Mezacar

Mezacar is an anticonvulsant drug.

Indications Mezacara

It is used in the following conditions:

• epilepsy;
• partial seizures of a simple or complex nature (with or without accompanying loss of consciousness; with or without the development of generalization symptoms of a secondary nature);
• convulsions of a mixed nature;
• tonic-clonic seizures (generalized form);
• manic behavior of an acute nature;
• alcohol withdrawal;
• BAR (as a supportive agent) – to reduce the severity of clinical symptoms during exacerbations, and also to prevent them;
• neuralgia affecting the trigeminal nerve (idiopathic in nature), and at the same time neuralgia in the area of the trigeminal nerve, developing against the background of sclerosis, which has a disseminated nature;
• neuralgia affecting the nerve located in the glossopharyngeal region (idiopathic form).

Release form

The pharmaceutical product is released in tablets - 10 pieces inside a cell plate. There are 5 such plates in a pack.

Pharmacodynamics

It has antimanic and normothymic (mood stabilizing) activity.

The active element activates the slowing GABAergic brain system. At the same time, it blocks the activity of potential-dependent Na channels (inside the membranes of nerve cells), due to which their work is stabilized. In addition, it weakens the action of neurotransmitter acids (glutamate with aspartate) and interacts with adenosine endings inside the brain.

Increases the seizure threshold and also corrects personality changes associated with epilepsy.

Pharmacokinetics

Absorption.

Orally administered carbamazepine is absorbed almost completely, although not at a very high rate. With a single use of the drug, plasma Cmax values are recorded after 12 hours. There are no clinically significant differences in the level of absorption of the drug when using its different oral forms. With a single oral administration of a 0.4 g tablet of carbamazepine, the average Cmax of the unchanged active ingredient is approximately 4.5 mcg / ml.

Food intake has no significant effect on the extent and rate of absorption of carbamazepine.

Equilibrium plasma parameters of the drug are observed after 7-14 days, taking into account the individual characteristics of metabolic processes (carbamazepine autoinduction of liver enzyme systems or heteroinduction by other medications used in combination), as well as the patient's condition, duration of therapy and dosage.

Significant interpersonal differences in equilibrium values are noted in the drug spectrum: in many patients they vary within the range of 4-12 μg/ml (range 17-50 μmol/l). The level of carbamazepine 10,11-epoxide (a medicinally active metabolic product) reaches almost 30% in comparison with the values of carbamazepine.

Distribution processes.

After complete absorption of the therapeutic component, the apparent distribution volume is within the range of 0.8-1.9 l/kg.

The substance can cross the placenta. Its synthesis with intraplasmic blood protein is 70-80%. The level of the unchanged element in saliva with cerebrospinal fluid is proportional to the portion of the active component not synthesized with proteins (20-30%).

Carbamazepine levels in breast milk are 25-60% of those in blood plasma.

Exchange processes.

Carbamazepine metabolism processes occur inside the liver, mainly via the epoxide pathway. The main metabolic products are formed – 10,11-transdiol derivative, and also its conjugate with glucuronic acid.

The main isoenzyme that converts the active element of the drug into carbamazepine 10,11-epoxide is the hemoprotein of the P450 3A4 subtype. During such exchange reactions, a “small” metabolic element is also formed – 9-hydroxy-methyl-10-carbamoyl acridan.

With a single oral use, approximately 30% of the active component is recorded in the urine (end epoxide metabolic products). Other important pathways for the transformation of carbamazepine are the cause of the formation of various monohydroxylate derivatives, and along with this, carbamazepine N-glucuronide, which is formed with the help of the UGT2B7 component.

Excretion.

After a single oral administration of the drug, the half-life of the unchanged element is on average 36 hours, and with repeated administration, the average figure is 16-24 hours (after autoinduction of the liver monooxygenase system), taking into account the duration of the therapeutic cycle.

In individuals also using other drugs that induce a similar liver enzyme system (for example, phenobarbital or phenytoin), the half-life of the substance is on average 9-10 hours.

The plasma half-life of the metabolic product 10,11-epoxide is approximately 6 hours (with a single dose of epoxide).

