Diphenin - instructions for use, dose, side effects, contraindications

Active substancePhenytoinPhenytoin

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Diphenine

pills inwards

LUHANSKY HFZ, OJSC Ukraine

Diphenine

pills inwards

UZOLE-SIBERIAN CHEMICAL PLANT, OJSC Russia

Dosage form: & nbspTabletki.

Composition:

Active substance: phenytoin (diphenine) -0.117 g (a mixture of 5,5-diphenylhydantoin-0.1 g and sodium bicarbonate-0.017 g in a ratio of 85:15);

Excipients: Mr.atria hydrogencarbonate - 0.0320 g, potato starch - 0.0495 g, calcium stearate - 0.0007 g, talc - 0.0008 g.

Description:

Round, flat-cylindrical tablets of white or almost white color, with a bevel.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.B.02 Phenytoin

Pharmacodynamics:

Phenytoin is an antiepileptic drug from the hydantoin derivative group.

The mechanism of anticonvulsant action of phenytoin is not fully established. It is believed that the specific effect of phenytoin is realized in epilepsy by reducing the excitability of neuronal epileptic focus and the effect on the neurotransmitters. Phenytoin affects the active and passive transport of sodium and calcium ions through cellular and subcellular membranes of nerve cells. Reduces the level of sodium in the neuron, reduces its intake, blocking Na⁺/TO⁺-ATPase of the brain and facilitates the active transport of sodium from the cell, thereby preventing the generation and propagation of high-frequency discharges. Phenytoin changes calcium-phospholipid interaction in the cell membrane and reduces active intracellular calcium transport, inhibits the release of neurotransmitter amino acids (glutamate, aspartate) from the nerve endings, thus providing an anticonvulsant effect. Phenytoin has the ability to suppress glutamate receptors. Phenytoin reduces the increased activity of the centers of the brain stem responsible for the tonic phase of tonic-clonic seizures (a large seizure fit).

Pharmacokinetics:

Has the effect of "first pass" through the liver. Bioavailability is less than 50%. Penetrates into the cerebrospinal fluid, saliva, semen, gastric and intestinal juice, bile, breast milk, penetrates the placenta. To a large extent (up to 90% or more) binds to plasma proteins. The time to reach the maximum concentration of the drug in the blood serum is 1.5-3 hours. The therapeutic concentration of the drug in the serum is 10-20 μg / ml (40-80 μmol / l). A stable concentration is usually achieved on the 7-10th day with an average daily dose of 300 mg / day. Peak concentrations in blood plasma are achieved after 1.5-3 hours after taking the drug.The concentration of phenytoin in the serum required to achieve a therapeutic effect may depend on the type of epileptic seizures.

Phenytoin is metabolized by liver enzymes to inactive metabolites. The basic inactive metabolite is 5- (R-hydroxyphenyl) -5-phenylhydantoin. Possible cumulation of the drug and as a consequence - the development of unforeseen toxic effects. Half-life is an average of 22 hours and can vary from 7 to 42 hours. It is excreted by the kidneys - 35-60%, with bile - 40-65%. Excretion increases with an alkaline reaction of urine.

Pharmacokinetics in special groups

In patients with renal or hepatic insufficiency, as well as in patients with hypoalbuminemia, the concentration of unbound phenytoin increases with phenytoin, which requires careful dose selection and use with caution.

Age

Serum concentration of phenytoin is 20% lower in patients older than 70 years compared with patients aged 20-30 years.

Floor and race do not have a significant effect on the pharmacokinetics of phenytoin.

Phenytoin penetrates the placenta and reaches the fetus, the fetus and mother show similar concentrations in the plasma. Phenytoin accumulates in the liver of the fetus.

Indications:

Large convulsive seizures (grand mal), accompanied by loss of consciousness, arbitrary urination, tonic convulsions, which turn into clonic, complex partial seizures; for the prevention and treatment of seizures occurring on time or after neurosurgical operations and / or severe brain injury.

Diphenin is ineffective for the prevention and treatment of febrile seizures, with absences and myoclonic seizures.

Contraindications:

Hypersensitivity to the drug components and preparations of the hydantoin derivative group; atherosclerotic blockade, sinus node weakness syndrome, pulmonary insufficiency, pronounced hypotension (systolic blood pressure less than 90 mmHg), bradycardia (less than 50 beats per minute), sinoatrial block, atrial fibrillation, atrial flutter, simultaneous reception with other antiepileptic drugs; the first three months after myocardial infarction and with a decrease in cardiac output (left ventricular ejection fraction more than 35%), children under 3 years old.

