Carbamazepine-Ferein - instructions for use, dose, side effects, contraindications

An antiepileptic agent, a dibenzazepine derivative, which exerts; also normotime, antimanic and analgesic effects. Activates the central brake GABA-ergic system. It blocks the potential-dependent sodium ropes of nerve cell membranes, which leads to functional stabilization of neurons, reduces the activity of the excitatory neurotransmitter acids (glutamate, aspartate) interacts with the central adenosine receptors (inhibition of adenylate cyclase activation).Increases the convulsive threshold, reduces the risk of developing an epileptic attack. It can be prescribed both as the main therapeutic agent, and in combination with other anticonvulsants. Corrects the epileptic personality changes, which leads to increased communication skills of patients and their social rehabilitation. In the case of essential neuralgia of the trigeminal nerve, in most cases it prevents the occurrence of paroxysmal pain. With alcohol withdrawal syndrome increases the lowered convulsive threshold of the central nervous system and, thus, reduces the risk of convulsive seizure, also reduces the severity of clinical manifestations of the syndrome (increased excitability, tremor, affective disorders). When diabetes insipidus reduces diuresis and reduces thirst (due to antidiuretic effect).

Pharmacokinetics:

Absorption - slow, but fairly complete (eating does not affect the speed and degree of absorption). After a single intake, the maximum concentration (C_max) is achieved after 12 hours. Equilibrium concentrations of the drug in the plasma are achieved after 1-2 weeks.Speed achieve depends on the individual metabolism: autoinduction liver enzyme systems geteroinduktsiya other simultaneously applicable medicaments as well as on the condition of the patient, the dose and duration of treatment. There are substantial interindividual differences equilibrium concentrations in the therapeutic range values: the majority of patients values ranging from 4 to 12 micrograms / ml (17-50 micromol / L). The concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite) are about 30% of the concentration of carbamazepine. The connection with plasma proteins in children is 55-59%, in adults 70-80%. Apparent volume of distribution - 0,8-1,9 l / kg. In the cerebrospinal fluid and saliva, concentrations are created in proportion to the amount of the active substance unbound with proteins (20-30%). Penetrates through the placental barrier. Concentration in breast milk is 25-60% of that in plasma. It is metabolized in the liver to form the major metabolites: active - carbamazepine-10,11-epoxide and inactive conjugate with glucuronic acid. The main isoenzyme providing the biotransformation of carbamazepine in carbamazepine-10,11-epoxide is cytochrome P450 (CYP3A4).As a result of these metabolic reactions, a low-activity metabolite of 9-hydroxy-methyl-10 carbamoylacridan is also formed. Can induce own metabolism. The concentration of carbamazepine-10,11-epoxide is 30% of the concentration of carbamazepine. Half-life (T1 / 2) after taking a single oral dose of 25-65 hours (an average of about 36 hours), after repeated administration, depending on the duration of treatment 12-24 hours (due to autoinduction of the monooxygenase system of the liver). In patients receiving additionally other anticonvulsants (monooxygenase system inducers - phenytoin, phenobarbital) T1 / 2 - an average of 9-10 hours. It is excreted as inactive metabolites with urine (70%) and with feces (30%). Children, due to faster elimination of carbamazepine, may require the use of higher doses of the drug at a rate of 1 kg of body weight in comparison with adults. There is no evidence that the pharmacokinetics of carbamazepine change in elderly patients (compared with older adults). Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function is not sufficient.

Indications:

Epilepsy (except absences, myoclonic or flaccid seizures) - partial seizures with complex and simple symptoms, primary and secondary generalized forms of seizures with tonic-clonic seizures, mixed forms of seizures (monotherapy or in combination with other anticonvulsant drugs); idiopathic neuralgia of the trigeminal nerve, trigeminal neuralgia with multiple sclerosis, idiopathic glossopharyngeal neuralgia, alcohol withdrawal syndrome, treatment of affective disorders, polydipsia and polyuria in diabetes insipidus, diabetic polyneuropathy.

Prevention of phase-related affective disorders (manic-depressive psychosis, schizoaffective disorder, etc.).

