Carbamazepine Welfarm, tablets 200 mg 50 pcs

Pharmacotherapeutic group: antiepileptic drug

ATX code: [N03AF01]

Pharmacological action Pharmacodynamics

Carbamazepine 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 to prevent the 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 noted, which included a positive effect on symptoms of anxiety and depression, as well as reduction of irritability and aggressiveness. There is no clear data on the effect of the drug on cognitive and psychomotor functions: some studies showed a dual or negative effect, which depended 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 for 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 seizure threshold, which is usually lowered in this condition, and reduces the severity of clinical manifestations of the syndrome, such as hyperexcitability, tremor and gait disturbances.

In patients with non-sugar diabetes, the drug reduces diuresis and sense of thirst.

As a psychotropic agent the drug is effective in affective disorders, namely in treatment of acute manic states, in maintenance treatment of bipolar affective (manic-depressive) disorders (both as monotherapy, and in combination with neuroleptic agents, antidepressants or lithium preparations), schizoaffective psychosis attacks, manic attacks, where it is used in combination with neuroleptics, and 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

Intake

After oral administration, carbamazepine is almost completely absorbed; absorption is relatively slow when the tablet form is taken. After a single tablet administration of carbamazepine the average maximum plasma concentration (Cmaõ) is reached after 12 hours.

Food intake does not significantly affect the rate and degree of absorption of carbamazepine. Equilibrium plasma concentration of carbamazepine 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 drugs, as well as on the patient’s condition before therapy, the drug dose and duration of treatment. There is significant individual variation in 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 blood 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 pathway of biotransformation is the epoxydiol pathway, resulting in the formation of 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 P450 3A4. These metabolic reactions also produce a small 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.

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 auto-induction of the liver monooxygenase system). It was shown that in patients concomitantly taking other drugs inducing microsomal liver enzymes (for example, phenytoin, phenobarbital) the half-life of carbamazepine is on the 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 taken dose is excreted in the urine and 28% in the feces. 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 urine as end products of the epoxidiol metabolic pathway.

Peculiarities of pharmacokinetics in certain groups of patients

In children, due to 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).

There are no data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function to date.

Indications

– Epilepsy:

– complex or simple partial epileptic seizures (with or without loss of consciousness) with or without secondary generalization;

– generalized tonic-clonic epileptic seizures;

– mixed forms of epileptic seizures.

Carbamazepine is generally ineffective for absences and myoclonus-epilepsy.

– Acute manic states and maintenance therapy for bipolar affective disorder to prevent exacerbations or to alleviate clinical manifestations of exacerbations.

– Alcohol withdrawal syndrome.

– Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis (typical and atypical).

– Idiopathic lingual neuralgia of the pharyngeal nerve.

Active ingredient

Composition

How to take, the dosage

The drug should be taken orally, regardless of meals, together 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 specific pharmacokinetics of antiepileptic drugs, doses of the drug Carbamazepine should be adjusted with caution in elderly patients.

Epilepsy

Whenever possible, the drug should be prescribed as monotherapy.

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 Carbamazepine is added to other antiepileptic drugs taken, the dose of Carbamazepine is increased gradually. If necessary, appropriate adjustments to the doses of the drugs taken are made.

The initial dose of carbamazepine for adults 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.

Tunnel neuralgia

The starting dose for adults is 200-400 mg daily. This is slowly increased until the pain has disappeared (usually to a dose of 200 mg 3-4 times a day). The dose is then gradually reduced to the minimum maintenance dose. The maximum recommended dose for adults is 1200 mg/day. When pain syndrome has resolved, 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 a day, then the dose is slowly increased until the pain syndrome resolves, which is usually achieved at a dose of 200 mg 3-4 times a day. 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 the dose of 400 mg 3 times per day). In severe manifestations of alcohol withdrawal, treatment is started with the use of the drug in combination with drugs providing sedative and hypnotic effects (e.g., clomethiazole, chlordiazepoxide). After resolution of the acute phase, treatment with the drug may be continued as monotherapy.

