delayed weight gain in the offspring was observed when the drug was used in lactating rats at a dose of 192 mg/kg per day.

Breastfeeding

Carbamazepine penetrates into breast milk, where its concentration is 25-60% of that in blood plasma. In connection with the above, if it is necessary to use the drug during breastfeeding, the ratio of the expected benefits of breastfeeding to the possible risk of side effects of the drug should be carefully evaluated. Children who receive breast milk should be monitored for the earliest possible diagnosis of side effects (e.g., marked somnolence, allergic skin reactions). Cholestatic hepatitis has been reported in children who received carbamazepine antenatally or with breast milk, and therefore these children should be monitored for the earliest possible diagnosis of hepatobiliary side effects.

Contraception

Patients of preserved reproductive potential should use reliable contraception during therapy and for 2 weeks after the last dose of the drug. Due to induction of microsomal liver enzymes, carbamazepine may weaken the therapeutic effect of oral contraceptives containing estrogen and/or progesterone. Patients with preserved reproductive potential should be advised to use alternative methods of contraception during therapy with the drug.

Effects on reproductive potential

There have been very rare reports of decreased male fertility and/or impaired spermatogenesis.

Similarities