Zeptol (Tablets) Instructions for Use

ATC Code

N03AF01 (Carbamazepine)

Active Substance

Carbamazepine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic drug, carboxamide derivative

Pharmacological Action

An iminostilbene derivative possessing a pronounced anticonvulsant (antiepileptic) effect, as well as a moderate antipsychotic, antidepressant (thymoanaleptic), and normothymic action. In addition, it exerts an analgesic effect, especially in trigeminal neuralgia. The mechanism of action is partially understood.

The anticonvulsant action is presumably associated with a reduction in the ability of neurons to maintain a high frequency of repetitive action potentials through the inactivation of sodium channels. Furthermore, the inhibition of neurotransmitter release by blocking presynaptic sodium channels and the development of action potentials, which in turn reduces synaptic transmission, also appears to be significant.

The mechanisms of action may involve gamma-aminobutyric acid (GABA) receptors, which may be linked to calcium channels; the influence of carbamazepine on neuro transmission modulator systems also seems to be significant. The antidiuretic effect of carbamazepine may be associated with a hypothalamic influence on osmoreceptors, which is mediated through the secretion of antidiuretic hormone, and is also due to a direct action on the renal tubules.

It is effective in focal (partial) epileptic seizures (simple and complex), with or without secondary generalization, in generalized tonic-clonic epileptic seizures, and in combinations of these seizure types (usually ineffective in petit mal seizures, absences, and myoclonic seizures).

In patients with epilepsy (especially children and adolescents), a positive effect on symptoms of anxiety and depression, as well as a reduction in irritability and aggressiveness, has been noted. The effect on cognitive function and psychomotor performance is dose-dependent. The onset of the anticonvulsant effect varies from several hours to several days (sometimes up to 1 month due to autoinduction of metabolism).

In essential and secondary trigeminal neuralgia, it prevents the occurrence of pain attacks in most cases. Pain relief in trigeminal neuralgia is noted within 8-72 hours.

In alcohol withdrawal syndrome, it increases the seizure threshold, which is usually lowered in this condition, and reduces the severity of clinical manifestations of the syndrome (increased excitability, tremor, gait disturbances). The antipsychotic (antimanic) effect develops after 7-10 days and may be due to inhibition of dopamine and norepinephrine metabolism. The prolonged-release dosage form ensures the maintenance of a more stable concentration of carbamazepine in the blood when taken 1-2 times/day.

Pharmacokinetics

Absorption 72-96%. C_max in plasma is reached within 6-24 hours. Plasma protein binding is about 75%. T_1/2 ranges from 30 to 40 hours. It is metabolized in the liver, mainly via the epoxide pathway, forming the main metabolites: the active one – Carbamazepine-10,11-epoxide and the inactive conjugate with glucuronic acid. A slightly active metabolite, 9-hydroxy-methyl-10-carbamoylacridan, is also formed. The concentration of carbamazepine-10,11-epoxide is 30% of the carbamazepine concentration. In cerebrospinal fluid and saliva, concentrations are created proportional to the amount of unbound active substance (20-30%). It crosses the placental barrier. The concentration in breast milk is 25-60% of that in plasma. It is excreted as inactive metabolites in urine (70%) and feces (30%).

It is an inducer of hepatic enzymes and stimulates its own metabolism. There are no data indicating that the pharmacokinetics of carbamazepine change in elderly patients.

Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function are currently insufficient.

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;
• Trigeminal neuralgia and neurogenic pain syndrome;
• Pain in peripheral nerve lesions in diabetes mellitus, pain in diabetic neuropathy, polyuria and polydipsia of neurohormonal origin in central diabetes insipidus;
• Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis (typical and atypical); idiopathic glossopharyngeal neuralgia;
• Alcohol withdrawal syndrome;
• Acute manic states and maintenance therapy of bipolar affective disorders to prevent exacerbations or alleviate the clinical manifestations of exacerbation.

