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The pharmacological activity of the drug oxapine is primarily due to the action of its metabolite, the monohydroxy derivative (MPP). The mechanism of action of oxcarbazepine and its MPP is mainly associated with the blockade of voltage-dependent sodium channels, which leads to stabilization of overexcited neuronal membranes, inhibition of serial neuronal discharges and a decrease in synaptic impulse conduction.
In addition, increased conductivity of potassium ions and modulation of high-potential activated calcium channels, which can also contribute to anticonvulsant effects. No significant interactions with brain neurotransmitters or receptor modulator centers have been identified.
Animal studies have shown that oxcarbazepine and its active metabolite (IHL) are potent and effective anticonvulsants. They protected animals from generalized tonic-clonic attacks and, to a lesser extent, from clonic attacks and stopped or reduced the frequency of chronic recurrent partial seizures in animals with aluminum implants. With daily treatment of animals for 5 days or 4 weeks with oxcarbazepine or IHL, respectively, resistance (i.e., weakening of anticonvulsant activity) with respect to tonic-clonic seizures was not observed.
Pharmacokinetics Absorption. After oral administration, oxcarbazepine is completely absorbed and metabolized to a large extent with the formation of a pharmacologically active metabolite (IHL).
After a single dose of 600 mg in healthy fasting volunteers, Cmax MHP in blood plasma is 34 μmol / L, Tmax ≈ 4.5 hours. During the study of the mass balance with the participation of men, only 2% of the total radioactivity in the blood plasma was due to unchanged oxcarbazepine, about 70% due to IHL, and the rest due to minor secondary metabolites that are rapidly excreted.
Food does not affect the rate and extent of absorption of oxcarbazepine. So, Oxapine can be taken regardless of the meal.
Distribution. The expected distribution of IHL is 49 liters. About 40% of IHL binds to plasma proteins, mainly albumin. In a therapeutically appropriate range, the degree of binding does not depend on the concentration of the drug in serum. Oxcarbazepine and MHP do not bind to alpha-1-acid glycoprotein.
Oxcarbazepine and IHL cross the placenta. In one case, the concentrations of MHP were the same in the blood plasma of the newborn and mother.
Metabolism. With the help of cytosolic enzymes, oxcarbazepine rapidly decreases in the liver to IHL, which is primarily responsible for the pharmacological effect of Oxapine. In the future, MHP is metabolized by conjugation with glucuronic acid. Small amounts (4% of the dose) are oxidized to a pharmacologically inactive metabolite (10, 11-dihydroxy derivative, BPH).
Oxcarbazepine is excreted mainly in the form of metabolites, mainly by the kidneys. More than 95% is excreted in the urine, with 1% in the form of unchanged oxcarbazepine. Excretion with feces is less than 4% of the dose taken. Approximately 80% of the dose is excreted in the urine in the form of MHP glucuronides (49%) or unchanged MHP (27%), while the amount of inactive BPH is approximately 3%, and oxcarbazepine conjugates - 13% of the dose. Oxcarbazepine is rapidly excreted from blood plasma with obvious half-lives between 1.3-2.3 hours, while the apparent half-life of MHP in blood plasma averaged 9.3 ± 1.8 hours.
Proportionality of a dose.
Stationary plasma concentrations of MHP in patients are achieved within 2-3 days when taking oxcarbazepine twice a day.In a stationary state, the pharmacokinetics of MHP is linear and demonstrates dose proportionality in the dose range of 300-2400 mg / day.
Special patient groups.
Patients with impaired liver function. The pharmacokinetics and metabolism of oxcarbazepine and MHP after a single oral dose of 900 mg were evaluated in healthy volunteers and in patients with impaired liver function. Mild and moderate hepatic impairment does not affect the pharmacokinetics of oxcarbazepine and IHL. Oxcarbazepine has not been studied in patients with severely impaired liver function.