Contraindications:

Hypersensitivity to carbamazepine or chemically similar drugs (eg, tricyclic antidepressants) or to any other component of the drug, acute intermittent porphyria (including history), simultaneous administration of monoamine oxidase inhibitors, disturbance of bone marrow hematopoiesis (anemia, leukopenia), atrioventricular blockade.

Carefully:

Hyponatremia of dilution (hypersecretion syndrome of antidiuretic hormone, hypopituitarism, hypothyroidism, insufficiency of the adrenal cortex), elderly age, alcohol intake (central nervous system is being intensified, carbamazepine metabolism is increasing), oppression of bone marrow hemopoiesis with medication (in anamnesis), prostatic hyperplasia, increased intraocular pressure, severe heart failure, liver failure, chronic renal failure.

Pregnancy and lactation:

In women of reproductive age, the drug should, if possible, be used as a monotherapy (using the lowest effective dose) - the incidence of congenital anomalies in newborns born to women who undergo combined antiepileptic treatment is higher than those who receive each of these as monotherapy .

At approach of pregnancy (at the decision of a question on purpose or appointment of a preparation during pregnancy) it is necessary to compare carefully expected benefits of therapy and its possible complications, especially in the first 3 months. pregnancy.

It is known that children born to mothers with epilepsy are predisposed to violations of intrauterine development, including malformations. Carbamazepine-Ferein®, like all other antiepileptic drugs, can increase the risk of these disorders. There are isolated reports of cases of congenital diseases and malformations, including non-vertebral arches (spina bifida).

Patients should be provided with information on the possibility of increasing the risk of malformations and the ability to undergo antenatal diagnostics. Antiepileptic drugs increase the deficiency of folic acid, which is often observed during pregnancy, which can contribute to an increase in the frequency of birth defects in children (additional folic acid intake is recommended before and during pregnancy). In order to prevent increased bleeding in newborns, in the last weeks of pregnancy, as well as newborns, vitamin K1 is recommended.

Carbamazepine penetrates into breast milk, it is necessary to compare the benefits and possible undesirable effects of breastfeeding in conditions of ongoing therapy. Mothers accepting carbamazepine, can breast-feed their children, provided that the child will be monitored for the development of possible adverse reactions (eg, severe drowsiness, allergic skin reactions).

Dosing and Administration:

Assign inside, regardless of food intake with a small amount of liquid.

With epilepsy

Where possible, the drug should be given as a monotherapy. Treatment begins with the application of a small daily dose, which is then slowly increased until an optimal effect is achieved.

The adherence of the drug to the already conducted antiepileptic therapy should be carried out gradually, while the doses of the drugs used do not change or, if necessary, correct.

For adults the initial dose is 100-200 mg 1-2 times a day. Then the dose is slowly increased, until the optimal therapeutic effect is reached (usually 400 mg 2-3 times a day, maximum - 1600-2000 mg / day).

For children from 4 months to 4 years, the average daily dose is 10-20 mg / kg body weight: from 4 months to 1 year - 100-200 mg per day, from 1 year to 5 years - 200-400 mg (in 1-2 hours ), from 6 to 10 years - 400-600 mg (in 2-3 doses), for 11-15 years - 600-1000 mg (in 2-3 administrations).

Supportive doses: 10-20 mg / kg per day (in several doses).

With neuralgia of the trigeminal nerve and neurogenic pain syndrome

The drug is prescribed starting from 100-200 mg 2 times a day, then gradually increase the dose by no more than 200 mg per day until the pain ceases, on average, up to 600-800 mg, then reduce up to the minimum effective dose. The effect usually occurs 1-3 days after the start of treatment. Assign the drug for a long time; with the premature cancellation of the drug pain can resume. In the treatment of elderly patients, the initial dose should be 100 mg 2 times a day.

Alcohol abstinence syndrome

The average dose is 200 mg 3 times a day. In severe cases, during the first days the dose can be increased (for example, up to 400 mg 3 times a day). At the beginning of treatment for severe manifestations of abstinence it is recommended to appoint in combination with detoxification therapy and sedative-hypnotic drugs.