ICD codes

Dosage Regimen

Tablets

Orally. The drug can be taken during, after meals, or between meals with a small amount of liquid.

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

Prolonged-release tablets (the whole tablet or half, if so prescribed by the doctor) should be swallowed whole, without chewing, with a small amount of liquid, because the active substance is released from the prolonged-release tablets slowly and gradually; they are prescribed 2 times/day. Considering that Zeptol is prescribed 2 times/day, the optimal treatment regimen is determined by the doctor based on the provided recommendations.

When transferring a patient from taking regular tablets to taking prolonged-release tablets, clinical experience shows that in some patients, when using prolonged-release tablets, it may be necessary to increase the dose of the drug.

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 Zeptol should, if possible, be prescribed as monotherapy. Treatment begins with a small daily dose, which is subsequently slowly increased until the optimal effect is achieved. To select the optimal dose of the drug, it is recommended to determine the concentration of the active substance in the plasma. The addition of Zeptol to an ongoing antiepileptic therapy should be carried out gradually, while the doses of the drugs used are not changed or, if necessary, appropriate correction of the doses of the drugs taken is made. If the patient forgot to take the next dose of the drug on time, the missed dose should be taken as soon as this omission is noticed; a double dose of the drug should not be taken.

For adults the initial dose is 100-200 mg 1-2 times/day. Then the dose is slowly increased to 400-600 mg 2 times/day. The maximum daily dose is 1600-2000 mg.

For children over 4 years of age treatment can be started with the drug at a dose of 100 mg/day; the dose is increased gradually – by 100 mg each week.

For children under 4 years of age Carbamazepine is preferably used in the form of a syrup due to the difficulties of using solid dosage forms in this age group.

Maintenance doses for children are 10-20 mg/kg/day (in several doses)

For trigeminal neuralgia and neurogenic pain syndrome 100-200 mg 2 times/day, then the dose is gradually increased by no more than 200 mg/day until pain cessation (on average, up to 600-800 mg), then reduced to the minimum effective dose. The effect usually occurs 1-3 days after the start of treatment. The drug is prescribed for a long time; premature discontinuation of the drug may lead to the recurrence of pain. When treating elderly patients, the initial dose is 100 mg 2 times/day.

Pain in peripheral nerve lesions in diabetes mellitus, pain in diabetic neuropathy 200-300 mg 2 times/day.

Polyuria and polydipsia of neurohormonal origin in central diabetes insipidus the average dose for adults is 200 mg 2 times/day. In children, the dose of the drug should be reduced according to the age and body weight of the child.

Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis; idiopathic glossopharyngeal neuralgia the average daily dose is 200-400 mg 2 times/day.

Alcohol withdrawal syndrome the average dose is 200 mg 2 times/day. In severe cases, in the first days the dose can be increased to 600 mg 2 times/day. At the beginning of treatment for severe withdrawal symptoms, it is prescribed in combination with detoxification therapy and sedative-hypnotic drugs (for example, with clomethiazole, chlordiazepoxide). After resolution of the acute phase, treatment with Zeptol can be continued as monotherapy.

Acute manic states and maintenance therapy of bipolar affective disorders in the first week, the daily dose is 200-400 mg. Subsequently, the dose is increased by 200 mg per week, bringing it to 1 g/day. The daily dose is evenly divided into 2 doses.

The transition to treatment with carbamazepine should be gradual, with a reduction in the dose of the previous drug. Treatment should be discontinued gradually. The duration of treatment is determined by the doctor.

Adverse Reactions

When assessing the frequency of various adverse reactions, the following gradations were used: very common – 10% or more; common – 1-10%; uncommon – 0.1-1%; rare – 0.01-0.1%; very rare – less than 0.01%.

Dose-dependent adverse reactions usually resolve within a few days, either spontaneously or after a temporary reduction in the drug dose. The development of adverse reactions from the CNS 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 drug.