Polyuria and polydipsia of neurohormonal nature in non-sugar diabetes of central genesis

The average dose for adults is 200 mg 2-3 times daily.

Pain syndrome in diabetic neuropathy

The average dose is 200 mg 2-4 times daily.

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.

Discontinuing 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.

Periatric use

The main indication for the use of the drug Carbamazepine in children is epilepsy. This dosage form of the drug should be used for the treatment of the same forms of epilepsy in children over 4 years old, as in adults. Treatment can be started with a dose of 100 mg/day; the dose is increased gradually, by no more than 100 mg per week.

Maintaining doses: for children, set at the rate of 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)

Maximum 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 and not to exceed the indicated dosages in the table.

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 P450 3A4 (CYP 3A4) is the main isoenzyme that ensures formation of carbamazepine-10,11-epoxide (active metabolite). Concomitant use of CYP 3A4 isoenzyme inhibitors with the drug may increase the concentration of carbamazepine in plasma, which, in turn, may cause adverse reactions. Concomitant use of inducers of CYP 3A4 isoenzyme 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.

The withdrawal of concomitantly taken inducers of CYP 3A4 isoenzyme may decrease the rate of biotransformation of carbamazepine, and, consequently, lead to increased plasma concentrations of carbamazepine. Carbamazepine is a potent inducer of CYP 3A4 isoenzyme and other enzymatic hepatic systems of the first and second phase of drug metabolism and in concomitant use with drugs metabolized by CYP 3A4 isoenzyme may cause induction of metabolism and decrease their plasma concentrations. Since 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 concentrations of carbamazepine-10,11-epoxide.

Drugs that may increase the plasma concentration of carbamazepine:

– analgesic and non-steroidal anti-inflammatory drugs:

dextropropoxyphene, ibuprofen;

– antineoplastic agents (androgen): danazol;

– antibiotics: macrolide (e.g., erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin;

– antidepressants: perhaps desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine;

– antiepileptic drugs: styripenolol, vigabatrin;

– Antifungal agents: azole derivatives (e.g., itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anticonvulsants may be recommended for patients receiving voriconazole or itraconazole;

Histamine H2 receptor blockers: loratadine, terfenadine;

Antipsychotics (neuroleptics): olanzapine;

– antituberculosis drugs: isoniazid;

– antiviral drugs: HIV protease inhibitors (e.g., ritonavir);

– antiglaucoma drugs (carboangiidrase inhibitors): acetazolamide;

– hypotensive drugs (slow calcium channel blockers): verapamil, diltiazem;

– anti-ulcer drugs (proton pump inhibitors, histamine H2 receptor blockers): omeprazole, possibly cimetidine;

– myorelaxants: oxybutynin, dantrolene;

– antiplatelet agents: ticlopidine;

– other drugs and foods: grapefruit juice, nicotinamide (only in high doses).

Because elevated 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.

Drugs that may increase plasma concentrations of carbamazepine-10,11-epoxide: 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), the drug dose should be adjusted and/or plasma carbamazepine-10,11-epoxide concentrations should be determined regularly in these situations.

Drugs that may decrease plasma concentrations of carbamazepine:

– antiepileptic agents: felbamate, mesuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin (to avoid phenytoin intoxication and the occurrence of subtherapeutic concentrations of carbamazepine, the recommended plasma concentration of phenytoin should be less than 13 µg/mL before adding carbamazepine to therapy) and fosphenytoin, primidone, and, although data are partially inconsistent, possibly also clonazepam;

The antineoplastic agents: cisplatin or doxorubicin;

– anti-tuberculosis drugs: rifampicin;

– bronchodilators: theophylline, aminophylline;

– acne treatments (retinoids): Isotretinoin;

– other drugs and foods: herbal preparations containing St. John’s wort.

