Difenin tablets 0.117g, # 20

Epilepsy (large seizures); status epilepticus with tonic-clonic seizures; epileptic seizures in neurosurgery (prevention and treatment).

Ventricular arrhythmias (including with glycoside intoxication or associated with intoxication with tricyclic antidepressants).

Trigeminal neuralgia (as a second-line agent or in combination with carbamazepine).

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

For oral administration for adults, the initial dose is 3-4 mg / kg / day, followed by an increase in the dose until the optimal therapeutic effect is achieved. In most cases, the maintenance dose is 200-500 mg / day in one or more doses.

Children - 5 mg / kg / day in two divided doses, followed by an increase in the dose of no more than 300 mg / day. Maintenance doses are 4-8 mg / kg / day.

For intravenous administration in adults and children, the initial dose is 15-20 mg / kg. Depending on the clinical situation, a single dose may be 50-100 mg / kg. For newborns, the starting dose is also 15-20 mg / kg.

In / m adults can be administered in a single dose of 100-300 mg.

phenytoin * - 117 mg

* a mixture of 5,5-diphenylhydantoin - 100 mg and sodium bicarbonate - 17 mg (in a ratio of 85:15).

Excipients: sodium bicarbonate - 0.032 g, potato starch - 0.0495 g, calcium stearate - 0.0007 g, talc - 0.0008 g.

Morgagni-Adams-Stokes syndrome, AV block II and III degree, sinoatrial block, sinus bradycardia, impaired liver and kidney function, heart failure, cachexia, porphyria, hypersensitivity to phenytoin.

Application during pregnancy and lactation

Phenytoin should not be used during pregnancy, unless the benefits to the mother outweigh the risks to the fetus. There are some data on the formation of tumors (including neuroblastoma), cleft lip and palate in children whose mothers received phenytoin during pregnancy.

Phenytoin is excreted in breast milk in concentrations sufficient to cause side effects in a nursing infant. Therefore, the use of phenytoin during lactation is not recommended.

Clinical and pharmacological group: Anticonvulsant drug

Pharmaco-therapeutic group: Antiepileptic drug

pharmachologic effect

Hydantoin derivative anticonvulsant. It has an anticonvulsant, antiarrhythmic, analgesic, muscle relaxant effect.

It is believed that the anticonvulsant effect is due to the stabilization of the membranes of neurons, axons and synapses, as well as the limitation of the spread of excitation and seizure activity. Like other hydantoin anticonvulsants, phenytoin has an excitatory effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex. This effect can also lead to a decrease in seizure activity, which is associated with increased discharges in the cerebellum.

The antiarrhythmic effect is due to the membrane-stabilizing activity of phenytoin in the cells of Purkinje fibers. Blocks transmembrane sodium current, reduces the permeability of the cell membrane for calcium ions. Abnormal ventricular automatism and membrane excitability are reduced. Phenytoin also shortens the refractory period, expands the QRS complex.

Increases the pain threshold for trigeminal neuralgia and shortens the duration of the attack, reducing agitation and the formation of repeated discharges.

The mechanism of muscle relaxant action, apparently, is similar to the mechanism of anticonvulsant action. Due to membrane stabilizing activity in case of movement disorders, it weakens prolonged repeated discharges and potentiation in nerve and muscle cells.

Hydantoin derivatives induce liver microsomal enzymes, thereby enhancing the metabolism of concurrently used drugs.

Pharmacokinetics

When taken orally, absorption is slow, variability is characteristic depending on the dosage form used. When administered intramuscularly, absorption is also slow, but almost complete - 92%.

Phenytoin penetrates into the cerebrospinal fluid, saliva, semen, gastric and intestinal juice, bile, and is excreted in breast milk. Penetrates through the placental barrier, the concentration in the mother's blood plasma is equal to the concentration in the fetal plasma. Protein binding 90% or more.

It is metabolized in the liver with the participation of isoenzymes CYP2C9, CYP2C19 with the formation of inactive metabolites. It was found that a constant amount of the active substance is metabolized due to saturation of the enzyme system responsible for the metabolism of phenytoin, which occurs when therapeutic concentrations are reached. Therefore, a small increase in dose can lead to a disproportionate increase in plasma concentrations of the active substance and T1 / 2.

Phenytoin is an inducer of isoenzymes CYP1A2, CYP3A4.