From the nervous system very common – dizziness, ataxia, drowsiness, feeling of fatigue; common – headache, diplopia, visual accommodation disturbances (e.g., blurred vision); uncommon – abnormal involuntary movements (e.g., tremor, “flapping” tremor – asterixis, dystonia, tics); nystagmus; rare – orofacial dyskinesia, oculomotor disturbances, speech disturbances (e.g., dysarthria), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rare – taste disturbances, neuroleptic malignant syndrome. The role of carbamazepine as a drug causing or contributing to the development of neuroleptic malignant syndrome, especially when prescribed together with neuroleptics, remains unclear.

From the psychiatric sphere rare – hallucinations (visual or auditory), depression, anorexia, anxiety, aggression, agitation, disorientation; very rare – psychosis activation.

Allergic reactions very common – allergic dermatitis, urticaria, which can be significantly pronounced; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reactions, erythema multiforme and nodosum, skin pigmentation disorders, purpura, acne, sweating, hair loss. Rare cases of hirsutism have been reported, but the causal relationship of this complication with the drug intake remains unclear.

Hypersensitivity reactions rare – delayed-type multiorgan hypersensitivity with fever, skin rashes, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function tests and destruction of intrahepatic bile ducts with a reduction in their number (the mentioned manifestations occur in various combinations). Other organs may also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon). Very rare aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioneurotic edema. If the above allergic reactions occur, the use of the drug should be discontinued.

From the hematopoietic organs very common – leukopenia; common – thrombocytopenia, eosinophilia; rare – leukocytosis, lymphadenopathy, folic acid deficiency; very rare – agranulocytosis, aplastic anemia, pancytopenia, anemia, true erythrocytic aplasia, megaloblastic anemia, variegate porphyria, porphyria cutanea tarda, acute “intermittent” porphyria, reticulocytosis, hemolytic anemia.

From the gastrointestinal tract very common – nausea, vomiting; common – dry mouth; uncommon – diarrhea, constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

From the liver very common – increased GGT activity (due to induction of this enzyme in the liver), which usually has no clinical significance; common – increased blood alkaline phosphatase activity; uncommon – increased transaminase activity; rare – hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, destruction of intrahepatic bile ducts with a reduction in their number, jaundice; very rare – granulomatous hepatitis, hepatic failure.

From the cardiovascular system rare – intracardiac conduction disturbances; decrease or increase in blood pressure; very rare – bradycardia, arrhythmias, atrioventricular block with fainting, collapse, chronic heart failure, exacerbation of coronary heart disease, thrombophlebitis, thromboembolism (e.g., pulmonary embolism).

From the endocrine system and metabolism common – edema, fluid retention, weight gain, hyponatremia and decreased blood osmolarity due to an effect similar to that of antidiuretic hormone, which in rare cases leads to water intoxication (dilutional hyponatremia), accompanied by lethargy, vomiting, headache, disorientation, and neurological disorders; very rare – increased blood prolactin concentration, accompanied or not accompanied by manifestations such as galactorrhea, gynecomastia; changes in thyroid function parameters – decreased concentration of L-thyroxine (free thyroxine, thyroxine, triiodothyronine) and increased concentration of thyroid-stimulating hormone (TSH), which usually is not accompanied by clinical manifestations; disorders of bone tissue metabolism (decreased calcium and 25-hydroxycolecalciferol in the blood), leading to osteomalacia/osteoporosis; increased cholesterol concentration, including high-density lipoprotein cholesterol, and triglycerides.

From the genitourinary system very rare – interstitial nephritis, renal failure, impaired renal function (e.g., albuminuria, hematuria, oliguria, increased urea/azotemia), frequent urination, urinary retention, sexual function disorders/impotence, spermatogenesis disorders (decreased sperm count and motility).

From the musculoskeletal system rare – muscle weakness; very rare – arthralgia, muscle pain or cramps.

From the sensory organs very rare – taste disturbances, lens opacity, conjunctivitis, increased intraocular pressure; hearing disorders, incl. tinnitus, hyperacusis, hypoacusis, changes in pitch perception.