Carefully:

Alcoholism, diabetes, systemic lupus erythematosus,atrial fibrillation, atrial flutter, elderly patients, pulmonary insufficiency, hyperthermia, renal and / or hepatic insufficiency, patients with suicidal behavior in the anamnesis, during an exacerbation of depressive disorder.

Pregnancy and lactation:

The drug is contraindicated during pregnancy. When pregnancy occurs, the patient should be informed of the potential threat to the fetus. Diphenine during pregnancy can lead to a disruption in the fetal development of the fetus. Children whose mothers took phenytoin in monotherapy, as well as in combination with other anticonvulsants, there was an increase in the frequency of malformations and mental disorders. In addition, it is known that the children of mothers with epilepsy are predisposed to the violation of intrauterine development, including congenital malformations. Several cases of malignant tumors have been reported, including neuroblastomas, in children whose mothers have taken phenytoin during pregnancy. In newborns, there have been cases of life-threatening bleeding associated with a decrease in the level of vitamin K and disorders ina system of blood coagulation in newborns exposed to phenytoin during the period of intrauterine development.

Women of childbearing age must comply with contraception when using the drug.

Phenytoin is excreted in breast milk in small amounts, but the use of the drug is not recommended for breastfeeding due to the development of possible adverse reactions in the newborn.

Dosing and Administration:

Inside, during or immediately after a meal.

The dosage regimen should be selected for each patient individually according to the response to therapy and taking into account the level of phenytoin in the blood plasma. Treatment begins with low doses with a gradual increase in them until the effect is achieved or until the toxic effects of the drug appear. In some cases, for an optimal selection of the dosing regimen, constant monitoring of plasma concentrations of phenytoin is necessary.

The therapeutic range of phenytoin concentration in plasma is 10-20 µg / ml (from 40 to 80 µmol / l), however, in the treatment of certain types of tonic-clonic seizures, the effect can be achieved with a less wide range of plasma concentrations of phenytoin.

It is necessary to follow the recommended unchanged dosing regimen during the first 7-10 days of treatment to achieve therapeutic concentrations of phenytoin in plasma. In the future, maintenance therapy should be performed with the lowest doses.

Dosing regimen in adults

Treatment begins with a dose of 100 mg (1 tablet) 2 to 4 times a day. In the next 7-10 days, an increase in the dose to a maximum of 600 mg per day is possible. The standard maintenance dose is 200 to 500 mg per day, divided into several doses. In exceptional cases, the daily dose may exceed the prescribed limits, in which case the dose adjustment should be carried out in accordance with the level of phenytoin in the plasma.

If a patient needs to be transferred from phenytoin to another anticonvulsant therapy, gradual withdrawal of phenytoin within 1 week is required.

Dosage regimen for renal and hepatic insufficiency

When the drug is used in this category of patients, a dose reduction may be required, taking into account the serum concentration of phenytoin.

It is necessary to review the dosage when combined with certain drugs (see.section "Interaction with other medicinal products").

Dosage regimen in children

The initial dose is 5 mg / kg / day, divided into 2-3 doses, with the subsequent transition to an individual dosing regimen, the maximum daily dose is 300 mg per day. The recommended daily maintenance dose is 4-8 mg / kg per day.

Side effects:

The following undesirable phenomena were noted during the therapy with phenytoin. A thorough analysis of the causes of development of adverse events is required, since not all of the side effects listed below are associated with the use of phenytoin.

Immune system disorders

Nodular periarteritis, anaphylactic and anaphylactoid reactions, hypersensitivity syndrome, in rare cases with fatal outcome. Clinical manifestations of hypersensitivity syndrome included, but were not limited to, arthralgia, eosinophilia, fever, impaired liver function, lymphadenopathy, or rash. It is also possible to develop systemic lupus erythematosus, a change in the level of immunoglobulin in the blood.

Disorders from the central nervous system

The highest incidence of side effects is typicalit is for the central nervous system that these phenomena are dose-dependent and include nystagmus, ataxia, speech impairment, movement coordination disorder, paresthesia, drowsiness, confusion, vertigo, insomnia, irritability, muscle twitching, perversion of taste sensations and headache.