Patients with impaired renal function. There is a linear relationship between creatinine clearance and renal clearance of IHL. With a single dose of 300 mg of oxcarbazepine in patients with impaired renal function (creatinine clearance of 30 ml / min), the half-life of MHP increases by 60–90% (16–19 h), and the AUC increases by 2 times compared with adult patients with normal function kidney (10 h).
Children. The pharmacokinetics of oxcarbazepine was evaluated in pediatric patients taking it in a dose range of 10-60 mg / kg / day. IHL clearance adjusted for body weight decreases as age and weight increase, approaching adult patients. Ground clearance for children aged 6 to 12 years is approximately 40% higher than clearance in adult patients. Consequently, the effect of IHL in these children is expected to be approximately equal to approximately the same when adjusted for body weight. 2/3 indicator in adults.
As body weight increases, it is expected that in patients over the age of 13 years, IHL clearance adjusted for body weight will reach that of adult patients.
Pregnancy. Data from a limited number of women indicate a gradual decrease in plasma levels of IHL during pregnancy.
Elderly patients. After taking oxcarbazepine once (at a dose of 300 mg) and repeatedly (at a dose of 600 mg / day) in elderly volunteers (60–82 years), the maximum plasma concentrations and AUC value for MHP were 30–60% higher than in younger volunteers age (18–32 years). A comparison of creatinine clearance in younger and older volunteers indicates that this difference is associated with an age-related decrease in creatinine clearance. There is no need for special dosage recommendations, since the doctor selects the therapeutic doses individually.
Floor. There were no pharmacokinetic differences depending on gender in children, adults, or the elderly.
Treatment of partial seizures with or without secondary generalized tonic-clonic seizures as monotherapy or adjunctive therapy in adults and children over 6 years of age.
In the case of monotherapy and adjunctive therapy, treatment with oxapine begins with a clinically effective dose divided into two uses. the dose can be increased depending on the clinical response of the patient. when replacing other antiepileptic drugs with oxapine, the dose of concomitant antiepileptic drug (s) should be gradually reduced at the beginning of the use of oxapine. as the total load on the patient with antiepileptic drugs increases, the dose of concomitant antiepileptic drugs may need to be reduced and / or the dose of oxapine should be increased more slowly. oxapine can be used regardless of food intake.
The following dosage recommendations apply to all patients in the absence of impaired renal function. There is no need to control the level of the drug in blood plasma in order to optimize Oxapine therapy. The tablets have a dividing line and can be divided into two halves so that it is easier for the patient to swallow the tablet. However, the tablet cannot be divided into two equal doses.
Monotherapy. The use of Oxapine should begin with a dose of 600 mg / day (8-10 mg / kg / day), divided into two applications. If there are clinical indications, the dose can be increased at approximately weekly intervals by no more than 600 mg / day from the initial dose to achieve the desired clinical response. The therapeutic effect is observed in the dose range of 600-2400 mg / day.
There is evidence that in patients not currently receiving antiepileptic drugs, an effective dose of oxcarbazepine as monotherapy is 1200 mg / day. However, it is known that a dose of 2400 mg / day is effective in patients who are more resistant to treatment, who are transferred to oxcarbazepine monotherapy with other antiepileptic drugs.
Under controlled hospital conditions, a dose increase of up to 2400 mg / day was achieved within 48 hours.
The use of Oxapine should begin with a dose of 600 mg / day (8-10 mg / kg / day), divided into 2 applications. If there are clinical indications, the dose can be increased at approximately weekly intervals by no more than 600 mg per day from the initial dose to achieve the desired clinical response. Therapeutic effects are observed in the dose range of 600-2400 mg / day. There is evidence that in patients who receive oxcarbazepine as adjunctive therapy, daily doses of 600 to 2400 mg / day are effective, although most patients were not able to tolerate a dose of 2400 mg / day without reducing the dose of concomitant antiepileptic drugs, mainly due to for adverse events from the central nervous system. The use of oxcarbazepine in daily doses above 2400 mg has not been studied.
