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

Active substance:
phenobarbital	50.0 mg or 100.0 mg
Excipients:
sucrose (sugar)	14.81 mg or 8.0 mg
potato starch	32.28 mg or 37.3 mg
stearic acid	1.0 mg or 1.5 mg
talc	1.91 mg or 3.2 mg

Description:TOrugular, flat-cylindrical tablets of white color, with a bevel.

Pharmacotherapeutic group:antiepileptic agent, barbiturates and their derivatives

ATX: & nbsp

N.03.A.A.02 Phenobarbital

Pharmacodynamics:

Pharmacological action - anticonvulsant, hypnotic, sedative. Interacts with barbiturate site GABA_A-benzodiazepine-barbiturate receptor complex and increases the sensitivity of GABA-receptors to the mediator (GABA), as a result, the duration of the neuronal canal opening for incoming chlorine ion currents increases and the intake of chloride ions into the cell increases. An increase in the content of chloride ions inside the neuron entails hyperpolarization of the cell membrane and lowers its excitability. As a result, the inhibitory effect of GABA and the inhibition of interneuronal transmission in various parts of the central nervous system (CNS) increase.

It was shown that at therapeutic concentrations phenobarbital enhances GABAergic transmission, inhibits glutamatergic neurotransmission, especially glutamate-alpha-amino-5-methylisoxazole-4-propionate mediated (AMPA) receptors. In high concentrations affects the current of sodium ions and blocks the current of calcium ions through the cell membranes (channels L- and Ntypes).

Barbiturates have a non-selective inhibitory effect on the central nervous system. They suppress sensory areas of the cerebral cortex, reduce motor activity and cause drowsiness, sedation and sleep.

The sedative-hypnotic effect is due mainly to the inhibition of the activity of the cells of the ascending activating reticular formation of the brain stem, thalamus nuclei, inhibition of the interaction of these structures with the cortex of the brain.

Anticonvulsant action is caused by activation of the GABAergic system, influence on the potential-dependent sodium channels, as well as suppression of glutamate activity. Phenobarbital reduces the excitability of neurons in the epileptogenic focus and prevents the appearance and propagation of impulses. It blocks high-frequency repeated discharges of neurons (due to the influence of sodium ions on the current). Barbiturates also increase the threshold of electrical stimulation of the motor cortex of the cerebral cortex.

In studies on laboratory models of epilepsy in animals, the effectiveness of phenobarbital in the prevention of all kinds of seizures, with the exception of absences, is shown.

Pharmacokinetics:

After ingestion completely, but slowly absorbed in the small intestine. Bioavailability - 80%. Binding to plasma proteins (predominantly with albumin) is 20-45%. The therapeutic concentration in the blood serum, optimal for the manifestation of an anticonvulsant effect, is 10-40 μg / ml. T_1/2from plasma in adults - 53-118 hours (average 79 hours), in children and newborns (less than 48 hours) - 60-180 hours, an average of 110 hours. It is distributed among organs and tissues, passes through the blood-brain barrier (BBB) . It passes well through the placenta and is distributed throughout the fetal tissues (the highest concentrations are found in the placenta, liver and fetal brain), it penetrates into breast milk.

Metabolized in the liver with the participation of microsomal enzymes with the formation of pharmacologically inactive metabolites. T_1/2- 2-4 days (in newborns up to 7 days). It is excreted by the kidneys in the form of glucuronides of metabolites and in unchanged form (25-50%). Excretion by the kidneys depends on the pH of the urine: with alkalinization of urine, the excretion in unchanged form increases and the concentration in the blood decreases more rapidly, while on acidification it vice versa. Phenobarbital characterized by pronounced cumulation.

If the renal function is impaired, the effect is significantly prolonged.

Indications:Treatment and prevention of all forms of epilepsy, except for absences (Petit mal).

Contraindications:

- Hypersensitivity to the components of the drug (including other barbiturates);

- severe hepatic or renal insufficiency;

- diabetes;

- I trimester of pregnancy (teratogenic effect is possible);

- the period of breastfeeding;

- myasthenia gravis;

- porphyria in the anamnesis (there may be an increase in symptoms due to the induction of enzymes responsible for the synthesis of porphyrin);

- alcoholism, drug addiction (including in history);

- severe anemia;

- Children under 3 years of age (solid dosage form);

- Respiratory diseases with dyspnea, obstructive syndrome.