In rare cases, dyskinesia was noted, including chorea, dystonia, tremor and fluttering tremor (similar phenomena were noted during phenothiazine and other neuroleptics); aggressiveness, degeneration of the cerebellum, decreased mental performance, depression, encephalopathy, fatigue, numbness, paradoxical convulsions.

With long-term therapy with phenytoin, peripheral neuropathy, mainly of the sensory type, was noted.

Disturbances from the skin

Severe skin reactions - Stevens-Johnson syndrome and toxic epidermal necrolysis; hirsutism, hypertrichosis, DRESS-syndrome (allergic reactions with concomitant eosinophilia and systemic manifestations). Disturbances from the skin by the type of scarlet-like or korepodobnyh rashes in a number of cases were accompanied by a fever.More often there are korepodobnye rashes. Perhaps the development of more serious, but more rare skin disorders, such as Stevens-Johnson syndrome; Bullous, exfoliative dermatitis, systemic lupus erythematosus or toxic epidermal necrolysis.

Impaired connective tissue

In rare cases, coarsening of facial features, lip augmentation, hirsutism, hypertrichosis, Peyronie's disease and Dupuytren's contracture are possible.

Violations from the organs of hematopoiesis

Violation of liver function, megaloblastic anemia, leukopenia, thrombocytopenia, granulocytopenia, agranulocytosis; pancytopenia, accompanied or not accompanied by suppression of bone marrow function, with the use of phenytoin, lymphadenopathy (local and generalized), lymphoma, pseudolymphoma, decreased immunoglobulin A in plasma, nodular polyarteritis, Hodgkin's disease, benign lymph node hyperplasia.

The development of lymphadenopathy indicates the need for differential diagnosis with other pathologies that manifest lymph node involvement.

Disturbances on the part of the organ of sight

Diplopia.

Disturbances from the respiratory, thoracic and mediastinal organs

Pneumonia.

Disorders from the gastrointestinal tract

Nausea, vomiting, constipation, gingival hyperplasia.

Disorders from the hepatobiliary system

Liver involvement, toxic hepatitis.

Impaired kidney and urinary system

Interstitial nephritis.

General disorders and disorders at the site of administration

Fatigue.

Musculoskeletal system disorders

Osteomalacia, osteopenia, osteoporosis, reduction of bone mineral density, bone fractures (with long-term use of phenytoin for more than 10 years), hypocalcemia, hypophosphatemia, decrease in the content of metabolites of vitamin D, rickets.

Overdose:

The lethal dose is from 2 to 5 g. Symptoms: nystagmus, ataxia, and dysarthria. Other signs - tremor, hyperreflexia, drowsiness, slurred speech, nausea, vomiting, coma and hypotension.

Death occurs as a result of respiratory and cardiovascular insufficiency.

Nystagmus can occur with an overdose of phenytoin of 20 μg / ml, ataxia - 30 μg / ml, dysarthria and lethargy appear with a plasma concentration of more than 40 μg / ml.Also, an overdose was reported with phenytoin at a dose 25 times the therapeutic dose, with a serum concentration of more than 100 μg / ml, followed by complete recovery.

Treatment: apply Activated carbon, laxative drugs, conduct symptomatic therapy. Antidote does not exist. It is necessary to maintain the function of respiration and cardiovascular system. It is possible to use hemodialysis.

Interaction:

The effect of other drugs on phenytoin

Amiodarone, antifungal agents (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole), chloramphenicol, chlordiazepoxide, diazepam, dicoumarin, diltiazem (with the effect of diltiazem decreases), disulfiram, fluoxetine, fluvoxamine, sertraline, H₂antagonists, for example, cimetidine, halothane, isoniazid, methylphenidate, nifedipine, omeprazole, estrogens, phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides, tolbutamide (increase in toxicity), trazodone, warfarin and viloxazine can increase the concentration of phenytoin in serum.

Folic acid, reserpine, rifampicin, sucralfate, theophylline and vigabatrin may reduce the serum phenytoin level.

It is possible to reduce the concentration of phenytoin in the blood plasma when combined with St. John's Wort preparations (Hypericum perforatum).

Preparations containing St. John's wort are not recommended for use with phenytoin. The appointment of phenytoin is possible after 2 weeks after the cessation of therapy with St. John's wort.