Elderly patients. Dose adjustment is recommended for elderly patients with impaired renal function.
Children. It is recommended to use Oxapine for children over the age of 6 years. With monotherapy and additional therapy, treatment with Oxapine should begin with a dose of 8-10 mg / kg / day, divided into two applications. With additional therapy, therapeutic effects are observed with an average maintenance dose of about 30 mg / kg / day. In the presence of clinical indications, the dose may increase at approximately weekly intervals by no more than 10 mg / kg / day from the initial dose to a maximum of 46 mg / kg / day to achieve the desired clinical response.
In all categories of patients (adults, elderly patients and children), if necessary, lower doses of the drug can be used.
Patients with liver failure. Correction of the dosage regimen is not required for patients with mild to moderate liver failure. The use of oxcarbazepine has not been studied in patients with severe hepatic impairment. Therefore, caution is required when treating patients with severe hepatic impairment.
Patients with renal failure. For patients with impaired renal function (creatinine clearance less than 30 ml / min), Oxapine therapy should be started with half the usual initial dose (300 mg / day), which is increased at least at weekly intervals to achieve the desired clinical response. With an increase in dose for patients with renal failure, more careful observation may be required.
Hypersensitivity to the active substance or any excipients of the drug.
On the part of the blood and lymphatic system: leukopenia, thrombocytopenia, inhibition of bone marrow hematopoiesis, aplastic anemia, agranulocytosis, pancytopenia, neutropenia.
On the part of the immune system: hypersensitivity reactions (including multi-organ hypersensitivity), which are characterized by features such as rashes and fever.With the development of hypersensitivity reactions, disorders of other organs or systems, such as the circulatory and lymphatic systems (e.g. eosinophilia, thrombocytopenia, leukopenia, lymphadenopathy, splenomegaly), the liver (e.g. abnormal results of functional liver tests, hepatitis), muscles and joints (e.g. joint edema, myalgia, arthralgia), nervous system (e.g. hepatic encephalopathy), kidneys (e.g. proteinuria, interstitial nephritis, renal failure), lungs (e.g. yshka, pulmonary edema, asthma, bronchospasm, interstitial lung disease), angioneurotic edema, anaphylactic reactions.
From the side of metabolism and nutrition: hyponatremia, clinically significant hyponatremia (sodium concentration - 125 mmol / l) associated with such signs and symptoms as convulsions, encephalopathy, depressed level of consciousness, confusion (additional undesirable effects are also indicated in the section Disorders of side of the nervous system), visual impairment (for example, blurry image), hypothyroidism, vomiting, nausea, folic acid deficiency.
From the side of the psyche: confusion, depression, apathy, agitation (e.g. nervousness), affective lability, emotional lability.
From the nervous system: drowsiness, headache, dizziness, ataxia, tremor, nystagmus, impaired attention, amnesia.
From the side of the organ of vision: diplopia, blur, image impairment, blurred vision.
From the side of the organ of hearing and balance: vertigo.
From the cardiovascular system: arrhythmia, atrioventricular block, arterial hypertension.
From the gastrointestinal tract: nausea, vomiting, diarrhea, constipation, abdominal pain, pancreatitis.
From the biliary tract and liver: hepatitis.
From the skin and subcutaneous tissue: rashes, baldness, acne, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyells syndrome), erythema multiforme.
From the musculoskeletal system and connective tissue: systemic lupus erythematosus.
Systemic disorders and complications at the injection site: a feeling of increased fatigue, asthenia.
Abnormalities identified as a result of laboratory tests: increased levels of liver enzymes, increased levels of alkaline phosphatase in the blood, decreased T4 (clinical significance unclear), increased levels of lipase and / or amylase.
