Apo-Carbamazepine (Tablets) Instructions for Use

Marketing Authorization Holder

Apotex, Inc. (Canada)

ATC Code

N03AF01 (Carbamazepine)

Active Substance

Carbamazepine (Rec.INN registered by WHO)

Dosage Form

Apo-Carbamazepine

Tablets 200 mg: bottle 100 or 500 pcs.

Dosage Form, Packaging, and Composition

100 pcs. – polyethylene bottles.
500 pcs. – polyethylene bottles – polyethylene film (1) – cardboard boxes.
500 pcs. – polyethylene bottles.
500 pcs. – polyethylene bottles – cardboard boxes.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

An antiepileptic agent, a derivative of the tricyclic iminostilbene. It is believed that the anticonvulsant action is associated with a decrease in the ability of neurons to maintain a high frequency of development of repeated action potentials through the inactivation of sodium channels. In addition, 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.

It has a moderate antimanic, antipsychotic effect, as well as an analgesic effect in neurogenic pain. The mechanisms of action may involve GABA receptors, which may be associated with calcium channels; also, the influence of carbamazepine on neuro transmission modulator systems appears to be significant.

The antidiuretic effect of carbamazepine may be associated with a hypothalamic influence on osmoreceptors, which is mediated through the secretion of ADH, and is also due to a direct effect on the renal tubules.

Pharmacokinetics

After oral administration, Carbamazepine is almost completely absorbed from the gastrointestinal tract. Plasma protein binding is 75%. It is an inducer of hepatic enzymes and stimulates its own metabolism.

The T_1/2 is 12-29 hours. 70% is excreted in the urine (as inactive metabolites) and 30% in the feces.

Indications

Epilepsy: grand mal, focal, mixed (including grand mal and focal) epileptic seizures. Pain syndrome predominantly of neurogenic origin, including essential trigeminal neuralgia, trigeminal neuralgia in multiple sclerosis, essential glossopharyngeal neuralgia. Prevention of seizures in alcohol withdrawal syndrome. Affective and schizoaffective psychoses (as a prophylactic agent). Diabetic neuropathy with pain syndrome. Central diabetes insipidus, polyuria and polydipsia of neurohormonal nature.

ICD codes

Dosage Regimen

The dosage is set individually. For oral administration in adults and adolescents 15 years and older, the initial dose is 100-400 mg. If necessary and taking into account the clinical effect, the dose is increased by no more than 200 mg/day at intervals of 1 week. The frequency of administration is 1-4 times/day. The maintenance dose is usually 600-1200 mg/day in several divided doses. The duration of treatment depends on the indications, treatment effectiveness, and the patient’s response to therapy.

In children under 6 years of age, 10-20 mg/kg/day in 2-3 divided doses is used; if necessary and taking into account tolerability, the dose is increased by no more than 100 mg/day at intervals of 1 week; the maintenance dose is usually 250-350 mg/day and does not exceed 400 mg/day. For children aged 6-12 years – 100 mg 2 times/day on the first day, then the dose is increased by 100 mg/day at intervals of 1 week until the optimal effect is obtained; the maintenance dose is usually 400-800 mg/day.

Maximum doses for oral administration in adults and adolescents 15 years and older – 1.2 g/day, in children – 1 g/day.

Adverse Reactions

From the central and peripheral nervous system often – dizziness, ataxia, drowsiness; headache, diplopia, accommodation disturbances are possible; rarely – involuntary movements, nystagmus; in some cases – oculomotor disturbances, dysarthria, peripheral neuritis, paresthesia, muscle weakness, symptoms of paresis, hallucinations, depression, feeling of fatigue, aggressive behavior, agitation, disturbances of consciousness, activation of psychoses, taste disturbances, conjunctivitis, tinnitus, hyperacusis.

From the digestive system nausea, increased GGT, increased ALP activity, vomiting, dry mouth; rarely – increased transaminase activity, jaundice, cholestatic hepatitis, diarrhea or constipation; in some cases – decreased appetite, abdominal pain, glossitis, stomatitis.

From the cardiovascular system rarely – myocardial conduction disturbances, arterial hypertension or hypotension; very rarely – circulatory collapse, thrombophlebitis, thromboembolism (e.g., pulmonary embolism); in some cases – bradycardia, arrhythmias, AV block with syncope, collapse, heart failure, manifestations of coronary insufficiency.

From the hematopoietic system leukopenia, eosinophilia, thrombocytopenia; rarely – leukocytosis; in some cases – agranulocytosis, aplastic anemia, erythrocyte aplasia, megaloblastic anemia, reticulocytosis, hemolytic anemia, granulomatous hepatitis.

From metabolism hyponatremia, fluid retention, edema, weight gain, decreased plasma osmolality; in some cases – acute intermittent porphyria, folic acid deficiency; calcium metabolism disorders, increased levels of cholesterol and triglycerides.

From the endocrine system gynecomastia or galactorrhea; rarely – thyroid function disorders.

From the urinary system rarely – renal function disorders, interstitial nephritis and renal failure.

From the respiratory system in some cases – dyspnea, pneumonitis or pneumonia.

Allergic reactions skin rash, itching; rarely – lymphadenopathy, fever, hepatosplenomegaly, arthralgia.