After a single use of carbamazepine in a 0.4 g dose, 72% of the component is excreted in the urine and 28% in the feces. About 2% of the dosage leaves the body through the urine unchanged and about 1% in the form of the therapeutically active metabolic element 10,11-epoxide.

Dosing and administration

The drug is taken orally, without reference to food intake. The selected daily dose should be divided into 2-3 uses. Dosage sizes are determined taking into account the diagnosis.

Standard adult serving sizes: 0.1-0.2 g 1-2 times per day; the dosage should be increased slowly until the desired result is achieved. Thus, the patient can take 0.8-2 g of the substance per day.

Standard dosage sizes for children: 0.1 g per day; the portion is gradually increased weekly (by 0.1 g). The usual portion is 10-20 mg/kg per day (in several doses).

[ 1 ]

Use Mezacara during pregnancy

Mezacar should not be prescribed if a woman is pregnant or breastfeeding.

Contraindications

Main contraindications:

• severe intolerance associated with medicinal elements;
• history of allergy to tricyclics;
• AV block;
• suppression of bone marrow activity;
• hepatic type of porphyria (this can be mixed, acute intermittent or late epidermal subtype), as well as its presence in the anamnesis;
• use of MAOI drugs.

Side effects Mezacara

Side effects include:

• changes in test results: lymphadenopathy, reticulocytosis, leukopenia, pancyto- or thrombocytopenia, agranulocytosis with leukocytosis and eosinophilia, as well as aplastic, hemolytic or megaloblastic anemia, porphyria, erythrocyte aplasia and vitamin B9 deficiency;
• immune disorders: intolerance of a delayed nature, epidermal rash, lymphadenopathy or vasculitis, and in addition hepatosplenomegaly, aseptic type of meningitis, which is supplemented by the development of myoclonus or eosinophilia of a peripheral nature, and the syndrome of disappearance of the bile ducts. Anaphylaxis, Quincke's edema or hypogammaglobulinemia may also be observed;
• endocrine disorders: weight gain, hyponatremia, edema, decreased plasma osmolarity, hyperhydria (vomiting, confusion, lethargy and headaches) and increased prolactin levels (gynecomastia, galactorrhea and bone metabolism disorders);
• metabolic disorders: folate deficiency and loss of appetite;
• mental health problems: feelings of agitation, anxiety, confusion or aggression, hallucinations, activation of psychosis and depression;
• neurological signs: ataxia, dizziness, drowsiness, cephalalgia and diplopia, as well as blurred vision and involuntary movements (dystonia, tremor (sometimes fluttering) and tics). In addition, orofacial dyskinesia, polyneuropathy, dysarthria and nystagmus, choreoathetosis, eye movement disorders, slurred speech, taste disorders, paresthesia, muscle weakness, aseptic meningitis and paresis;
• visual impairment: glaucoma, conjunctivitis, accommodation disorder and clouding of the lens of the eye;
• hearing problems: tinnitus, hearing impairment and increased or decreased hearing sensitivity;
• cardiovascular problems: conduction disorders within the heart, congestive heart failure, high or low blood pressure, syncope and thromboembolism, as well as bradycardia, exacerbation of coronary heart disease, thrombophlebitis, arrhythmia and circulatory collapse;
• respiratory disorders: pneumonitis, dyspnea or pneumonia;
• digestive disorders: constipation or diarrhea, nausea, glossitis, dry mouth, abdominal pain and stomatitis. In addition, pancreatitis, hepatitis, liver failure, increased GGT, transaminases and alkaline phosphatase, jaundice, bile duct disappearance syndrome, as well as granulomatous hepatitis;
• Epidermal lesions: erythroderma, SLE, pruritus, dermatitis of allergic origin, SJS, urticaria, photosensitivity and epidermal necrolysis. In addition, erythema multiforme or nodular, acne and purpura, hirsutism, severe alopecia, hyperhidrosis and skin pigmentation disorder;
• musculoskeletal disorders: arthralgia, muscle weakness and muscle spasms;
• urogenital problems: tubulointerstitial nephritis, urinary retention, impotence, renal failure, spermatogenesis disorders, renal dysfunction (albuminuria with hematuria, azotemia or oliguria) and increased frequency of urination;
• systemic disorders: feeling of weakness.