Hypersensitivity. During the post-registration period, reports of hypersensitivity reactions of class I (immediate) were received, which included rash, itching, urticaria, angioedema and reports of anaphylaxis. cases of anaphylaxis and angioedema, in which the larynx, glottis, lips and eyelids were involved, have been reported in patients after taking the first dose or subsequent doses of oxcarbazepine. if the patient develops such reactions after treatment with oxapine, the drug should be discontinued and alternative treatment should begin. patients who have hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of these patients may experience hypersensitivity reactions (for example, severe skin reactions) when taking oxapine. hypersensitivity reactions, including multi-organ hypersensitivity reactions, can also develop in patients without a history of hypersensitivity to carbamazepine. such reactions can affect the skin, liver, circulatory and lymphatic systems and other organs, either separately or together as a systemic reaction. when signs and symptoms appear that indicate a hypersensitivity reaction, oxapine should be discontinued immediately.
Dermatological effects. Serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyells syndrome), and erythema multiforme associated with oxcarbazepine, have been reported very rarely. Patients with serious skin reactions may require hospitalization, as these diseases can be life threatening and, in very rare cases, can be fatal. Cases associated with the use of oxcarbazepine have occurred in both children and adults. The median time to reaction was 19 days. Several isolated cases of recurrence of a serious skin reaction have been reported with repeated administration of oxcarbazepine. Patients who develop a skin reaction to treatment with oxcarbazepine should be examined immediately, and Oxapine itself should be canceled immediately, unless there is an obvious lack of connection between the rash and the drug. In case of cancellation of treatment, attention should be paid to replacing Oxapine with another antiepileptic drug therapy in order to avoid seizures as a result of drug withdrawal. Oxapine should not be reassigned to those patients who have been discontinued with oxcarbazepine because of a hypersensitivity reaction.
Hyponatremia. In 2.7% of patients who received oxcarbazepine, a decrease in plasma sodium levels below 125 mmol / L was observed, which was usually asymptomatic and did not require treatment correction. Clinical experience has shown that serum sodium levels return to normal after a dose reduction of oxcarbazepine, discontinuation of the drug, or conservative treatment of the patient (for example, limiting fluid intake). In patients with previous kidney disease associated with low sodium levels, or in patients who have been taking sodium-lowering drugs (e.g., diuretics, desmopressin), and NSAIDs (e.g., indomethacin), serum sodium levels should be measured before starting Oxapine therapy. . Later, plasma sodium levels should be measured after about two weeks and then once a month during the first three months of therapy or depending on clinical need. These risk factors may especially apply to elderly patients. As for patients receiving Oxapine, at the beginning of taking sodium-lowering drugs, you must follow the same approach to assessing sodium levels. If clinical symptoms indicating the development of hyponatremia are observed with Oxapine therapy, you can consider measuring the level of sodium in the blood serum. In other patients, serum sodium may be evaluated as part of their standard laboratory tests.
All patients with heart failure and secondary heart failure should be weighed regularly to determine if fluid retention is present. In case of fluid retention or worsening heart condition, serum sodium levels should be checked. If hyponatremia is observed, limiting the amount of water is an important measurement detector. Since in very rare cases, oxcarbazepine can lead to impaired cardiac conduction, it is worthwhile to carefully monitor patients with a previous conduction disorder (for example, atrioventricular block, arrhythmia).
Liver function. Very rare cases of hepatitis were reported, which in most cases regressed with a favorable prognosis. If liver disease is suspected, liver function should be evaluated and the possibility of discontinuing Oxapine should be considered.
Hematologic effects. During the post-registration period, in very rare cases, agranulocytosis, aplastic anemia, and pancytopenia have been reported in patients treated with oxcarbazepine.With the development of any sign of severe bone marrow suppression, consider discontinuing the drug.
Suicidal behavior. Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for several reasons. There is a slight increase in the risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of increasing the risk when taking oxcarbazepine. Therefore, patients should be checked for signs of suicidal thoughts and behavior, and consideration should be given to prescribing appropriate treatment. Patients (and those who care about them) should be advised to seek medical attention if signs of suicidal thoughts or behavior appear.