When used concomitantly with the above drugs, carbamazepine dose adjustment may be required.

The effect 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.

Doses of the following drugs may need to be adjusted when concomitant use with carbamazepine:

– analgesic and non-steroidal anti-inflammatory drugs: buprenorphine, methadone, paracetamol (long-term use of carbamazepine and paracetamol (acetaminophen) may lead to hepatotoxic effects), phenazone, tramadol;

– tetracycline antibiotics: doxycycline, rifabutin;

– indirect anticoagulants: warfarin, phenprocoumon, dicoumarol and acenocoumarol;

– antidepressants: bupropion, citalopram, mianserine, nefazodone, sertraline, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine);

– antiemetics: Aprepitant;

– Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine, the recommended plasma concentration of phenytoin should not exceed 13 mcg/mL before adding carbamazepine to therapy. There are reports that against the background of carbamazepine administration, plasma concentrations of mefenitoin may increase (in rare cases);

– antifungal agents: itraconazole, voriconazole. Alternative anticonvulsants may be recommended in patients receiving voriconazole or itraconazole;

– Anthelminthics: praziquantel, albendazole;

– antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus;

– antipsychotics (neuroleptics): clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone;

– antiviral agents: HIV protease inhibitors (indinavir, ritonavir, saquinavir);

– anxiolytics: alprazolam, midazolam;

– bronchodilators: theophylline;

– contraceptives: hormonal contraceptives (alternative methods of contraception must be selected);

– cardiovascular drugs:

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

– glucocorticosteroids: prednisolone, dexamethasone;

– erectile dysfunction agents: tadalafil;

– immunosuppressive agents: cyclosporine, everolimus, tacrolimus, sirolimus;

– thyroid agents: levothyroxine;

– other drugs and foods: estrogen and/or progesterone drugs.

Combinations to be taken into account

In concomitant use of carbamazepine with levetiracetam in some cases an increase in the toxic effects of carbamazepine was noted.

The increase in hepatotoxicity caused by isoniazid has been reported in cases where it was 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). 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 were used simultaneously. The drug may reduce the effect of hormonal contraceptives due to induction of microsomal enzymes.

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

Interaction with serological reactions

Carbamazepine may cause false positive results in 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 absences and myoclonic seizures

The drug is usually 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 the drug carbamazepine should be discontinued.

Decrease in platelet and leukocyte counts

A transient or persistent decrease in platelet or leukocyte counts has been noted with varying frequency during use. However, in most cases these phenomena are transient and usually are not 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 with low (or decreasing) leukocyte or platelet counts during treatment, the patient’s condition and a detailed clinical blood count should be closely monitored. If there are signs of significant bone marrow depression, carbamazepine should be withdrawn.

Dermatological reactions

In the use of carbamazepine very rarely reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) have been reported. Carbamazepine should be immediately discontinued and 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’s 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.

. Data from a retrospective analysis of Japanese and Nordic patients demonstrated an association between severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, drug-induced rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis, and spot-nodule 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 European populations, about 10% in Japanese. The frequency of the allele is less than 5% in populations in Australia, Asia, Africa, and North America, with exceptions ranging from 5% to 12%. Frequencies greater than 15% have been established in certain ethnic groups in South America (Argentina and Brazil), North American natives (Navajo and Siocs tribes, Sanora Ceri in Mexico), South India (Tamil Nadu), and 10-15% among other natives of these regions. When using carbamazepine for possible carriers of the HLA-A*3101 allele (e.g., Japanese, Caucasoid, 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 who are already receiving therapy with 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).

Analysis of Chinese and Thai patients retrospectively demonstrated 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 population groups 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 Caucasoid, Negroid, Hispanic, Native American, and Japanese populations is insignificant (< l %).

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 their 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 be used in carriers of this allele only if the benefit of therapy outweighs the possible risk. Genotyping is not recommended for nationalities with a low incidence of this allele in their populations. Genotyping for this allele is not recommended in patients already treated with carbamazepine because severe skin reactions were observed in most cases in the first months of use, depending on the presence of HLA-B*l502.

