Carbamazepine-ALSI, tablets 200 mg 40 pcs

Carbamazepine is a dibenzoazepine derivative and has antiepileptic, neurotropic, psychotropic and antidiuretic effects.

As an antiepileptic, it stabilizes the membranes of overexcited neurons, suppresses serial discharges of neurons and reduces synaptic transmission of excitatory impulses.

This action is presumably achieved through blockade of sodium channels, which prevents the reappearance of sodium-dependent action potentials in depolarized neurons. Reduces the release of the neurotransmitter glutamate.

The psychotropic effects of carbamazepine appear to be due to inhibition of dopamine and noradrenaline metabolism.

It reduces seizure frequency, anxiety, depression, irritability and aggressiveness in patients with epilepsy. Effects on cognitive function in patients with epilepsy are variable.

Prevent the appearance of paroxysmal pain in neuralgia. In alcohol withdrawal syndrome increases the threshold of seizure readiness, reduces increased nervous excitability, tremor, gait disturbances.

It is used for the treatment of affective disorders as an antipsychotic and normothetic agent. In non-sugar diabetes it reduces diuresis and feeling of thirst.

Indications

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

– generalized tonic-clonic seizures. Mixed forms of epileptic seizures.

Active ingredient

Composition

One tablet contains:

the active ingredient:

carbamazepine 200 mg;

auxiliary substances:

potato starch – 80.5 mg,

colloidal silica (aerosil) – 16.4 mg,

talc – 3.1 mg,

Interaction

Concomitant use with CYP3A4 isoenzyme inhibitors may lead to increased plasma concentrations of carbamazepine. Concomitant use of CYP3A4 isoenzyme inducers may lead to accelerated metabolism of carbamazepine and possible decrease in its plasma concentration. Cancellation of concomitant use of CYP3A4 isoenzyme inducers may reduce the rate of biotransformation of carbamazepine and lead to increased plasma levels of carbamazepine. In concomitant use with drugs metabolized by CYP3A4 isoenzyme, induction of metabolism and reduction of their plasma concentrations are possible.

Drugs that may increase the plasma concentration of carbamazepine or carbamazepine-10,11-epoxide:

dextropropoxyphene, ibuprofen, danazol, macrolide antibiotics (e.g., erythromycin, troleandomycin, jozamycin, clarithromycin), fluoxetine, fluvoxamine nefazodone, paroxetine, trazodone, viloxazine, stiripentol, vigabatrin, azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole), loratadine, terfenadine loxapine, olanzapine, quetiapine, isoniazid, viral protease inhibitors for HIV therapy (e.g., ritonavir), acetazolamide, verapamil, diltiazem, omeprazole, oxybutynin, dantrolene, ticlopidine, nicotinamide (in adults, high dose only), possibly cimetidine, desipramine, primidone, valproic acid.

Drugs that may decrease the plasma concentration of carbamazepine:

Felbamate, metsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin, fosphenytoin, primidone, progabide, theophylline, aminophylline, isotretinoin, rifampicin, cisplatin, doxorubicin; herbal preparations containing St. John’s wort and, although data are conflicting, possibly also clonazepam, valproic acid, or valpromide.

The effect of carbamazepine on plasma concentrations of concomitant drugs:

Carbamazepine may reduce plasma concentrations or reduce or even completely negate the effects of the following drugs: methadone, paracetamol, antipyrine, tramadol, doxycycline, oral anticoagulants (warfarin, phenprocoumon, dicoumarol, acenocoumarol), bupropion, citalopram, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clobazam, clonazepam, etoximide, felbamate lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide, itraconazole, praziquantel, imatinib, clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, used in the treatment of HIV infection (indinavir, ritonavir, saquinavir), alprazolam; midazolam, theophylline, dihydropyridine calcium channel blockers (e.g., felodipine), digoxin, oral contraceptives (alternative methods of contraception should be selected), glucocorticosteroids (e.g., prednisolone, dexamethasone); cyclosporine, everolimus, sodium levothyroxine, estrogens and/or progesterone. There are reports that plasma levels of phenytoin may both increase and decrease with carbamazepine administration, and plasma levels of mefenitoin may increase (in rare cases).

Combinations to consider:

Isoniazid-induced hepatotoxicity may be increased when used concomitantly with carbamazepine.

In case of co-administration with levetiracetam, the toxic effects of carbamazepine may be increased.

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

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

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

The co-administration with grapefruit juice may increase plasma levels of carbamazepine.

Directions for use

Orally, regardless of meals with small amounts of liquid.

Epilepsy: If possible, carbamazepine should be prescribed as monotherapy. Treatment begins with a small daily dose, which is then slowly increased until optimal effect is achieved. Carbamazepine should be added to existing antiepileptic therapy gradually.