Carefully:

- Depression and / or suicidal tendencies;

- bronchial asthma in history;

- impaired liver and / or kidney function;

- hyperkinesis;

- hyperthyroidism (there may be an increase in symptoms, because barbiturates displace thyroxine, associated with plasma proteins);

- hypofunction of the adrenal glands (possible weakening of the systemic action of exogenous and endogenous hydrocortisone under the action of barbiturates);

- acute or persistent pain (paradoxical agitation may occur or important symptoms may masquerade);

- pregnancy (II and III trimester).

Pregnancy and lactation:

Women of reproductive age need to be informed in detail about the importance of planning and monitoring pregnancy before starting treatment with phenobarbital.The fact that a woman is planning a pregnancy is the basis for reviewing the need for antiepileptic therapy. Women of reproductive age should be informed about the risks and benefits of using antiepileptic medication during pregnancy.

The risk associated with epilepsy and antiepileptic drugs in general

In children born to mothers with epilepsy taking any antiepileptic drugs, the total level of malformations is approximately 2-3 times (about 3%) higher than in the whole in the population. Despite the established fact of an increased incidence of malformations in children born to a mother receiving antiepileptic therapy, the corresponding role of drugs and the disease itself in the occurrence of malformations has not been formally established. The most common developmental malformations are the hare's lip, the developmental defects of the cardiovascular system and the neural tube.

Epidemiological studies allow a link between the use of antiepileptic drugs in vitro and risk of delayed development. Many factors can increase this risk, including maternal epilepsy and genetic factors.Despite this potential risk, treatment for epilepsy can not be interrupted suddenly, as this can cause seizures, which can have serious consequences for both the mother and the fetus.

Application during pregnancy is possible only on strict indications, if it is impossible to use other means. The intake of barbiturates by pregnant women is the cause of an increase in the frequency of abnormalities of the fetus. The overall risk of malformations in the first trimester of pregnancy is increased, as is the case with the use of other traditional antiepileptic drugs. Phenobarbital, apparently, mainly causes defects associated with craniofacial anomalies, abnormalities of the fingers, less often hare lip, wolf mouth. In newborns, whose mothers were taking phenobarbital in the third trimester of pregnancy, the development of physical dependence and withdrawal syndrome is possible (there are reports of the development of an acute withdrawal syndrome manifested in epileptic seizures and excessive excitability immediately after childbirth or for 14 days in newborns exposed to prolonged intrauterine exposure to barbiturates).The use of phenobarbital as an anticonvulsant during pregnancy can lead to a clotting disorder (associated with vitamin K deficiency) in newborns, which can cause bleeding during the neonatal period (usually the first day after delivery). Use during labor can cause respiratory depression in a newborn, especially premature (in connection with the underdevelopment of liver function).

Prenatal monitoring is recommended for early detection of teratogenic effects (eg, ultrasound and determination of alpha-fetoprotein).

The use of folate before and during pregnancy can reduce the incidence of neural tube defects in children at high risk. Women who do not use contraceptives should be informed about the advisability of taking folic acid.

At the time of treatment, breastfeeding should stop (penetrates into breast milk and may cause central nervous system depression in infants).

Dosing and Administration:

Inside. The dosage regimen is set strictly individually depending on the indications, the course of the disease, tolerability, age.Treatment should be started with the lowest effective dose corresponding to a particular form of pathology. In patients with impaired liver and / or kidney function, elderly and weakened patients, treatment should begin with smaller doses.

Treatment and prevention of all warts of epilepsy, except for absences (Petit mal)

Adults: 60-180 mg at night.

Children: 5-8 mg / kg per day.

Elderly patients: the clearance of phenobarbital is reduced, in connection with which it is necessary to reduce the dose.

The dosage regimen is chosen individually for each patient, as a rule, the plasma concentration of phenobarbital should be 15-40 μg / ml (65-170 μm / l).

Side effects:

Frequency of side effects: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000 ), very rarely (<1/10000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).

From the nervous system and sense organs: drowsiness, lethargy, dizziness, ataxia, nystagmus, paradoxical reaction (especially in elderly and weakened patients - agitation), inhibition, irritability, headache, tremor of hands, hallucinations, depression, nightmarish dreams, sleep disturbance, fainting, respiratory depression center, nervousness,anxiety, hyperkinesia (in children), disruption of the thinking process, the effect of the consequences (asthenia, feeling of weakness, lethargy, decreased psychomotor reactions and concentration of attention).