Hormonal contraceptives. Patients of reproductive age should be warned that the simultaneous administration of Oxapine with hormonal contraceptives can lead to the ineffectiveness of this type of contraceptive. When using Oxapine, other types of contraception are recommended.
Alcohol. Drinking alcohol during treatment with Oxapine may cause a cumulative sedative effect.
Cancel therapy. As with all antiepileptic drugs, Oxapine should be discontinued gradually to minimize the potential increase in seizure frequency.
Use during pregnancy and lactation.
Pregnancy. The general risk associated with epilepsy and antiepileptic drugs. It was shown that in children born to women with epilepsy, the prevalence of congenital malformations is 2-3 times higher than the frequency in the general group of patients, which is approximately 3%. In the group of patients receiving treatment, an increase in the incidence of defects was observed during polytherapy, however, to what extent drug therapy and / or diseases are responsible for this has not yet been clarified.
Moreover, effective antiepileptic therapy cannot be interrupted, since an exacerbation of the disease is very harmful for both the mother and the fetus.
Oxcarbazepine Risk The amount of clinical data on taking the drug during pregnancy remains insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, at dose levels that are toxic to the female body, an increase in embryo death, developmental delays and malformations was observed.
Given the above, you must keep in mind:
- if a woman who is taking Oxapine becomes pregnant or is planning a pregnancy, you should carefully reevaluate the use of this drug. The minimum effective doses should be prescribed and, if possible, monotherapy should be preferred, at least during the first three months of pregnancy;
- patients should be advised on the possibility of increasing the risk of malformations and provide the possibility of prenatal screening;
- during pregnancy, effective antiepileptic treatment with oxcarbazepine cannot be interrupted, since an exacerbation of the disease is very harmful for both the mother and the fetus.
Monitoring and prevention. Antiepileptic drugs can cause folic acid deficiency, which, possibly, will affect the development of fetal abnormalities. Folic acid supplementation before and during pregnancy is recommended. Since the effectiveness of taking such supplements has not been proven, a special antenatal diagnosis can be offered even to those women who additionally receive folic acid.
Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, a 10-monohydroxy derivative (IHL), may gradually decrease during pregnancy.Careful monitoring of the clinical response in women receiving Oxapine therapy during pregnancy is recommended to ensure adequate control of the seizures that persist. The need to determine changes in the concentration of IHL in blood plasma should be considered. If doses increased during pregnancy, it is also necessary to consider monitoring plasma levels of IHL in the postpartum period.
Newborns. Blood clotting disorders in newborns caused by antiepileptic drugs have been reported. Vitamin K should be used as a precaution1 during the last few weeks of pregnancy and the newborn.
The period of breastfeeding. Oxcarbazepine and its active metabolite (IHL) pass into breast milk. For both compounds, the ratio of the concentration in breast milk and the concentration in the blood plasma was 0.5. The effect of oxcarbazepine on an infant through breast milk is unknown. So, if necessary, treatment should stop breast-feeding.
Children. Oxcarbazepine is not recommended for children under 6 years of age, since safety and effectiveness have not been properly proven.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The use of oxcarbazepine has been associated with adverse reactions, such as dizziness or drowsiness. Therefore, patients should be informed about a possible violation of their physical and / or mental ability to work with mechanisms or drive vehicles.
Induction of enzyme synthesis.
Oxcarbazepine and its pharmacologically active metabolite (monohydroxy derivative, MHP) are weak in vitro and in vivo inducers of the CYP 3A4 and CYP 3A5 cytochrome P450 enzymes responsible for the metabolism of a very large number of drugs, in particular immunosuppressants (e.g. cyclosporin, tacrolimus o, . below) and some other antiepileptic drugs (eg carbamazepine), which leads to a decrease in plasma concentrations of these drugs (the table shows the results for ugim antiepileptic drugs).