Contraindications

• Hypersensitivity to carbamazepine and other components of the drug, as well as to substances with a structure similar to carbamazepine (e.g., tricyclic antidepressants);
• Children under 4 years of age (for children under 4 years of age, Carbamazepine is preferably used in the form of a syrup due to the difficulties of using solid dosage forms in this age group);
• Disorders of bone marrow hematopoiesis (anemia, leukopenia);
• History of episodes of bone marrow hematopoiesis suppression or all types of porphyrias;
• Atrioventricular block;
• Concomitant administration of lithium preparations and MAO inhibitors.

Use in Pregnancy and Lactation

Treatment of epilepsy with Zeptol during pregnancy should be carried out with particular caution.

In women of childbearing age, Zeptol should, if possible, be used as monotherapy, since the frequency of congenital fetal anomalies in children born to women who were treated with a combination of antiepileptic drugs is higher than in those who received each of these drugs as monotherapy. The minimum effective dose of Zeptol should be prescribed.

Regular monitoring of the plasma concentration of carbamazepine is recommended.

If pregnancy occurs in a woman receiving Zeptol, or if the question of prescribing Zeptol during pregnancy arises, it is necessary to carefully compare the expected benefits of therapy and its possible complications, especially in the first trimester of pregnancy.

It is known that children born to mothers with epilepsy are more predisposed to intrauterine developmental disorders, including malformations. It has been reported that Carbamazepine, like all major antiepileptic drugs, can increase the risk of these disorders, although definitive confirmation obtained from controlled studies using Zeptol as monotherapy is not yet available. There are reports of cases of congenital diseases and malformations, including spina bifida and other congenital anomalies (including craniofacial and cardiovascular system), which were observed in patients taking Zeptol. Patients should be provided with information about the possibility of an increased risk of malformations and the possibility of undergoing antenatal diagnosis. It is known that folate deficiency develops during pregnancy. It has been reported that antiepileptic drugs enhance this deficiency. This may contribute to an increased frequency of congenital defects in children born to women taking antiepileptic drugs. Therefore, folic acid supplementation is recommended before and during pregnancy.

To prevent increased bleeding in newborns, it is recommended to prescribe vitamin K₁ to women in the last weeks of pregnancy and to newborns.

Carbamazepine is excreted in breast milk, with concentrations ranging from 25-60% of plasma levels. Therefore, the benefits and possible adverse consequences of breastfeeding during ongoing Zeptol therapy should be weighed. Mothers taking Zeptol may continue breastfeeding, provided that the infant is monitored for the development of possible side effects (e.g., pronounced drowsiness, allergic skin reactions). Regular monitoring of carbamazepine concentration in breast milk is recommended.

Several cases of epileptic seizures and/or respiratory depression in newborns have been described, whose mothers were taking the drug concurrently with other anticonvulsants. Furthermore, several cases of vomiting, diarrhea, and/or poor feeding in newborns have also been reported, whose mothers were receiving Zeptol. These reactions may represent manifestations of withdrawal syndrome in newborns.

Women of childbearing potential are recommended to use non-hormonal contraceptive methods during treatment with carbamazepine.

Pediatric Use

In children under 4 years of age, Carbamazepine is preferably used in the form of a syrup due to the difficulties of using solid dosage forms in this age group.

Special Precautions

The drug is usually ineffective in absence (petit mal) and myoclonic seizures. In patients with mixed types of epileptic seizures, the drug should be used with caution and only under conditions of regular medical supervision (due to the possible increase in seizures). If seizures increase, the use of Zeptol should be discontinued.

During the use of the drug, a transient or persistent decrease in the number of platelets or leukocytes has been observed with varying frequency. However, in most cases, these phenomena are transient and usually do not herald the onset of aplastic anemia or agranulocytosis. Before starting treatment and periodically during treatment, clinical blood tests should be performed, including platelet count and possibly reticulocyte count, as well as serum iron concentration determination.