Overdose

Signs of poisoning: feeling of intense drowsiness, agitation or disorientation, decreased consciousness, blurred vision, nystagmus, ataxia and hallucinations. In addition, slurred speech, coma, hypo- or hyperreflexia, dysarthria, seizures and dyskinesia, as well as mydriasis, psychomotor disorders, hypothermia, myoclonus and pulmonary edema. Along with this, respiratory depression, cardiac arrest, cardiac conduction disorder, tachycardia, fainting, decreased or increased blood pressure, hyperhydria and rhabdomyolysis are possible. Metabolic acidosis, food retention in the stomach, anuria or oliguria, fluid or urine retention, increased CPK (muscle fraction) values, hyperglycemia or hyponatremia may be observed.

People with such disorders should be hospitalized, undergo gastric lavage, prescribed sorbents, and given supportive measures. It is also necessary to determine blood levels of carbamazepine, monitor cardiac function, and correct electrolyte imbalances.

Interactions with other drugs

Medicines that have the ability to increase carbamazepine levels in blood plasma.

Because negative symptoms may develop with an increase in the above-mentioned parameters (for example, a feeling of drowsiness, and also diplopia, severe dizziness or ataxia), the dose of Mezakar should be changed or its plasma values should be monitored when combined with similar substances. Among these medications:

• anti-inflammatory and pain-relieving drugs: ibuprofen or dextropropoxyphene;
• androgens: substance danazol;
• antibiotics: macrolides (for example, josamycin with erythromycin, ciprofloxacin and troleandomycin with clarithromycin);
• antidepressants: fluoxetine, viloxazine, desipramine with trazodone, nefazodone with fluvoxamine and paroxetine;
• anticonvulsants: vigabatrin and stiripentol;
• Antifungals: azoles (eg, ketoconazole with itraconazole and voriconazole with fluconazole). Alternative anticonvulsants may be prescribed for people using itraconazole or voriconazole;
• antihistamines: terfenadine or loratadine;
• antipsychotics: loxapine with olanzapine and quetiapine;
• anti-tuberculosis drugs: isoniazid;
• agents that inhibit carbonic anhydrase activity: component acetazolamide;
• antiviral drugs: substances that inhibit HIV protease (for example, ritonavir);
• medications for the treatment of cardiovascular diseases: verapamil with diltiazem;
• drugs used for gastrointestinal diseases: omeprazole or cimetidine;
• muscle relaxants: dantrolene with oxybutynin;
• antiplatelet drugs: ticlopidine;
• other means: this includes grapefruit juice, as well as nicotinamide (for adults and only in large portions).

Substances that have the ability to increase intraplasmic levels of the active carbamazepine metabolic product – 10,11-epoxide.

Among such medications are progabide, loxapine, valpromide with quetiapine, and also valproic acid with primidone and valnoctamide. The dosage portion of the drug when used simultaneously with these substances should be adjusted (or its plasma values should be monitored).

Medicines that reduce intraplasmic carbamazepine levels.

A change in the dosage of the medication may be necessary when combined with the following substances:

• anticonvulsants: methsuximide, phensuximide and felbamate with phenobarbital and oxcarbazepine, as well as phenytoin (to prevent poisoning with phenytoin and subdrug values of carbamazepine, it is necessary to change the plasma level of the former to 13 mcg/ml before starting to use the latter), primidone with fosphenytoin and clonazepam (there is conflicting information regarding it);
• antitumor drugs: doxorubicin or cisplatin;
• anti-tuberculosis drugs: rifampicin;
• anti-asthmatic drugs or bronchodilators: aminophylline or theophylline;
• dermatological agents: isotretinoin.

Interaction with other drugs.

Mefloquine can lead to the development of an antagonistic effect relative to the anticonvulsant action of Mezacar, therefore the dosage of the latter must be changed accordingly.

Isotrenoine is known to alter the bioavailability or clearance of carbamazepine with its metabolic product, which is why plasma levels of carbamazepine need to be monitored during therapy.

The effect of the drug on the plasma levels of substances combined with it.