For adults, the starting dose is 100-200 mg once or twice daily. Then the dose is slowly increased to 400 mg 2-3 times a day. The maximum daily dose is 2000 mg.

In children under 5 years of age, the starting dose is 20-60 mg per day with an increase of 20-60 mg every other day. In children from 5 years of age, the starting dose is 100 mg/day, with subsequent increases of 100 mg per week. The maintenance dose for children is 10-20 mg/kg body weight per day in 2-3 doses. To ensure accurate dosing, in children under 5 years of age, liquid oral dosage forms of carbamazepine should be used.

The neuralgia of the trigeminal or pharyngeal nerves: the initial dose is 200-400 mg/day, then the dose is gradually increased by no more than 200 mg per day until the pain stops (on average, to 600 to 800 mg), then reduced to the minimum effective dose. When treating elderly patients, the starting dose is 100 mg twice a day.

Alcohol withdrawal syndrome: the average dose is 200 mg 3 times a day. In severe cases, in the first days, the dose may be increased to 400 mg 3 times a day. At the beginning of treatment in severe withdrawal phenomena it is prescribed in combination with detoxification therapy, sedatives and hypnotics.

Polyuria and polydipsia in nonsanguineous diabetes: the average dose for adults is 200 mg 2 to 3 times a day. In children, the dose is adjusted for body weight and age.

Pain syndrome in diabetic neuropathy: 200 mg 2 to 4 times a day.

Acute manic states and maintenance therapy of bipolar affective disorder: daily dose 400-1600 mg (average daily dose 200-600 mg) in 2-3 doses per day. In acute cases, the dose is increased rather quickly. In maintenance therapy, the dose increase should be gradual and small.

Special Instructions

Before starting treatment, as well as periodically during treatment, clinical blood tests (including platelet count, reticulocyte count, and serum iron concentration), general urine tests and determination of blood urea level should be performed. The drug has weak anticholinergic activity. Therefore, in case of using the drug in patients with elevated intraocular pressure it is necessary to continuously monitor this parameter.

Periodic determination of plasma concentration of carbamazepine is recommended in cases of increased frequency of epileptic seizures, when treating children, in pregnant women, in case of its use as part of complex therapy, development of pronounced side effects.

There have been isolated reports of male fertility and/or spermatogenesis disorders. However, the causal relationship of these disorders with taking the drug has not been proven to date.

Cross reactions of hypersensitivity may occur between carbamazepine and phenytoin or oxcarbazepine.

At the time of treatment it is necessary to refrain from potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

At the time of therapy it is necessary to refrain from drinking alcohol, because carbamazepine increases the inhibitory effect of alcohol on the central nervous system.

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Synopsis

Features

Absorption is slow but fairly complete (food intake does not significantly affect the rate and extent of absorption). After a single dose, the maximum concentration in plasma is reached after 12 hours. Equilibrium concentrations of the drug in plasma are reached after 1-2 weeks.

A significant individual differences of the value of equilibrium concentrations in the therapeutic range are observed among patients. The binding to blood plasma proteins is 70 – 80%. Concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the amount of active substance unbound to proteins (20 – 30%). Concentration in breast milk is 25-60% of that in plasma. It penetrates through the placental barrier.

It is metabolized in liver mainly by epoxide way with forming of metabolites: active – carbamazepine-10,11-epoxide and inactive – 9-hydroxy-methyl-10 carbamoylacridan. The main isoenzyme providing biotransformation of carbamazepine to carbamazepine-10,11-epoxide is a cytochrome P450 3A4 isoenzyme. The content of carbamazepine-10,11-epoxide is about 30% of the level of carbamazepine in plasma. Biotransformation of carbamazepine-10,11-epoxide to carbamazepine-10,11-transdiol occurs by the microsomal enzyme epoxide hydrolase.

The other pathway of carbamazepine metabolism is the formation of various monohydroxylated derivatives as well as N-glucuronides. The elimination half-life after a single dose is on average about 36 hours (varies from 25 to 65 hours), after repeated administration – 16-24 hours. In patients receiving in addition other antiepileptic drugs inducing liver enzymes, on average 9-10 hours.

Extracted mainly as inactive metabolites in the urine (about 70%) and feces (about 30%). About 2% is excreted in the urine as unchanged carbamazepine and 1% as carbamazepine-10,11-epoxide.

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

There is no evidence that the pharmacokinetics of carbamazepine changes in elderly patients. There are no data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function.

Contraindications

With caution use in: low white blood cell or platelet levels; mixed forms of epileptic seizures including absences; elderly; cardiac, hepatic or renal failure; elevated intraocular pressure; dilution hyponatremia; hypothyroidism; prostatic hyperplasia; pregnancy (increased risk of intrauterine disorders, including malformations).