Patients should be informed about the early signs of toxicity characteristic of potential hematological disorders, as well as symptoms related to the skin and liver. The patient is informed of the need to consult a doctor immediately if adverse reactions such as fever, sore throat, rash, mouth ulcers, unexplained bruising, petechiae, or purpura occur.

In cases where low white blood cell or platelet counts (or a tendency towards their decrease) are observed during treatment, the patient’s condition and complete blood count parameters should be closely monitored. If signs of significant bone marrow suppression are detected, Zeptol should be discontinued.

Very rarely, severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), have been reported with the use of Zeptol. Zeptol should be discontinued immediately if signs and symptoms suggestive of the development of severe dermatological reactions – such as Stevens-Johnson syndrome or Lyell’s syndrome – are noted. If severe (sometimes life-threatening) skin reactions develop, the patient should be hospitalized. In most cases, Stevens-Johnson syndrome and Lyell’s syndrome developed during the first months of therapy with the drug.

The influence of factors such as the dose of anticonvulsant drugs, patient compliance, concomitant therapy with other drugs, comorbidities, or the level of monitoring for dermatological reactions on the incidence of severe skin reactions (and mortality in patients with Stevens-Johnson syndrome and Lyell’s syndrome) has not been established.

Mild skin reactions (isolated maculopapular or maculopapular exanthema) are mostly transient and non-severe and usually resolve within a few days or weeks even with continued treatment or after dose reduction.

Nevertheless, since differential diagnosis between early manifestations of severe skin reactions and mild transient skin rashes can be difficult, the patient should be under medical supervision if any skin reactions develop (to promptly discontinue drug therapy if the patient’s condition worsens).

According to a retrospective analysis of the drug’s use in patients of Chinese ethnicity, there is a correlation between the frequency of severe dermatological reactions and the presence of the HLA-B*1502 allele of the human leukocyte antigen (HLA) gene in the patient’s genome.

When carbamazepine was used in patients in Asian countries (Thailand, Malaysia, Philippines), where the HLA-B*1502 allele is predominantly prevalent, an increased frequency (from ‘very rare’ to ‘rare’) of severe dermatological reactions, including Stevens-Johnson syndrome and Lyell’s syndrome, was observed. The prevalence of the HLA-B*1502 allele is: in the Philippines, Thailand, Hong Kong, and Malaysia – over 15%, in Taiwan – 10%, in Northern China – 4%, in South Asia, including India – 2-4%, in Japan and Korea – less than 1%. The prevalence of this allele in individuals of Caucasian, African, and Amerindian (Latin Americans and Native Americans) races is negligible.

When prescribing carbamazepine to potential carriers of the HLA-B*1502 allele (e.g., individuals of Chinese ethnicity), genotyping for this allele is recommended. The drug should be prescribed to carriers of this allele only if the benefit of therapy outweighs the potential risk. For individuals of Caucasian, African, and Amerindian races, genotyping for the HLA-B*1502 allele before prescribing Zeptol is not mandatory.

Genotyping for this allele is not recommended for patients already receiving Zeptol therapy, as severe skin reactions were mostly observed in the first months of drug use (regardless of the presence of the HLA-B*1502 allele).

However, the results of genotyping for the HLA-B*1502 allele should not affect the level of patient monitoring and physician vigilance regarding severe skin reactions. The development of Stevens-Johnson and Lyell syndromes is possible in patients negative for the HLA-B*1502 allele. Also, in many cases, individuals of Chinese ethnicity positive for the HLA-B*1502 allele did not develop Stevens-Johnson or Lyell syndromes when using Zeptol.

The influence of other factors, such as the dose of anticonvulsant drugs, patient compliance, concomitant therapy with other drugs, comorbidities, or the level of monitoring for dermatological reactions, on the incidence of severe skin reactions (and mortality in patients with Stevens-Johnson syndrome and Lyell’s syndrome) has not been established.