It has been shown that identifying patients with the presence of 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 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 under medical supervision if any skin reactions develop (in order to discontinue therapy promptly if the patient’s condition worsens).

The presence of the HLA-A*3101 allele in the genome is associated with the development of less severe skin reactions (such as hypersensitivity to anticonvulsants 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 drug rash with eosinophilia and systemic manifestations, delayed multi-organ manifestations of hypersensitivity with the development of fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in liver function parameters and bile duct destruction syndrome with decreased number, which can occur in any combination. Other internal organs (including lungs, kidneys, pancreas, myocardium, colon) may also be affected.

In case of manifestations and symptoms of hypersensitivity to the drug Carbamazepine, the drug should be stopped immediately.

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

A hypersensitivity cross-reaction also occurs between carbamazepine and phenytoin.

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 medications, which reduce sodium content (e.g., diuretics, medications which influence on 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. If hyponatremia is present, water restriction is an important criterion to determine if there is a clinical indication.

Hypothyroidism

Carbamazepine can decrease serum thyroid hormone concentrations through enzyme induction, which requires increasing the dose of replacement therapy drugs 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

Hepatic function tests should be performed before and during treatment with Carbamazepine, especially in patients with a history of liver disease and in elderly patients. Carbamazepine should be discontinued immediately if pre-existing liver dysfunction worsens or if active liver disease develops.

Renal dysfunction

Before initiating treatment with the drug and periodically during therapy, a study of total urine analysis and determination of blood urea concentration is recommended.

M-cholinoblocking activity

The drug has weak m-cholinoblocking activity. Therefore, if the drug is used in patients with elevated intraocular pressure and urinary retention, continuous monitoring of this parameter is necessary.

Mental disorders

As latent mental 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 treated with 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 (their caregivers) should be strongly encouraged to seek medical attention if symptoms of suicidal behavior or intentions occur.

Endocrinological disorders

The drug may decrease the effectiveness of medications containing estrogens and/or progesterone, so women of childbearing age should use alternative methods of pregnancy protection during treatment with the drug.

There have been isolated reports of male fertility and/or spermatogenesis abnormalities to date.

The determination of plasma carbamazepine concentrations

Although there is little correlation between drug dose, plasma carbamazepine concentrations, clinical efficacy or tolerability, regular determination of carbamazepine concentrations 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.

Influence on the ability to drive vehicles, mechanisms The ability of a patient taking Carbamazepine to react quickly, especially at the beginning of therapy or during dose adjustment, may be impaired due to both the disease itself (such as seizures) and due to side effects such as dizziness, drowsiness, ataxia, diplopia, accommodation disorders and visual disturbances. Patients should be advised of the possible dangers of driving and operating machinery.

Contraindications

– Hypersensitivity to carbamazepine or chemically similar drugs (e.g., tricyclic antidepressants) or to any other component of the drug.

– Atrioventricular block.

– A history of episodes of suppression of medullary hematopoiesis.

– Liver porphyria (e.g., acute intermittent porphyria, cutaneous porphyria, variegate porphyria).

– Use in combination with monoamine oxidase inhibitors (structural similarity to tricyclic antidepressants).

– Children under 4 years of age.

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 hematologic reactions to other medications, or withdrawal of previous carbamazepine therapy, the drug should be administered only after careful consideration of the relationship between the expected benefits of therapy and the possible risks of therapy, and while ensuring careful and regular monitoring of the condition.

The drug should be administered with caution:

– patients with dilution hyponatremia, hypothyroidism;

– elderly patients (given the possibility of drug interactions and the different pharmacokinetics of antiepileptic drugs);

– Patients with mixed forms of epileptic seizures, including absences, typical or atypical, and myoclonic seizures (given the possible worsening of seizures);

Patients with elevated intraocular pressure and prostatic hyperplasia (given the weak m-cholin-blocking activity of carbamazepine).