Contraindications

AV block, previous myelodepression, history of intermittent porphyria, simultaneous use of MAO inhibitors and lithium preparations, hypersensitivity to carbamazepine.

Use in Pregnancy and Lactation

If it is necessary to use during pregnancy (especially in the first trimester) and during lactation, the expected benefit of treatment for the mother and the risk to the fetus or child should be carefully weighed. In this case, Carbamazepine is recommended to be used only as monotherapy in the minimum effective doses.

Women of childbearing age during treatment with carbamazepine are advised to use non-hormonal contraceptives.

Use in Hepatic Impairment

Use with caution in severe liver function impairment.

Use in Renal Impairment

Use with caution in severe renal function impairment.

Pediatric Use

Use with caution in children.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Carbamazepine is not used for atypical or generalized petit mal epileptic seizures, myoclonic or atonic epileptic seizures. It should not be used to relieve ordinary pain; as a prophylactic agent during prolonged periods of remission of trigeminal neuralgia.

Use with caution in concomitant cardiovascular diseases, severe liver and/or kidney function impairment, in diabetes mellitus, increased intraocular pressure, with a history of hematological reactions to the use of other drugs, hyponatremia, urinary retention, hypersensitivity to tricyclic antidepressants, with a history of interruption of carbamazepine treatment, as well as in children and elderly patients.

Treatment should be carried out under medical supervision. During long-term treatment, it is necessary to monitor the blood picture, functional state of the liver and kidneys, plasma electrolyte concentrations, and conduct an ophthalmological examination. Periodic determination of the carbamazepine level in plasma is recommended to monitor the effectiveness and safety of treatment.

Treatment with MAO inhibitors should be discontinued at least 2 weeks before starting therapy with carbamazepine.

Do not consume alcohol during treatment.

Effect on ability to drive vehicles and operate machinery

During treatment, one should refrain from engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

With simultaneous use of inhibitors of the CYP3A4 isoenzyme, an increase in the plasma concentration of carbamazepine is possible.

With simultaneous use of inducers of the CYP3A4 isoenzyme system, acceleration of carbamazepine metabolism, a decrease in its plasma concentration, and a decrease in therapeutic effect are possible.

With simultaneous use, Carbamazepine stimulates the metabolism of anticoagulants and folic acid.

With simultaneous use with valproic acid, a decrease in the concentration of carbamazepine and a significant decrease in the concentration of valproic acid in plasma are possible. At the same time, the concentration of the carbamazepine metabolite – Carbamazepine-epoxide (probably due to inhibition of its conversion to Carbamazepine-10,11-trans-diol), which also has anticonvulsant activity, increases, so the effects of this interaction may be leveled, but adverse reactions more often occur – blurred vision, dizziness, vomiting, weakness, nystagmus. With simultaneous use of valproic acid and carbamazepine, the development of a hepatotoxic effect is possible (apparently due to the formation of a secondary metabolite of valproic acid, which has a hepatotoxic effect).

With simultaneous use, valpromide reduces the hepatic metabolism of carbamazepine and its metabolite carbamazepine-epoxide due to inhibition of the epoxide hydrolase enzyme. The specified metabolite has anticonvulsant activity, but with a significant increase in plasma concentration, it can have a toxic effect.

With simultaneous use with verapamil, diltiazem, isoniazid, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, cimetidine, acetazolamide, danazol, desipramine, nicotinamide (in adults, only in high doses), erythromycin, troleandomycin, josamycin, clarithromycin; with azoles (including itraconazole, ketoconazole, fluconazole), terfenadine, loratadine, an increase in the plasma concentration of carbamazepine with the risk of developing adverse effects (dizziness, drowsiness, ataxia, diplopia) is possible.

With simultaneous use with hexamidine, the anticonvulsant effect of carbamazepine is weakened; with hydrochlorothiazide, furosemide – a decrease in blood sodium content is possible; with hormonal contraceptives – a weakening of the effect of contraceptives and the development of acyclic bleeding is possible.

With simultaneous use with thyroid hormones, an increase in the elimination of thyroid hormones is possible; with clonazepam – an increase in the clearance of clonazepam and a decrease in the clearance of carbamazepine is possible; with lithium preparations – mutual enhancement of neurotoxic action is possible.

With simultaneous use with primidone, a decrease in the plasma concentration of carbamazepine is possible. There are reports that primidone may increase the plasma concentration of the pharmacologically active metabolite – carbamazepine-10,11-epoxide.

With simultaneous use with ritonavir, an increase in the adverse effects of carbamazepine is possible; with sertraline – a decrease in the concentration of sertraline is possible; with theophylline, rifampicin, cisplatin, doxorubicin – a decrease in the plasma concentration of carbamazepine is possible; with tetracycline – a weakening of the effects of carbamazepine is possible.

With simultaneous use with felbamate, a decrease in the plasma concentration of carbamazepine is possible, but an increase in the concentration of the active metabolite carbamazepine-epoxide, while a decrease in the plasma concentration of felbamate is possible.

With simultaneous use with phenytoin, phenobarbital, the plasma concentration of carbamazepine decreases. Mutual weakening of the anticonvulsant action is possible, and in rare cases – its enhancement.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.