Mild skin reactions (isolated macular or maculopapular exanthema) are mostly transient and non-severe and usually resolve within a few days or weeks even with continued treatment or after dose reduction.

Nevertheless, since differential diagnosis between early manifestations of severe skin reactions and mild transient skin rashes can be difficult, the patient should be under medical supervision if any skin reactions develop (to promptly discontinue drug therapy if the patient’s condition worsens).

The relationship between the presence of the HLA-B*1502 allele in the genome and the development of non-severe skin reactions (such as hypersensitivity reactions, isolated macular or maculopapular exanthema) has not been established.

In case of hypersensitivity to Zeptol, patients may experience isolated lesions of the skin, liver (including damage to the intrahepatic bile ducts), blood and lymphatic systems, or other organs, or a combination thereof, which should be considered a systemic reaction. If manifestations and symptoms of hypersensitivity to Zeptol occur, the drug should be discontinued immediately.

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

Cross-hypersensitivity reactions may also occur between carbamazepine and phenytoin.

Before starting treatment and periodically during therapy, a general urine test and blood urea concentration determination are recommended. Before prescribing carbamazepine and during treatment, liver function tests are necessary, especially in patients with a history of liver disease and in elderly patients. If pre-existing liver function impairments worsen or active liver disease appears, the drug should be discontinued immediately.

Before starting treatment, an ophthalmological examination, including fundus examination and intraocular pressure measurement, is recommended. If the drug is prescribed to patients with elevated intraocular pressure, constant monitoring of this parameter is necessary.

To date, isolated reports of impaired male fertility and/or spermatogenesis disorders have been registered (the relationship of these disorders with carbamazepine intake has not yet been proven).

The drug may reduce the effectiveness of drugs containing estrogens and/or progesterone, so women of childbearing potential should use alternative methods of contraception during treatment with the drug.

Although the relationship between carbamazepine dose, its concentration, and clinical efficacy or tolerability is very weak, regular determination of carbamazepine concentration may be useful in the following situations: with a sharp increase in seizure frequency; to check if the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if impaired drug absorption is suspected; if toxic reactions are suspected when the patient is taking multiple medications.

Since latent mental disorders may worsen during drug use, elderly patients should be monitored for symptoms such as confusion and psychomotor agitation. In some cases, treatment with antiepileptic drugs has been accompanied by the occurrence of suicide attempts/suicidal ideation. This has also been confirmed by a meta-analysis of randomized placebo-controlled studies with antiepileptic drugs.
Since the mechanism of suicide attempts with the use of antiepileptic drugs is unknown, their occurrence cannot be ruled out in patients treated with Zeptol. Patients and caregivers should be warned to monitor for the emergence of suicidal thoughts/suicidal behavior and, if symptoms occur, to seek medical help immediately.

Abrupt discontinuation of carbamazepine may provoke epileptic seizures. If it is necessary to abruptly interrupt treatment, the patient should be switched to another antiepileptic drug under the cover of an appropriate drug for such cases (e.g., intravenously or rectally administered diazepam, or intravenously administered phenytoin).

MAO inhibitors should be discontinued at least 2 weeks before prescribing the drug, or, if the clinical situation allows, even longer. Alcohol consumption should be avoided during treatment.

Effect on Ability to Drive and Operate Machinery

The ability of a patient taking Zeptol to react quickly, especially at the start of therapy or during dose titration, may be impaired due to dizziness and drowsiness. Therefore, caution should be exercised when driving a car or operating machinery.

Overdose

Symptoms: usually reflect disorders of the CNS, cardiovascular system, and respiratory system.

CNS and Sensory Organs: CNS depression, disorientation, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (initially), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Cardiovascular System: tachycardia, decreased BP, sometimes increased BP, impaired intraventricular conduction with QRS complex widening; fainting, cardiac arrest.

Respiratory System: respiratory depression, pulmonary edema.

Digestive System: nausea and vomiting, delayed gastric emptying, decreased colon motility.

Urinary System: urinary retention, oliguria or anuria; fluid retention; hyponatremia.