Non-diabetes mellitus

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

Diabetic neuropathy accompanied by pain

The average dose is 200 mg 2-4 times a day.

For the prevention of affective disorders

In the first week, the daily dose is 200-400 mg (2 tablets). Subsequently, the dose is increased by 200 mg per week, bringing it to 1 g.The daily dose is divided evenly for 3-4 doses. Just as with the use of other antiepileptic drugs, the transition to treatment with carbamazepine-Ferein® should be gradual, with a decrease in the dose of the previous drug. The drug should also be discontinued gradually. The duration of treatment is set individually by the doctor.

Side effects:

Dose-dependent adverse reactions usually occur within a few days, both spontaneously and after a temporary dose reduction. The development of adverse reactions may be due to a relative overdose of the drug or significant fluctuations in the concentration of the active substance in the blood plasma. In such cases it is recommended to monitor the level of active substance in the blood plasma.

From the central nervous system: very often - dizziness, ataxia, drowsiness, general weakness; often - headache, paresis of accommodation; sometimes - abnormal involuntary movements (eg, tremor, "fluttering" tremor - asterixis, dystonia, tics); nystagmus; rarely - orofacial dyskinesia, oculomotor disorders, speech disorders (eg, dysarthria or slurred speech), choreoathetoid disorders, peripheral neuritis, paresthesia, muscle weakness, paresis.The role of carbamazepine as a drug that causes or contributes to the development of malignant neuroleptic syndrome, especially when it is prescribed in conjunction with neuroleptics, remains unclear.

From the psychic sphere: rarely - hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, agitation, disorientation; very rarely - activation of psychosis.

Allergic reactions: often - hives; sometimes - exfoliative dermatitis, erythroderma; rarely - lupus-like syndrome, itching; very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, multiform and erythema nodosum. Rarely, multiorgan hypersensitivity reactions with a fever, skin rashes, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function (these manifestations occur in various combinations). Other organs may also be involved (eg, lungs, kidneys, pancreas, myocardium, large intestine).Very rarely - aseptic meningitis with myoclonus, anaphylactic reaction, angioedema, hypersensitivity reactions on the part of the lungs characterized by fever, dyspnoea, pneumonitis or pneumonia. If the above hypersensitivity reactions occur, the drug should be discontinued.

On the part of the organs of hematopoiesis: very often - leukopenia; often - thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, very rarely - agranulocytosis, aplastic anemia, pure red cell aplasia, megaloblastic anemia, acute intermittent porphyria, reticulocytosis, hemolytic anemia.

From the digestive system): very often - nausea, vomiting, often - dry mouth; sometimes - diarrhea or constipation, abdominal pain; very rarely - glossitis, stomatitis, pancreatitis.

From the side of the liver: very often - increased activity of gamma-glutamyltransferase (due to the induction of this enzyme in the liver), which usually has no clinical significance; often - increased alkaline phosphatase activity; sometimes - increased activity of "liver" transaminases; rarely - hepatitis, cholestatic,parenchymal (hepatocellular) or mixed type, jaundice; very rarely - granulomatous hepatitis, hepatic insufficiency.

From the cardiovascular system: rarely - violations of intracardiac conduction; decrease or increase in blood pressure; very rarely - bradycardia, arrhythmia, atrioventricular blockade with syncope, collapse, aggravation or development of congestive heart failure, exacerbation of coronary heart disease (including the appearance or increase in angina attacks), thrombophlebitis, thromboembolic syndrome.

From the endocrine system and metabolism: often - swelling, fluid retention, weight gain, hyponatremia (decreased plasma osmolarity due to an effect similar to that of an antidiuretic hormone, which in rare cases leads to hyponatremia of the dilution, accompanied by lethargy, vomiting, headache, disorientation and neurologic disorders); very rarely - an increase in the level of prolactin (may be accompanied by galactorrhea and gynecomastia); level reduction L-tiroxine (free T4,T3) and an increase in thyroid-stimulating hormone (usually not accompanied by clinical manifestations); disorders of calcium-phosphorus metabolism in bone tissue (decrease in Ca concentration²⁺ and 25-OH-cholecalciferol in blood plasma); osteomalacia; hypercholesterolemia (including high-density cholesterol and lipoproteins and hypertriglyceridemia.