From the side of the musculoskeletal system: with prolonged use - violation of osteogenesis and development of rickets, a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy.

From the digestive system: nausea, vomiting, constipation, with prolonged use - a violation of liver function (hepatitis, cholestasis).

On the part of the organs of hematopoiesis: agranulocytosis, metal regional anemia (with prolonged use), thrombocytopenia.

From the side of the cardiovascular system: lowering blood pressure, bradycardia.

Allergic reactions*: skin rash, hives, local edema (especially the eyelids, cheeks or lips), shortness of breath, exfoliative dermatitis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis, erythema multiforme; possible fatal outcome.

Other: withdrawal syndrome: minor symptoms (within 8-12 hours after stopping the use of the drug) - anxiety, motor anxiety, muscle twitching, trembling of hands, weakness, dizziness,impaired vision, nausea, vomiting, sleep disturbance, "nightmarish" dreams, orthostatic hypotension; the main symptoms (within 16 hours and lasts up to 5 days) - convulsions, hallucinations; with long-term use - drug dependence (mental and physical), violation of libido, impotence.

To avoid the development of the "withdrawal" syndrome, discontinuation of treatment should be gradual.

* Syndrome of hypersensitivity to antiepileptic drugs is a reaction that rarely occurs during therapy with anticonvulsant drugs. The syndrome can be potentially lethal and characterized by fever, rash, lymphadenopathy and other reactions, often on the part of the liver. The mechanism of the syndrome is unknown. The interval between the first intake of the drug and the appearance of symptoms - usually 2-3 weeks, there were reports of the onset of the syndrome after three or more months of taking anticonvulsants. With a diagnosed syndrome, it is necessary to stop taking the drug and provide the necessary supportive therapy.

Overdose:

Symptoms of toxic poisoning may not appear for several hours after taking phenobarbital. The toxic dose varies considerably.Ingestion 1 g causes serious poisoning in adults, taking 2-10 g usually causes death. Therapeutic levels of phenobarbital in human blood is 5-40 mcg / ml lethal - 100-200 mcg / ml. Barbiturate intoxication should be differentiated from alcohol intoxication, intoxication bromides with various neurological disorders.

Symptoms of acute toxicity: nystagmus, unusual eye movements, ataxia, marked weakness and drowsiness, severe confusion, slurred speech, agitation, dizziness, headache, respiratory depression, Cheyne-Stokes respiration, weakening or absence of reflexes, constriction of the pupils (in severe poisoning alternating with paralytic extension), oliguria, tachycardia, hypotension, hypothermia, cyanosis, weak pulse, cold and clammy skin, hemorrhage (at the points of pressing), coma. In severe poisoning may develop pulmonary edema, circulatory collapse with decreased peripheral vascular tone, apnea stop breathing and heart; possible fatal outcome. In life-threatening overdose possible to suppress the electrical activity of the brain (EEG can be "flat") which should not be construed as clinical death, becausethis effect is completely reversible if the damage associated with hypoxia has not developed. Overdose can cause the development of complications such as pneumonia, arrhythmia, congestive heart failure, kidney failure.

Treatment of acute overdose: acceleration of the removal of phenobarbital and maintenance of vital functions. To reduce absorption (if phenobarbital not absorbed completely from the gastrointestinal tract (GIT)) - the induction of vomiting (if the patient in consciousness and did not lose the gag reflex) followed by the appointment of activated carbon, while taking measures to prevent aspiration of vomit. If the induction of vomiting is contraindicated, it is necessary to wash the stomach. To accelerate the withdrawal of the absorbed drug prescribed salt laxatives, conduct forced diuresis (with preserved kidney function), use alkaline solutions (for urine alkalinization). Monitor the vital functions and water balance.

Supporting measures: it is necessary to ensure the patency of the airways, it is possible to use artificial ventilation of the lungs (IVL) and the use of oxygen;the appointment of an analeptic is not recommended (with severe poisoning may worsen the condition); maintenance of normal arterial pressure (BP) (with hypotension - the use of vasoconstrictor) and body temperature; if necessary, infusion therapy or other anti-shock measures; measures should be taken to prevent hypostatic pneumonia (including physiotherapy in the chest area), pressure sores, aspiration and other complications; when suspected of pneumonia - the appointment of antibiotics; it is recommended to avoid overloading with liquid or sodium, especially when the cardiovascular system is impaired. In severe poisoning, the development of anuria or shock, it is possible to perform peritoneal dialysis or hemodialysis (during and after dialysis, it is necessary to monitor the concentration of phenobarbital in the blood).