Oxcarbazepine and MHP in vitro are weak inducers of UDP-glucuronyltransferases (effects on specific enzymes in this class are unknown). So, oxcarbazepine and IHL in vivo can slightly induce the effect on the metabolism of drugs, which are mainly excreted by conjugation via UDP-glucuronyl transferase. At the beginning of treatment with Oxapine or with a change in dose, 2-3 weeks may be required to achieve a new level of induction. In case of cancellation of therapy with Oxapine, it may be necessary to reduce the dose of concomitant drugs, a decision on which should be made on the basis of clinical observation and / or when observing the plasma level of the drug. Induction is likely to gradually decrease 2–3 weeks after discontinuation of therapy.
Hormonal contraceptives. Oxcarbazepine has been shown to affect two components of oral contraceptives: ethinyl estradiol and levonorgestrel. The average AUC values of ethinyl estradiol and levonorgestrel decreased by 48–52% and 32–52%, respectively. So, the concomitant use of Oxapine with hormonal contraceptives can lead to the ineffectiveness of these contraceptives. Another reliable contraceptive method must be used.
Inhibition of enzyme synthesis.
Oxcarbazepine and IHL suppress CYP 2C19. Consequently, the combined use of Oxapine in high doses with drugs that are mainly metabolized by CYP 2C19 (e.g. phenytoin) may result in an interaction.Plasma phenytoin levels increased by 40% when doses of oxcarbazepine were prescribed that exceeded 1200 mg / day (the table shows the results for other anticonvulsants). In this case, a reduction in the concomitant use of phenytoin may be required.
Potential interactions between oxcarbazepine and other antiepileptic drugs have been evaluated in clinical trials. Information on the effect of these interactions on the mean values of AUC and Cmin set out in the table.
Table. Information on the interaction of antiepileptic drugs with oxcarbazepine
|Antiepileptic drug||The effect of oxcarbazepine on an antiepileptic drug||The effect of the antiepileptic drug on IHL|
|Carbamazepine||0–22% decrease (30% increase in carbamazepine epoxide levels)||40% reduction|
|Clobazam||Not investigated||No effect|
|Felbamate||Not investigated||No effect|
|Lamotrigine||Slight decrease *||No effect|
|Phenobarbital||14-15% increase||30–31% reduction|
|Phenytoin||0-40% increase||29–35% reduction|
|Valproic acid||No effect||0–18% reduction|
*Preliminary results show that oxcarbazepine can lead to a decrease in the concentration of lamotrigine, which is probably important when used in children, but the potential for the interaction of oxcarbazepine is less than that observed with the simultaneous use of drugs that induce enzyme synthesis (carbamazepine, phenobarbital and phenytoin).
In adults, potent inducers of the synthesis of cytochrome P450 enzymes (that is, carbamazepine, phenytoin, and phenobarbitone) have been shown to lower plasma levels of MHP (by 29–40%). At the age of 6–12 years, MHP clearance increased by approximately 35% when taking one of the three antiepileptic drugs that induce enzyme synthesis compared with monotherapy. Combination therapy with oxcarbazepine and lamotrigine increased the risk of adverse events (nausea, drowsiness, dizziness, and headache). With the simultaneous administration of one or more antiepileptic drugs with oxcarbazepine, the possibility of careful dose adjustment and / or control of blood plasma levels can be considered individually. This is especially true for pediatric patients who received lamotrigine at the same time.
When taking oxcarbazepine, self-induction of the enzyme was not observed.
Interactions with other drugs
Cimetidine, erythromycin, viloxazine, warfarin, and dextropropoxyphene did not affect the pharmacokinetics of IHL.
The interaction between oxcarbazepine and MAOI drugs is theoretically possible, given the structural association of oxcarbazepine with tricyclic antidepressants.
Patients receiving treatment with tricyclic antidepressants participated in clinical trials, clinically significant interactions were not observed.
Combination therapy with lithium and oxcarbazepine may increase neurotoxicity.
Isolated cases of overdose have been reported. maximum accepted