Laboratory Parameters: leukocytosis or leukopenia, hyponatremia, possible metabolic acidosis, possible hyperglycemia and glucosuria, increased activity of the muscle fraction of creatine phosphokinase.

Treatment: There is no specific antidote. Treatment is based on the patient’s clinical condition; hospitalization, determination of plasma carbamazepine concentration (to confirm poisoning by this drug and assess the degree of overdose), gastric lavage, and administration of activated charcoal are indicated (delayed gastric evacuation may lead to delayed absorption on days 2 and 3 and reappearance of intoxication symptoms during recovery).

Forced diuresis, hemodialysis, and peritoneal dialysis are ineffective (dialysis is indicated in cases of severe poisoning combined with renal failure). In young children, exchange blood transfusion may be necessary. Symptomatic supportive treatment in the intensive care unit, monitoring of heart function, body temperature, corneal reflexes, kidney and bladder function, correction of electrolyte disorders. For decreased BP: Trendelenburg position, plasma substitutes, if ineffective – intravenous dopamine or dobutamine; for cardiac arrhythmias – treatment is selected individually; for convulsions – administration of benzodiazepines (e.g., diazepam), with caution (due to possible increased respiratory depression) administration of other anticonvulsant drugs (e.g., phenobarbital). If dilutional hyponatremia (water intoxication) develops – fluid restriction and slow intravenous infusion of 0.9% NaCl solution (may help prevent cerebral edema). Hemoperfusion on charcoal sorbents is recommended.

Drug Interactions

Cytochrome P450 3A4 (CYP3A4) is the main enzyme responsible for the formation of carbamazepine-10,11-epoxide (an active metabolite). Concurrent use of Zeptol with inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of carbamazepine and cause adverse reactions. Concomitant use of inducers of the CYP3A4 isoenzyme may lead to accelerated metabolism of carbamazepine and thus to a possible decrease in its plasma concentration and, consequently, a possible reduction in the therapeutic effect of the drug. Discontinuation of concurrently taken inducers of the CYP3A4 isoenzyme may reduce the rate of carbamazepine biotransformation and lead to an increase in its plasma concentration.

Carbamazepine is a strong inducer of the CYP3A4 isoenzyme and other hepatic enzyme systems of the first and second phases of drug metabolism and, when used concomitantly with drugs metabolized by the CYP3A4 isoenzyme, can induce their metabolism and reduce their plasma concentration.

Since the conversion of Carbamazepine-10,11-epoxide to Carbamazepine-10,11-trans-diol occurs via microsomal epoxide hydrolase, the use of Zeptol together with inhibitors of microsomal epoxide hydrolase may lead to an increase in the plasma concentration 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;
• Macrolide antibiotics: erythromycin, josamycin, clarithromycin, troleandomycin;
• Antidepressants: possibly – desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine;
• Antiepileptic drugs: stiripentol, vigabatrin;
• Antifungal agents: azole derivatives (itraconazole, ketoconazole, fluconazole, voriconazole);
• H₁-histamine receptor blockers: terfenadine, loratadine;
• Antipsychotic agents (neuroleptics): olanzapine;
• Antituberculosis drugs: isoniazid;
• Antiviral agents: HIV protease inhibitors (e.g., ritonavir);
• Antiglaucoma agents (carbonic anhydrase inhibitors): acetazolamide;
• Blood pressure-lowering drugs (calcium channel blockers): verapamil, diltiazem;
• Antiulcer agents (proton pump inhibitors, histamine H₂-receptor blockers): omeprazole, cimetidine;
• Muscle relaxants: oxybutynin, dantrolene;
• Antiplatelet agents: ticlopidine;
• Other drugs and food: grapefruit juice, nicotinamide (in adults, only in high doses).

Since an increase in plasma carbamazepine concentration may lead to adverse reactions (e.g., dizziness, drowsiness, ataxia, diplopia), in these situations, the drug dose should be adjusted and/or plasma carbamazepine concentration should be regularly determined.