Interaction:

Phenobarbital is a potent inducer of the hepatic enzyme system containing cytochrome P450 (mainly isoenzyme CYP3A4). Induction with phenobarbital occurs when it is used in doses as low as 60 mg per day. This property is the basis of pharmacokinetic interactions with other drugs, i.e. phenobarbital boosts both its own metabolism and the metabolism of many other drugs that undergo biotransformation in the liver. The latter have different effects on the action of barbiturates.

- Alcohol - simultaneous reception with alcohol can lead to a potentiation of the depressant effect on the central nervous system. The same effects are observed with simultaneous admission with other CNS depressants.

- Antidepressants - including MAO inhibitors, SSRIs and TCAs, can reduce the antiepileptic activity of phenobarbital by reducing the convulsive threshold.

- Antiepileptic means - plasma concentrations of phenobarbital increase with simultaneous reception with oxcarbazepine, phenytoin and sodium valproate. Vigabatrin - there is evidence of a decrease in the plasma concentration of phenobarbital.

- Neuroleptics - simultaneous use of aminazine or thioridazine with phenobarbital may lead to a mutual decrease in plasma concentration.

- Folic acid - the administration of folic acid preparations for the treatment of folate deficiency, which can be observed with the use of phenobarbital, causes a decrease in the plasma level of phenobarbital,which leads to inadequate control of seizures in some patients.

- Memantine - the effectiveness of phenobarbital may decrease.

- Methylphenidate - can increase the plasma concentration of phenobarbital.

- Drugs based on St. John's wort - the effectiveness of phenobarbital can be reduced with simultaneous application.

Effects of phenobarbital on other drugs

Phenobarbital increases the metabolic rate of the following drugs, which leads to a decrease in plasma concentrations:

- antiarrhythmics - disopyramide and quinidine - It is possible to reduce the concentrations of anti-arrhythmic effect. When appointing or abolishing phenobarbital, control of plasma concentrations of antiarrhythmics is necessary. You may need to change their dosing regimen;

- antibacterial drugs - levomycetin, doxycycline, metronidazole and rifampicin. It is necessary to avoid simultaneous use of telithromycin against the background and within 2 weeks after taking phenobarbital;

- anticoagulants;

- antidepressants - paroxetine, mianserin and tricyclic antidepressants;

- antiepileptic means - carbamazepine, lamotrigine, tiagabine, zonisamide, primidon and, possibly, ethosuccide;

- antifungal drugs - the antifungal effect of griseofulvin can be reduced or absent while taking with phenobarbital. Phenobarbital probably reduces plasma concentrations of itraconazole and posaconazole. It is not recommended to share with voriconazole;

- antipsychotics - phenobarbital, possibly reduces the plasma concentration of aripiprazole;

- antiviral drugs - phenobarbital possibly reduces plasma concentrations of abacavir, amprenavir, darunavir, lopinavir, indinavir, nelfinavir, saquinavir;

- anxiolytics and hypnotics - clonazepam;

- aprepitant - phenobarbital it is possible to reduce the concentration in the plasma of aprepitant;

- beta-blockers - metoprolol, timolol and, perhaps, propranolol;

- calcium channel blockers phenobarbital leads to a decrease in the level of felodipine, isradipine, diltiazem, verapamil, nimodipine and nifedipine, which may require increasing their doses;

- cardiac glycosides - when used simultaneously with phenobarbital, the concentration in the blood of digitoxin can be halved;

- cyclosporine and tacrolimus; corticosteroids;

- cytostatics - phenobarbital possibly reduces the plasma concentrations of etoposide and irinotecan;

- diuretics - do not recommend simultaneous use of phenobarbital with eplerenone;

- haloperidol - plasma concentrations are reduced by about half when used simultaneously with phenobarbital;

- antagonists of hormones - gestrinone and, perhaps, toremifene;

- methadone - when used concomitantly with phenobarbital plasma concentrations and withdrawal symptoms may appear, which may require an increase in the dose of methadone;

- montelukast;

- estrogens - decreased contraceptive effect;

- progestogens - decreased contraceptive effect;

- theophylline - may require an increase in the dose of theophylline;

- thyroid hormones - may require an increase in thyroid hormone doses for hypothyroidism;

- tibolone;

- troposetron;

- vitamins - barbiturates possibly increase the need for vitamin D.