From the genitourinary system: very rarely - interstitial nephritis, kidney failure, renal dysfunction (eg, albuminuria, hematuria, oliguria, urea / azotemia increase), frequent urination, urinary retention, impaired sexual function / impotence.

From the side of the musculoskeletal system: very rarely - arthralgia, myalgia or convulsions.

From the sense organs: very rarely - a violation of taste, clouding of the lens, conjunctivitis; Hearing impairment, incl. noise in the ears, hyperacusia, hypoacusia, changes in perception of the height of sound.

Other: disorders of skin pigmentation, purpura, acne, sweating, alopecia. There have been reports of rare cases of hirsutism, but the causal relationship between this complication and carbamazepine is not clear.

Overdose:

Symptoms

The symptoms and complaints that occur during an overdose usually reflect violations from the central nervous system, cardiovascular system and respiratory system.

central nervous system: suppression of central nervous system functions, disorientation, drowsiness, agitation, hallucinations, coma, blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (first), hyporeflexia (later), convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

The cardiovascular system: tachycardia, lowering blood pressure, sometimes raising blood pressure, conduction disorders with QRS complex expansion, syncope, cardiac arrest.

From the respiratory system: respiratory depression, pulmonary edema.

Gastrointestinal tract: nausea and vomiting, delayed passage of food from the stomach, decreased motility of the colon.

urinary system: urine retention, oliguria or anuria, fluid retention, hyponatremia of dilution.

Laboratory and instrumental data: leukocytosis or leukopenia, hyponatremia, metabolic acidosis is possible, hyperglycemia and glucosuria are possible, muscle fraction of creatine phosphokinase is increased.

Treatment

There is no specific antidote.Treatment is based on the clinical condition of the patient; (for confirmation of poisoning with this agent and evaluation of the degree of overdose), evacuation of stomach contents, gastric lavage, administration of activated charcoal (late evacuation of gastric contents can lead to delayed absorption on days 2 and 3 and the re-emergence of symptoms of intoxication during the recovery period). Intense diuresis, hemodialysis and peritoneal dialysis are ineffective (dialysis is indicated by a combination of severe poisoning and kidney failure). In young children, there may be a need for exchange blood transfusion. Symptomatic supportive treatment in the intensive care unit, monitoring of heart function, body temperature, corneal reflexes, kidney and bladder function, correction of electrolyte disorders. With a decrease in blood pressure: the position with the lowered head end, plasma substitutes, with inefficiency - intravenously dopamine or dobutamine; with heart rhythm disturbances, individual treatment is selected; with convulsions - the introduction of benzodiazepines (for example, diazepam), with caution (because of the possible increase in respiratory depression), the introduction of other anticonvulsants (eg, phenobarbital). With the development of hyponatremia of dilution (water intoxication) - restriction of the introduction of fluids and slow intravenous infusion of 0.9% sodium chloride solution (may help prevent the development of cerebral edema).

It is recommended to carry out hemosorption on carbon sorbents.

Interaction:

Carbamazepine enhances the activity of microsomal liver enzymes and can reduce the effectiveness of drugs metabolized in the liver. Cytochrome P450 (CYP3A4) is the main enzyme that provides the metabolism of carbamazepine. Simultaneous administration of carbamazepine with inhibitors of CYP3A4 may lead to an increase in its concentration in the blood plasma. Co-administration with CYP3A4 inducers can lead to an acceleration of the metabolism of carbamazepine and a decrease in its concentration in the blood plasma; on the contrary, their removal can reduce the rate of biotransformation of carbamazepine and lead to an increase in its concentration.

Increase the concentration of carbamazepine in plasma: verapamil, diltiazem, felodipine, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, cimetidine, acetazolamide, danazol, desipramine, nicotinamide (in adults, only in high doses); macrolides (erythromycin, josamycin, clarithromycin, troleandomycin); azoles (itraconazole, ketoconazole, fluconazole), terfenadine, loratadine, isoniazid, propoxyphene, grapefruit juice, viral protease inhibitors used in HIV therapy.