Pharmacokinetic studies of the interaction between nelfinavir and phenytoin after oral administration have shown that nelfinavir reduces the AUC phenytoin (total) and free phenytoin by 29% and 28%, respectively. Thus, the concentration of phenytoin should be controlled during co-administration with nelfinavir, and nelfinavir can reduce the concentration of phenytoin in the plasma.

Carbamazepine, phenobarbital, valproic acid, sodium valproate, antineoplastic agents, some antacids and ciprofloxacin can increase or decrease the level of phenytoin in the serum.

Monoamine oxidase inhibitors and re-uptake inhibitors serotonin reduce the anticonvulsant effect of antiepileptic drugs (reduces the convulsive threshold).

Effect of phenytoin on other drugs

Phenytoin reduces the effectiveness of antifungal drugs (eg, azoles), antitumor drugs, calcium channel blockers (felodipine, verapamil, isradipine, dihydropyridines, nicardipine and nifedipine).

Phenytoin reduces plasma concentrations of nisoldipine, clozapine, corticosteroids, cyclosporine, dicumarin, digitoxin, doxycycline, furosemide, lamotrigine, neuromuscular blockers, estrogens (reduces contraceptive effect), oral contraceptives, paroxetine, sertraline, quinidine, rifampicin, theophylline and vitamin D.

The effect of phenytoin is enhanced when combined with aspirin.

Special instructions:

During treatment, careful selection of doses is necessary (with epilepsy, the concentration in the blood is determined on the 7-10th day of treatment), since an increase in the dose may be accompanied by a disproportionate increase in the plasma concentration in the blood.

In most patients, stable serum concentrations of phenytoin are maintained when taking stable doses.Nevertheless, in some patients, there may be significant variations in serum concentrations of phenytoin with equivalent doses. A patient with large fluctuations in plasma phenytoin levels, despite the use of standard doses, presents a complex clinical problem. Definitions in the blood serum level in such patients is crucial. In some cases, the development of an epileptic fit can be prevented at a serum phenytoin concentration of 6-9 μg / ml (24-36 μmol / L). Although the relationship between drug concentration, clinical efficacy and tolerability is different in patients, treatment efficacy should be assessed by clinical signs of the disease and by serum drug concentration, especially when there is a change in seizure frequency in the treatment of children and adolescents with suspected development of toxic reactions and in cases of combined anticonvulsant therapy.

It is not recommended to use Diphenin in monotherapy of absences and the appointment of combined therapy in the case of joint development of tonic-clonic seizures and absences

It is not recommended to use in patients with porphyria, as Diphenin can provoke an exacerbation of the disease.

During the treatment it is necessary to control the calcium and phosphorus content in blood serum. With long-term treatment, it is possible to develop osteopenia, osteoporosis, osteomalacia due to a decrease in bone mineral density, bone fractures due to the development of hypovitaminosis D, hypocalcemia and hypophosphatemia. The exact mechanism of the influence of phenytoin on the metabolism in bone tissue is unknown; with prolonged therapy with phenytoin requires concomitant administration of vitamin D preparations.

When Diphenin is used in children during growth, the risk of side effects from the connective tissue increases.

When treating Diphenin at the beginning of therapy monthly, and then every six months, it is necessary to conduct a clinical analysis of blood, liver enzymes, alkaline phosphatase, and also to monitor the function of the thyroid gland. Patients should be informed of the importance of strictly adhering to the prescribed dosing regimen, sudden discontinuation of the drug is unacceptable and can trigger an epileptic attack.

Diphenin should be immediately withdrawn when hypersensitivity reactions or symptoms, presumably indicative of the possible development of Stevens-Johnson syndrome or Lyell syndrome, appear. Drug-induced hypersensitivity syndrome (systemic idiosyncrasy reaction) is a rare but potentially dangerous complication of antiepileptic therapy. Clinical manifestations include fever, maculopapular rash, lymphadenopathy, leukocytosis in combination with eosinophilia and / or lymphocytosis. In the pathological process, various systems of organs can be involved with the development of hepatitis, nephritis, pneumopathy and others. The syndrome is described with the use of phenytoin, carbamazepine, phenobarbital, valproate (very rare).

The etiology and pathogenesis of the syndrome is unknown. The development of the syndrome is most often observed in the period from 2 to 4 weeks after initiation of phenytoin therapy with possible development in the period of 3 or more months from the beginning of therapy. In the case of the development of the syndrome, withdrawal of phenytoin and the appointment of appropriate therapy are required. A higher risk of developing the syndrome is noted in patients with a decrease in immunity and systemic allergic reactions in the anamnesis.