Side effects

Certain types of adverse reactions, such as central nervous system (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), digestive system (nausea, vomiting), and allergic skin reactions are very common or frequent, especially at the beginning of treatment with the drug, or when an excessively high initial dose of the drug is used or when treating elderly 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 in the central nervous system may be a consequence of a 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 following gradations are used to estimate the incidence of various adverse reactions: very common – ≥ 10, common – ≥ 1/100 – < 1/10, infrequent – ≥ 1/1000 – < 1/100, rare – ≥ 1/10000 – < 1/1000, very rare – < 1/10000, including individual reports. Blood and lymphatic system disorders:

very common – leukopenia;

often – thrombocytopenia, eosinophilia;

rarely – leukocytosis, lymphadenopathy, folic acid deficiency;

very rare – agranulocytosis, aplastic anemia, pancytopenia, anemia, true erythrocytic aplasia, megaloblastic anemia, variegate porphyria, late cutaneous porphyria, acute intermittent porphyria, reticulocytosis, and possibly hemolytic anemia. Agranulocytosis and aplastic anemia may develop while taking the drug. However, due to the fact that these conditions occur very rarely, it is difficult to quantify the risk of their occurrence. 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.

Disorders of the immune system:

rarely – delayed-type multiorgan hypersensitivity with fever, skin rash, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function indexes and intrahepatic bile duct destruction with reduction of their number (the specified manifestations occur in various combinations). Other organs may also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon);

very rarely – aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioedema. In case of the above reactions of hypersensitivity, the drug should be discontinued. Endocrine system disorders:

often – 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 rarely – increase in blood prolactin concentration, accompanied or not accompanied by such manifestations as galactorrhea, gynecomastia; changes in the parameters of thyroid function – decreased concentration of blood L-thyroxine (free thyroxine, thyroxine, triiodothyronine) and increased concentration of thyroid hormone, which is usually not accompanied by clinical manifestations; disorders of bone metabolism (decrease of calcium and 25-hydroxycholecalciferol in blood), which leads to osteomalacia/osteoporosis; increase of cholesterol concentration, including high-density lipoprotein cholesterol, and triglycerides in blood.

Mental disorders:

Rarely – hallucinations (visual or auditory), depression, anorexia, anxiety, aggression, agitation, disorientation;

very rarely – activation of psychosis.

Nervous system disorders:

very often – dizziness, ataxia, somnolence, feeling of fatigue;

often – headache, diplopia, visual accommodation disorders (e.g., blurred vision);

infrequent – abnormal involuntary movements (for example, tremor, “fluttering” tremor /asterixis/, muscular dystonia, tics), nystagmus;

Rarely – orofacial dyskinesia, oculomotor disorders, speech disorders (e.g., dysarthria), choreoathetosis, peripheral neuropathy, paresthesias, paresis; very rarely – taste disorders, malignant neuroleptic syndrome.

Disorders of the visual organ:

very rarely – clouding of the lens, conjunctivitis, increased intraocular pressure.

Hearing organ disorders and labyrinth disorders:

very rarely – hearing disorders, including tinnitus, hyperacusis, hypoacusis, changes in pitch perception.

Cardiac disorders:

seldom – disorders of intracardiac conduction;

very rarely – bradycardia, arrhythmias, AV block with fainting, chronic heart failure, exacerbation of coronary disease.

Vascular disorders:

rarely – increase or decrease of blood pressure;

very rarely – collapse, thrombophlebitis, thromboembolism (for example, pulmonary embolism).

Respiratory system, chest and mediastinum disorders: very rare – hypersensitivity reactions characterized by fever, dyspnea, pneumonitis or pneumonia.

Disorders of the gastrointestinal tract:

very often – nausea, vomiting; often – dry mouth; infrequently – diarrhea, constipation;

rarely – abdominal pain;

very rarely – glossitis, stomatitis, pancreatitis.