T1 / 2 depends on the dose, the concentration of the active substance in the plasma.

It is excreted by the kidneys in the form of metabolites and through the intestines.

Indications

Epilepsy (large seizures); status epilepticus with tonic-clonic seizures; epileptic seizures in neurosurgery (prevention and treatment).

Ventricular arrhythmias (including with glycoside intoxication or associated with intoxication with tricyclic antidepressants).

Trigeminal neuralgia (as a second-line agent or in combination with carbamazepine).

Dosage regimen

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

For oral administration for adults, the initial dose is 3-4 mg / kg / day, followed by an increase in the dose until the optimal therapeutic effect is achieved. In most cases, the maintenance dose is 200-500 mg / day in one or more doses.

Children - 5 mg / kg / day in two divided doses, followed by an increase in the dose of no more than 300 mg / day. Maintenance doses are 4-8 mg / kg / day.

For intravenous administration in adults and children, the initial dose is 15-20 mg / kg. Depending on the clinical situation, a single dose may be 50-100 mg / kg. For newborns, the starting dose is also 15-20 mg / kg.

In / m adults can be administered in a single dose of 100-300 mg.

Side effect

From the side of the central nervous system and peripheral nervous system: possibly - nystagmus, ataxia, confusion, mood changes, muscle weakness, impaired coordination of movements, dizziness, sleep disturbances, blurred speech or stuttering, hand tremors, transient nervousness; rarely, peripheral neuropathy.

From the digestive system: possibly - nausea, vomiting, constipation, toxic hepatitis, liver damage. Gingival hyperplasia can occur during the first 6 months of therapy and begins with gingivitis, more often observed in patients under 23 years of age.

From the hematopoietic system: rarely - thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia, megaloblastic anemia.

From the endocrine system: possibly - hypertrichosis, enlargement of facial features, including thickening of the lips, expansion of the tip of the nose and extension of the lower jaw.

From the side of metabolism: possibly - impaired absorption of glucose due to inhibition of insulin release, impaired metabolism of vitamin D and the development of hypocalcemia.

From the musculoskeletal system: possibly - Dupuytren's contracture; rarely - peripheral polyarthropathy. With prolonged use, the absence of an adequate diet that satisfies the need for vitamin D, or sufficient solar radiation during the treatment period, osteomalacia and rickets may develop.

Allergic reactions: rarely - skin rash, which may be a prodromal sign of more severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), eosinophilia, fever, drug lymphadenopathy.

Others: rarely - Peyronie's disease.

Contraindications for use

Morgagni-Adams-Stokes syndrome, AV block II and III degree, sinoatrial block, sinus bradycardia, impaired liver and kidney function, heart failure, cachexia, porphyria, hypersensitivity to phenytoin.

Application during pregnancy and lactation

Phenytoin should not be used during pregnancy, unless the benefits to the mother outweigh the risks to the fetus. There are some data on the formation of tumors (including neuroblastoma), cleft lip and palate in children whose mothers received phenytoin during pregnancy.

Phenytoin is excreted in breast milk in concentrations sufficient to cause side effects in a nursing infant. Therefore, the use of phenytoin during lactation is not recommended.

Application for violations of liver function

Contraindicated in liver dysfunction.

Application for impaired renal function

Contraindicated in cases of impaired renal function.

Application in children

When using the drug in children during the growth period, the risk of developing side effects from the connective tissue increases.

Use in elderly patients

Phenytoin undergoes intensive metabolism in the liver, therefore, elderly patients require a correction of the dosage regimen.

special instructions

With increased sensitivity to one of the hydantoin anticonvulsants, hypersensitivity to other drugs in this group is possible.

Abrupt cessation of phenytoin treatment in patients with epilepsy may trigger withdrawal.

In patients with epilepsy, if it is necessary to abruptly withdraw phenytoin (for example, with the development of allergic reactions or hypersensitivity reactions), anticonvulsants other than hydantoin derivatives should be used.

Phenytoin undergoes intensive metabolism in the liver, therefore, patients with impaired liver function, as well as elderly people, need to adjust the dosage regimen.

During the period of treatment, especially long-term, a diet that satisfies the need for vitamin D, exposure to UV radiation is recommended.

When using the drug in children during the growth period, the risk of developing side effects from the connective tissue increases.