Patients with impaired liver function, and elderly people need a correction of the dosing regimen.

In acute alcohol intoxication, the concentration of phenytoin in the blood rises, with chronic intoxication decreases. It is necessary to warn the patient about the need to stop using alcohol-containing beverages while treating Diphenin.

When treating Diphenin, it is possible to develop toxic effects from the central nervous system when the allowable therapeutic concentration of phenytoin in the plasma is exceeded: delirium, psychosis, encephalopathy or, in rare cases, cerebellar dysfunction.

In some cases, treatment with antiepileptic drugs, including Diphenin, was accompanied by the appearance of suicidal thoughts / attempts. This was also confirmed by a meta-analysis of randomized clinical trials. Epilepsy can also provoke the appearance of suicidal thoughts. Patients and their environment should be warned about the possibility of suicidal thoughts and, if they occur, you should immediately seek medical help.

Phenytoin can reduce serum T4 concentrations. Phenytoin can lead to an increase in serum glucose, alkaline phosphatase and gamma glutamyl transpeptidase (GGT).

Diphenin influences glucose metabolism and insulin production, it is possible that hyperglycemia develops at a toxic concentration of phenytoin in the plasma, therefore, it is impossible to use Diphenin in the treatment of convulsions against a background of hypoglycemia or convulsions caused by metabolic disorders.

When treating with antiepileptic drugs, including Diphenin, cases of severe exfoliative dermatitis, accompanied by fever, eosinophilia and systemic manifestations (DRESS-syndrome), with the development of life-threatening conditions and fatal outcome are described.

Syndrome of drug-induced hypersensitivity with eosinophilia (DRESS) is characterized as a life-threatening systemic multi-organ reaction, manifested by rashes, fever, lymphadenopathy, leukocytosis with eosinophilia, hepatitis, and involvement of other organs, with the development of nephritis, hematologic disorders, myocarditis, myositis, etc. . At occurrence of the first signs it is necessary to spend immediately full inspection of the patient and to stop treatment by Dipheninum.

There have been cases of acute hepatotoxicity in the use of phenytoin, which may include jaundice, hepatomegaly, high levels of transaminases, leukocytosis and eosinophilia. This can be as one of the manifestations DRESS-syndrome, and isolated syndrome. In such patients it is necessary to immediately stop therapy with Diphenin.

When using Diphenin, there may be changes in the hemopoietic system, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia, sometimes with fatal outcomes. There were cases of lymphadenopathy, benign lymph node hyperplasia, pseudolymph and Hodgkin's disease. It is necessary to closely monitor patients with the development of these reactions against the background of phenytoin therapy, and timely correction of therapy. Macrocytosis and megaloblastic anemia are successfully eliminated in the course of treatment with folic acid. When the lymph nodes are affected, fever, rash and liver damage can occur, but these manifestations may be absent. With any lymphadenopathy, a long period of monitoring of the patients' condition is required, considering the possibility of usingantiepileptic drugs of other groups.

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

During the period of treatment, it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of the psychomotor reaction.

Form release / dosage:

Tablets, 0.117 g.

Packaging:

For 10 tablets in a contour mesh box made of polyvinyl chloride film and foil of aluminum printed lacquered.

For 10 tablets in a contour non-cellular package of paper with a polymer coating.

For 20 tablets in cans of orange glass with a screw neck with screw caps, or a polymer can with the first opening and a shock absorber, or a can of polyethylene terephthalate for medicines with a screw cap or with a control of the first opening.

Each bank or 1, 2, 3, 5 contour mesh or non-jawed packages, together with the instruction for use, is placed in a pack of cardboard.

200, 400, 500 or 600 contour non-jawed packages with an equal number of instructions for use are placed in a cardboard box (for hospitals).

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after expiration date

Terms of leave from pharmacies:On prescription

Registration number:LP-003509

Date of registration:16.03.2016

Expiration Date:16.03.2021

The owner of the registration certificate:UZOLE-SIBERIAN CHEMICAL PLANT, OJSC UZOLE-SIBERIAN CHEMICAL PLANT, OJSC Russia

Manufacturer: & nbsp

UZOLE-SIBERIAN CHEMICAL PLANT, OJSC Russia

Information update date: & nbsp07.08.2016

Illustrated instructions

Instructions

Diphenine (Diphenine )