Felbamate reduces the concentration of carbamazepine in plasma and increases the concentration of carbamazepine-10,11-epoxide, while a simultaneous decrease in serum felbamate concentration is possible.

The concentration of carbamazepine is reduced phenobarbital, phenytoin, primidon, metsuksimide, fensuksimid, theophylline, rifampicin, cisplatin, doxorubicin, perhaps: clonazepam, valpromid, valproic acid, oxcarbazepine and herbal preparations containing St. John's wort (Hypericum perforatum).

There are reports of the possibility of displacing valproic acid and primidone carbamazepine from plasma protein binding and increasing the concentration of pharmacologically active metabolite (carbamazepine-10,11-epoxide).

Isotretinoin changes the bioavailability and / or clearance of carbamazepine and carbamazepine-10,11-epoxide (carbamazepine concentration in the plasma is monitored).

Carbamazepine can reduce plasma concentrations (reduce or even completely eliminate effects) and require correction of the doses of the following drugs: clobazam, clonazepam, ethosuximide, primidon, valproic acid, alprazolam, glucocorticosteroids (prednisolone, dexamethasone), cyclosporine, doxycycline, haloperidol, methadone, oral preparations containing estrogens and / or progesterone (the choice of alternative methods of contraception), theophylline, oral anticoagulants (warfarin, fenprocumone, dicumarol), lamotrigine, topiramate, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clozapine, felbamate, tiagabine, oxcarbazepine, protease inhibitors HIV infection (indinavir, ritonavir, saquinovir), calcium channel blockers (a group of dihydropyridines, for example, felodipine), itraconazole, levothyroxine, midazolam, olazapine, praziquantel, risperidone, tramadol, and ziprasidone.

It has been reported that in patients receiving carbamazepine phenytoin plasma levels may either rise or fall, and mephenytoin level - increase (in rare cases).

Carbamazepine when combined with paracetamol increases the risk of its toxic effect on the liver and reduces therapeutic effectiveness (acceleration of the metabolism of paracetamol).

The simultaneous appointment of carbamazepine with phenothiazines, pimozide, thioxanthenes, molindone, haloperidol, maprotiline, clozapine and tricyclic antidepressants leads to increased inhibitory action on the central nervous system and weaken the anticonvulsant effect of carbamazepine.

Simultaneous administration with diuretics (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Reduces the effects of nondepolarizing muscle relaxants (pancuronium).

Reduces the tolerance of ethanol.

Accelerates the metabolism of indirect anticoagulants, hormonal contraceptives, folic acid; prazikvantela, can enhance the elimination of thyroid hormones.

Accelerates the metabolism of funds for general anesthesia (enflurane, halothane,ftorotan) with an increased risk of hepatotoxic effects; enhances the formation of nephrotoxic metabolites of methoxyflurane.

Enhances the hepatotoxic effect of isoniazid.

Special instructions:

Monotherapy epilepsy begins with the appointment of small doses, individually increasing them to achieve the desired therapeutic effect. It is advisable to determine the concentration in the plasma in order to select the optimal dose, especially with combination therapy. When transferring a patient to Carbamazepine-Ferein®, the dose of the previously prescribed antiepileptic drug should be gradually reduced until it is completely eliminated.

A sudden discontinuation of the drug may trigger epileptic seizures. If it is necessary to abruptly terminate treatment, it is necessary to transfer the patient to another antiepileptic agent under the cover of the drug shown in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).

There are several cases of vomiting, diarrhea or reduced feeding, seizures and / or respiratory depression in newborns whose mothers were taking carbamazepine concomitantly with other anticonvulsants (perhaps these reactions are manifestations in newborn withdrawal syndrome).