With acute alcohol intoxication, the concentration of phenytoin in the plasma may increase, with chronic alcoholism it may decrease.

Influence on the ability to drive vehicles and use mechanisms

During the period of treatment, a slowdown in the speed of psychomotor reactions is observed. This must be taken into account by persons engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug interactions

With simultaneous use with drugs that have a depressing effect on the central nervous system, it is possible to increase the inhibitory effect on the central nervous system.

With the simultaneous use of amiodarone, antifungal agents (including amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole), metronidazole, chloramphenicol, chlordiazepoxide, diazepam, dicumarol, histamine H1 blockers, methyloxaphoniate, halothenidine , estrogens, salicylates, succinimides, sulfinpyrazone, sulfonamides, tolbutamide, trazodone, an increase in the concentration of phenytoin in blood plasma is possible, which leads to an increase in its therapeutic effect and increases the risk of side effects.

The therapeutic effect of antifungal agents, clozapine, GCS, dicumarol, digitoxin, doxycycline, furosemide, estrogens, oral contraceptives, quinidine, rifampicin, vitamin D changes with the simultaneous use of phenytoin.

With simultaneous use with phenothiazine derivatives (including chlorpromazine, prochlorperazine, thioridazine), phenobarbital, antineoplastic agents, an increase or decrease in the concentration of phenytoin in blood plasma is possible. The effect of phenytoin on the plasma concentration of phenobarbital is unpredictable.

With simultaneous use with acetazolamide, osteomalacia, rickets are possible.

With simultaneous use with acyclovir, it is possible to reduce the concentration of phenytoin in the blood plasma and reduce its effectiveness.

With the simultaneous use of valproic acid during the first few weeks, the total concentration of phenytoin in blood plasma may decrease due to its displacement from the sites of binding to plasma proteins by sodium valproate, induction of liver microsomal enzymes and acceleration of phenytoin metabolism. Further, there is an inhibition of the metabolism of phenytoin by valproate and, as a result, an increase in the concentration of phenytoin in the blood plasma. Phenytoin reduces the concentration of valproate in the blood plasma, probably by increasing its metabolism in the liver. It is believed that phenytoin, as an inducer of hepatic enzymes, also increases the formation of a secondary, but hepatotoxic metabolite, valproic acid.

With simultaneous use, plasma concentrations of verapamil, nimodipine, felodipine decrease.

A case of an increase in the concentration of phenytoin in blood plasma and the development of toxic effects while being used with gabapentin is described.

With simultaneous use, it is possible to reduce the concentration of desipramine in the blood plasma.

With simultaneous use with diltiazem, nifedipine, an increase in the concentration of phenytoin in the blood plasma and the risk of developing a toxic effect may occur.

With simultaneous use with disulfiram, it is possible to increase the concentration of phenytoin in the blood plasma with the development of toxic reactions; with imipramine, clarithromycin - an increase in the concentration of phenytoin in the blood plasma is possible.

With simultaneous use with carbamazepine, folic acid, reserpine, sucralfate, vigabatrin, a decrease in the concentration of phenytoin in blood plasma and a decrease in its therapeutic effect is possible.

In patients receiving phenytoin, the effectiveness of paracetamol may decrease.

When taking pyridoxine at a dose of 200 mg / day, it is possible to reduce the concentration of phenytoin in the blood plasma.

With simultaneous use with ritonavir, there are reports of an increase in the concentration of phenytoin in the blood plasma. It is believed that interaction is possible, but its nature has not been definitively established.

With simultaneous use with sucralfate, the absorption of phenytoin decreases.

With simultaneous use with theophylline, it is possible to reduce the plasma concentrations of phenytoin and theophylline and reduce their effectiveness.

With simultaneous use with felbamate, an increase in the concentration of phenytoin in blood plasma is possible.

With simultaneous use with phenylbutazone, cases of an increase in the concentration of phenytoin in blood plasma with the development of toxic reactions have been described.

In the treatment of folate deficiency, the use of folic acid preparations reduces the effectiveness of phenytoin.

With simultaneous use with cimetidine, the concentration of phenytoin in the blood plasma increases, there is a risk of developing a toxic effect.

With simultaneous use with ciprofloxacin, it is possible to decrease or increase the concentration of phenytoin in blood plasma. The interaction is ambiguous.