Carbamazepine can reduce plasma levels of certain drugs, as well as weaken or neutralize their therapeutic activity. Taking into account clinical data, it may be necessary to change the dosage of the following medications:

• anti-inflammatory or analgesic substances: methadone with buprenorphine and paracetamol (long-term administration of carbamazepine together with paracetamol (or acetaminophen) can provoke the development of hepatotoxicity), and also tramadol with phenazone (antipyrine);
• antibiotics: among these substances are rifabutin or doxycycline;
• Oral anticoagulants: for example, phenprocoumon, acenocoumarol with warfarin, and dicoumarol;
• antidepressants: these include nefazodone with bupropion, trazodone with sertraline, citalopram, and tricyclics (eg, amitriptyline with imipramine, clomipramine, and nortriptyline);
• antiemetic drug: aperpitant;
• anticonvulsants: clonazepam, tiagabine, clobazam with felbamate, valproic acid, ethosuccimide with primidone, as well as lamotrigine, zonisamide, oxcarbazepine and topiramate. There is information about both an increase in plasma phenytoin values under the influence of carbamazepine and their decrease, as well as (single) an increase in plasma mephenytoin values;
• antifungals: voriconazole with itraconazole and ketoconazole. People who use itraconazole or voriconazole should use alternative anticonvulsants;
• anthelmintic agents: albendazole or praziquantel;
• antitumor drugs: cyclophosphamide with imatinib, as well as temsirolimus and lapatinib;
• neuroleptics: haloperidol with aripiprazole, clozapine with risperidone, as well as bromperidol with ziprasidone and olanzapine, as well as quetiapine and paliperidone;
• antiviral drugs: medications that slow down the activity of HIV protease (for example, saquinavir with indinavir and ritonavir);
• anxiolytics: midazolam with alprazolam;
• antiasthmatic agents and bronchodilators: theophylline;
• contraceptives: hormonal contraception (it is necessary to consider the option of selecting alternative contraceptives);
• substances for the treatment of cardiovascular diseases: Ca channel blockers (dihydropyridine category), including digoxin with lovastatin, felodipine, simvastatin, cerivastatin with quinidine, as well as ivabradine with propranolol and atorvastatin;
• corticosteroids: dexamethasone or prednisolone;
• substances used for impotence: tadalafil;
• immunosuppressants: tacrolimus with cyclosporine and sirolimus with everolimus;
• thyroid drugs: levothyroxine;
• other substances: drugs containing progesterone or estrogen (it is necessary to select an alternative contraception), sertraline with buprenorphine, mianserin and gestrinone, as well as toramiphene with tibolone.

Combinations of drugs that require separate study.

The combination of the drug with levetiracetam may cause potentiation of Mezacar toxicity.

The combination of drugs with isoniazid may provoke potentiation of the latter's hepatotoxicity.

Administration together with lithium agents or metoclopramide, as well as with neuroleptics (thioridazine or haloperidol) can cause potentiation of negative neurological signs (with the latter combination – even in the case of therapeutic plasma parameters).

The use of the drug together with certain diuretics (furosemide or hydrochlorothiazide) may cause symptomatic hyponatremia.

Carbamazepine can act as an antagonist of non-depolarizing muscle relaxants (e.g. pancuronium). In this case, one can expect the need to increase the doses of these drugs, and patients should be closely monitored to prevent neuromuscular blockade.

Like other psychotropic drugs, carbamazepine can reduce tolerance to alcoholic beverages, which is why patients should refrain from drinking them during therapy.

Prohibited combinations.

Because the structure of carbamazepine is close to tricyclics, the drug cannot be combined with MAOIs. The latter must be discontinued at least 14 days before starting to use Mezacar.

Effect of drug on serologic test data.

Carbamazepine may produce a false positive reaction in the UPPER assay used to determine perphenazine levels.

Carbamazepine together with 10,11-epoxide may give false-positive results in polarized fluorescence immunoassays used to determine tricyclic activity.

[ 2 ]

Storage conditions

Mezakar must be stored at temperatures in the range of 15-25°C.

Shelf life

Mezakar can be used for a period of 24 months from the date of manufacture of the medicinal substance.

Application for children

Children have a more pronounced elimination of carbamazepine, which is why they may require larger doses of the drug (in terms of kilograms of weight). Tablets can be prescribed to children over 5 years of age.

Analogues

Analogues of the drug are Finlepsin, Zeptol with Tegretol, Carbalex with Carbapine, and also Carbamazepine and Timonil.