Liver and biliary tract disorders:

very common – increased activity of gamma-glutamintransferase in blood (due to induction of this enzyme in the liver), which usually has no clinical significance;

often – increased activity of alkaline phosphatase in blood; infrequent – increased activity of transaminases in blood;

seldom – hepatitis of cholestatic, parenchymatous (hepatocellular) or mixed type, destruction of intrahepatic bile ducts with decreasing of their number, jaundice;

very rarely – granulomatous hepatitis, liver failure.

Dermal and subcutaneous tissue disorders:

very common – allergic dermatitis, urticaria, which can be significantly pronounced;

infrequent – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, itching;

Overdose

Overdose usually has central nervous system, cardiovascular and respiratory system symptoms, as well as the symptoms listed under “Adverse effects”.

In case of overdose, the following symptoms and complaints are possible:

Central nervous system (CNS): Depression of CNS functions; impaired consciousness, disorientation, drowsiness, 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, increased or decreased blood pressure, conduction disorders with enlarged QRS complex; cardiac arrest and fainting caused by cardiac arrest.

Gastrointestinal system: vomiting, delayed evacuation of food from the stomach, decreased motility of the large intestine.

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

Muscular system: there are reports of rhabdomyolysis associated with the use of carbamazepine.

Laboratory changes: 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 to assess the degree of overdose. Gastric evacuation, gastric lavage, and use of activated charcoal are performed. Late evacuation of the 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. There may be a recurrence of symptoms of overdose on the 2nd and 3rd day after its onset, which is due to delayed absorption of carbamazepine.

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Pregnancy use

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 disorders, including birth defects. At present, there are no definitive data on the presence of a causal relationship of these disorders with maternal use of carbamazepine as monotherapy.

There have been reports of cases of congenital diseases and malformations, including spina bifida and other congenital anomalies: defects in craniofacial structures, cardiovascular and other organ systems, and hypospadias. According to the North American Pregnancy Registry, the incidence of gross malformations relating to structural anomalies requiring surgical, medical, or cosmetic correction diagnosed within 12 weeks of birth was 3.0% among pregnant women receiving carbamazepine monotherapy in the first trimester and 1.1% among pregnant women not taking any anti-epileptic drugs.

The treatment with carbamazepine in pregnant women with epilepsy should be used with extreme caution.

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 assessed, especially in the first trimester of pregnancy.

When clinically effective, women of childbearing age should use carbamazepine as monotherapy, because the incidence of congenital fetal anomalies is higher when using combined antiepileptic therapy than when using the drugs as monotherapy. Depending on the drugs in combination therapy, the risk of birth defects may increase, especially when valproate is added to therapy.

The lowest effective dose of carbamazepine should be used. Regular monitoring of plasma concentrations of the active substance is recommended. If effective anticonvulsant control is available, pregnant women should maintain a minimum plasma concentration of carbamazepine (therapeutic range 4-

12 mcg/ml) because there are reports of possible dose-dependent risk of birth defects (for example, the incidence of birth defects was lower with doses less than 400 mg daily than with higher doses). Patients should be informed about 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 may have a negative impact on the mother and the fetus.

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 who take antiepileptics, so supplemental folic acid supplementation is recommended before and during pregnancy.

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

There have been several reported cases of epileptic seizures and/or respiratory depression in newborns whose mothers took the drug 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.

Carbamazepine penetrates into breast milk, where its concentration is 25-60% of the plasma concentration. In connection with the above stated, if it is necessary to use the drug during breastfeeding, the ratio of expected benefits of breastfeeding to 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). In children who received carbamazepine antenatally or with breast milk, cases of cholestatic hepatitis have been described, in connection with which monitoring of such children should be conducted in order to diagnose adverse effects of the hepatobiliary system. Patients of childbearing age should be warned about decreased efficacy of oral contraceptives when used concomitantly with carbamazepine.

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