Drugs that may increase the plasma concentration of carbamazepine-10,11-epoxide loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, and valpromide.

Since an increase in plasma carbamazepine-10,11-epoxide concentration may lead to adverse reactions (e.g., dizziness, drowsiness, ataxia, diplopia), in these situations, the dose of Zeptol should be adjusted and/or plasma carbamazepine-10,11-epoxide concentration should be regularly determined.

Drugs that may decrease the plasma concentration of carbamazepine

• Antiepileptic drugs: felbamate, oxcarbazepine, phenobarbital, phenytoin, fosphenytoin, primidone, methsuximide, phensuximide, and although data are partially conflicting, possibly also clonazepam;
• Antineoplastic agents: cisplatin or doxorubicin;
• Antituberculosis drugs: rifampicin;
• Bronchodilators: theophylline, aminophylline;
• Acne treatment agent (retinoids): isotretinoin
• Other drugs and food: herbal preparations containing St. John’s wort (Hypericum perforatum).

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

Effect of carbamazepine on the plasma concentration of drugs used as concomitant therapy.

When used concomitantly with carbamazepine, a decrease in plasma concentration, reduction, or even complete cessation of effect of some drugs is possible. When used concomitantly with carbamazepine, dose adjustment of the following drugs may be required

• analgesics and nonsteroidal anti-inflammatory drugs: buprenorphine, methadone, paracetamol, phenazone, tramadol;
• tetracycline antibiotics: doxycycline;
  • indirect anticoagulants: warfarin, phenprocoumon, dicumarol, and acenocoumarol;
• antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine);
• antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide.

There are reports that during the administration of carbamazepine, the plasma concentration of phenytoin may either increase or decrease, and the concentration of mephenytoin may increase (in rare cases).

• antifungal agents: itraconazole;
• antihelminthic agents: praziquantel;
• antineoplastic agents: imatinib;
• antipsychotic agents (neuroleptics): clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone;
• antiviral agents: HIV protease inhibitors (indinavir, ritonavir, saquinavir);
• anxiolytic agents: alprazolam, midazolam;
• bronchodilators: theophylline;
• contraceptives: hormonal contraceptives (alternative methods of contraception should be selected);
• drugs that lower blood pressure (dihydropyridine group slow calcium channel blockers): felodipine;
• cardiac glycosides: digoxin;
• glucocorticosteroids: prednisolone, dexamethasone;
• immunosuppressive agents: cyclosporine, everolimus;
• drugs for the treatment of thyroid diseases: levothyroxine;
• other drugs and food products: drugs containing estrogens and/or progesterone.

Combinations to be considered

When carbamazepine and levetiracetam were used concomitantly, an increase in the toxic effect of carbamazepine was noted in some cases.

There are reports of increased hepatotoxicity caused by isoniazid when it was used concomitantly with carbamazepine.

Concomitant use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptic agents (haloperidol, thioridazine) may lead to an increased frequency of undesirable neurological reactions (in the case of the latter combination – even at therapeutic plasma concentrations of the active substances).

Concomitant use of carbamazepine with some diuretic agents (hydrochlorothiazide, furosemide) may lead to hyponatremia accompanied by clinical manifestations.

Carbamazepine may exhibit antagonism to the action of non-depolarizing muscle relaxants (e.g., pancuronium bromide). When using such a combination of drugs, it may be necessary to increase the dose of these muscle relaxants; careful monitoring of patients should be carried out, as a faster than expected cessation of the effect of muscle relaxants is possible.

Bleeding between menstrual periods has been reported in women when hormonal contraceptives were used concomitantly. The drug may reduce the therapeutic effect of hormonal contraceptive drugs due to the induction of microsomal enzymes.

Carbamazepine, like other psychotropic drugs, may reduce tolerance to alcohol. In this regard, the patient is advised to refrain from drinking alcohol.

Storage Conditions

Store the drug in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.