Side effects

Nervous system disorders: dizziness, ataxia, somnolence, fatigue, headache, diplopia, accommodation disorders, tremor, muscle dystonia, tics, nystagmus, orofacial dyskinesia, eye movement disorders, dysarthria, choreoathetoid disorders, peripheral neuropathy, paresthesias, paresis, taste disorders, malignant neuroleptic syndrome.

Psychiatric disorders: hallucinations (visual or auditory), depression, anorexia, anxiety, aggressive behavior, agitation, disorientation, increased psychosis.

Skin and its appendages: allergic dermatitis, urticaria, exfoliative dermatitis, erythroderma, systemic lupus erythematosus, itching, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitization reactions, erythema multiforme and nodularis, skin pigmentation disorders, purpura, acne, sweating, hair loss. Rare cases of hirsutism have been reported, but the causal relationship of this complication to the drug remains unclear.

Hematopoietic system disorders: Leukopenia, thrombocytopenia, eosinophilia, leukocytosis, lymphoadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, pancytopenia, anemia, true red cell aplasia, megaloblastic anemia, variegate porphyria, late cutaneous porphyria, acute intermittent porphyria, reticulocytosis, hemolytic anemia.

Hepatobiliary system disorders: increased values of gamma-glutamantransferase, alkaline phosphatase, transaminases; hepatitis (cholestatic, parenchymatous (hepatocellular) or mixed type), jaundice, granulomatous hepatitis, liver failure.

Gastrointestinal tract: nausea, vomiting, dry mouth, diarrhea, constipation, abdominal pain, glossitis, stomatitis, pancreatitis.

High sensitivity reactions: delayed-type multiorgan hypersensitivity with fever, skin rash, vasculitis, lymphoadenopathy, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function indices (the above manifestations occur in various combinations). Other organs (lungs, kidneys, pancreas, myocardium, colon) may also be involved. Aseptic meningitis with myoclonus and eosinophilia; anaphylactic reaction, angioedema.

Cardiovascular system disorders: intracardiac conduction disorders; decreased or increased blood pressure, bradycardia, arrhythmia, atrioventricular block with fainting, collapse, congestive heart failure, worsening of coronary heart disease, thrombophlebitis, thromboembolism.

Endocrine system and metabolic disorders: edema, fluid retention, increased body weight, hyponatremia and decreased plasma osmolarity due to an effect similar to that of antidiuretic hormone, which in rare cases leads to water intoxication (dilution hyponatremia), accompanied by lethargy, vomiting, headache, disorientation and neurological disorders; increased prolactin levels, accompanied or not accompanied by galactorea, gynecomastia decreased concentration of triiodothyronine and thyroxine, increased concentration of thyroid hormone, which is usually not accompanied by clinical manifestations; disorders of bone tissue metabolism (decrease of plasma concentration of calcium and 25-hydroxycalciferol), which leads to osteomalacia; increased concentration of cholesterol, including high-density lipoprotein cholesterol and triglycerides.

Urogenital system disorders: interstitial nephritis, renal failure, albuminuria, hematuria, oliguria, azotemia, frequent urination, urinary retention, disorders of sexual function, disorders of spermatogenesis.

Senses: taste disorders, blurred lens, increased intraocular pressure, conjunctivitis; hearing disorders.

Muscular system disorders: arthralgia, muscle pain, muscle weakness, cramps.

Respiratory system: hypersensitivity reactions characterized by fever, shortness of breath, pneumonitis or pneumonia.

Change in the results of laboratory tests: hypogammaglobulinemia.

Overdose

Symptoms

Central nervous system: depression of central nervous system functions up to coma, disorientation, somnolence, agitation, hallucinations, feeling of “fog” before eyes, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia changing to hyporeflexia, seizures, psychomotor disorders, myoclonus, hypothermia, mydriasis;

– respiratory system: respiratory depression, pulmonary edema;

– cardiovascular system: tachycardia, decreased or increased blood pressure, cardiac conduction disorder with enlarged QRS complex, cardiac arrest;

– digestive system: vomiting, delayed evacuation of food from the stomach, decreased motility of the colon;

– urinary system: urinary retention, oliguria or anuria, fluid retention, dilution hyponatremia;

-laboratory parameters: metabolic acidosis, hyperglycemia, increased muscle fraction of creatine phosphokinase, hyponatremia.

Treatment: there is no specific antidote. Gastric lavage, administration of activated charcoal (late evacuation of gastric contents may lead to delayed absorption for 2-3 days and reappearance of intoxication symptoms), hospitalization, symptomatic therapy. Forced diuresis, hemodialysis and peritoneal dialysis are ineffective (dialysis is indicated in combination of severe poisoning and renal failure). Hemosorption on carbon sorbents is recommended.

Similarities