Before the appointment of the drug and during the treatment it is necessary to study the liver function, especially in patients whose history includes information on liver diseases, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or when there is an active liver disease, the drug should be immediately canceled. Also, before the start of treatment, it is necessary to conduct blood sample studies (including platelet count, reticulocyte count), serum iron level, total urine test, urea level in blood, electroencephalogram, determination of serum electrolyte concentration (and periodically during treatment, because possibly the development of hyponatremia). Subsequently, these indicators should be monitored during the first month of treatment on a weekly basis, and then on a monthly basis.

The drug should be immediately withdrawn when hypersensitivity reactions or symptoms, presumably indicative of the development of Stevens-Johnson syndrome or Lyell syndrome, appear.Slightly expressed skin reactions (isolated macular or maculopapular exanthema) usually pass for several days or weeks even after continuing treatment or after reducing the dose of the drug (the patient at this time should be under close medical supervision).

The drug has a weak anticholinergic activity, when appointing patients with increased intraocular pressure, its constant monitoring is necessary. It should take into account the possibility of activation of latent psychoses, and in elderly patients - the possibility of developing disorientation or arousal.

To date, individual reports of male fertility impairment and / or spermatogenesis disorders have been reported (the relationship of these abnormalities to the use of Carbamazepine-Ferein® has not yet been established).

There are reports of women developing bleeding during menstruation in cases when oral contraceptives were used simultaneously. The drug may adversely affect the reliability of oral contraceptives, so women of reproductive age should be treated with alternativemethods of protection from pregnancy.

The drug should be used only under medical supervision. It is necessary to inform patients about the early signs of toxicity inherent in probable hematologic disorders, as well as symptoms from the skin and liver. The patient is informed of the need to consult a doctor immediately if there are undesirable reactions such as fever, sore throat, rash, ulceration of the oral mucosa, unjustified bruising, hemorrhages in the form of petechiae or purpura. In most cases, a transient or persistent decrease in the number of platelets and / or leukocytes is not a harbinger of the onset of aplastic anemia or agranulocytosis.

Nevertheless, before the start of treatment, and also periodically during the treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the level of iron in the blood serum. Non-progressive asymptomatic leukopenia does not require withdrawal, however, treatment should be discontinued if progressive leukopenia or leukopenia occurs, accompanied by clinical symptoms of an infectious disease.Before the beginning of treatment it is recommended to conduct an ophthalmological examination, including examination of the fundus by a slit lamp and measurement of intraocular pressure, if necessary. In the case of prescribing patients with increasing intraocular pressure, a constant monitoring of this indicator is required.

It is recommended to stop drinking alcohol.

Although the relationship between the dose of carbamazepine, its concentration and clinical efficacy or tolerability is very low, nevertheless, regular determination of the level of carbamazepine can be useful in the following situations: with a sharp increase in the frequency of seizures; to check whether the patient is taking the drug properly; during pregnancy; in the treatment of children or adolescents: with suspicion of impaired absorption of the drug; if there is a suspicion of the development of toxic reactions in the event that the patient takes several medicines.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, it is necessary to refrain from engaging in potentially dangerous activities that require increased concentration and speed psychomotor reactions.

Form release / dosage:

Tablets of 200 mg.

Packaging:

For 10 tablets in a planar cell package.

For 50 tablets in a can of orange glass, or in a can of glass for medicines, or in a polymer can, or in a plastic vial.

By 2, 3, 5, 10, 20 contour cell packs together with instructions for medical use in a pack of cardboard.

1 bottle or bottle together with instructions for medical use in a pack of cardboard.

Storage conditions:In dry, protected from light, out of reach of children, at a temperature not exceeding 25⁰ FROM.

Shelf life:

2 years.

After expiration date the drug should not be used.

Terms of leave from pharmacies:On prescription

Registration number:P N002704 / 01

Date of registration:09.10.2008

Expiration Date:Unlimited

The owner of the registration certificate:BRYNTSALOV-A, CJSC BRYNTSALOV-A, CJSC Russia

Manufacturer: & nbsp

BRYNTSALOV-A, CJSC Russia

Information update date: & nbsp09.10.2008

Illustrated instructions

Instructions

Carbamazepine-Ferein® (Carbamazepine-Ferein®)