Enhances the effects of sodium oxybutyrate. Joint use is not recommended.

Phenobarbital can change diagnostic tests with cyanocobalamin, with metiapone, phentolamine (false positive test).

Special instructions:

Being an inducer of microsomal enzymes of the liver, it increases its detoxification function, reduces the concentration of bilirubin in the blood serum.

In patients with impaired liver function phenobarbital should be applied in a reduced dose.

Suicidal ideation and behavior were noted in patients treated with antiepileptic drugs for a number of indications. A meta-analysis of the results of randomized, placebo-controlled studies of antiepileptic drugs also showed a slight increase in the risk of suicidal ideation and behavior. The mechanism of occurrence of this risk is unknown, and the available information does not exclude the possibility of its increase with respect to phenobarbital.

Therefore, patients should be monitored for suicidal ideation and behavior, if appropriate, appropriate treatment should be recommended. Patients (and also their carers) should be warned about the need to seek medical help in case of suicidal thoughts or behavior.

When dermatological complications appear phenobarbital should be canceled.Hypersensitivity reactions are more common when there is an anamnesis of bronchial asthma, hives, angioedema, and others.

During treatment it is necessary to monitor the function of the liver, kidneys, a general blood test.

Be wary when prescribing for depression (possibly worsening, especially in elderly patients).

It should be borne in mind that in elderly people and weakened patients with usual doses agitation, depression or confusion of consciousness are possible.

In children, barbiturates can cause unusual arousal, irritability, hyperactivity.

The risk of dependence is increased with the use of large doses and with an increase in the duration of admission, as well as in patients with a drug and alcohol dependence in the anamnesis. The constant use of barbiturates in doses 3-4 times higher than therapeutic, leads to the development of physical dependence in 75% of patients.

Cancellation should be carried out gradually, by reducing the dose for a long time to reduce the risk of the syndrome of "withdrawal". A sudden cessation of reception with epilepsy can cause seizures or status epilepticus.

When using phenobarbital for the treatment of epilepsy, monitoring of its concentration in the blood is recommended. With long-term treatment, it is necessary to periodically determine the concentration of folate in the blood, monitor the pattern of peripheral blood, liver and kidney function.

If it is necessary to use barbiturates during childbirth, it is recommended to take delivery while the resuscitation equipment is ready.

When using phenobarbital, life-threatening conditions were recorded: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Patients should be warned about the signs and symptoms of these conditions and carefully monitor the reactions from the skin. The highest risk for SJS or TEN is noted during the first week of treatment. If symptoms or symptoms appear SJS or TEN (eg, progressive skin rash, often with blisters or damage to the mucosa), treatment with phenobarbital should be discontinued. If a patient develops an anamnesis SJS when using phenobarbital, phenobarbital should not be prescribed to such a patient.

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

During the treatment with the drug, you should be careful and warn patients about the dangers to yourself and others when carrying out potentially dangerous activities that require increased concentration and speed of psychomotor reactions (driving and other vehicles, working with moving mechanisms, dispatcher, operator, and so on .P).

Form release / dosage:

Tablets, 50 mg and 100 mg.

Packaging:

For 6 or 10 tablets in a contour non-cellular package of paper with a polymer coating.

For 6 or 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

1, 2, 5 contour cell or contour non-jawed packages of 6 tablets with instructions for use are placed in a pack of cardboard.

1, 2, 5 contour mesh or contour non-jawed packages of 10 tablets with instructions for use are placed in a pack of cardboard.

200, 400, 500, 600, 1000 contour mesh or contour non-jawed packages with an equal number of instructions for use are placed in a cardboard box (for hospitals).

Storage conditions:

List III list of narcotic drugs, psychotropic substances and their precursors subject to control in the Russian Federation.

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 expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003783

Date of registration:12.08.2016

Expiration Date:12.08.2021

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: & nbsp07.09.2016

Illustrated instructions

Instructions

Phenobarbital (Phenobarbital)