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

Active substanceIsoniazid + EthambutolIsoniazid + Ethambutol

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Protubetam®

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FARMASINTEZ, JSC (Irkutsk) Russia

Phthisoetham®

pills inwards

AKRIKHIN HFK, JSC Russia

Dosage form: & nbspTabletki.

Composition:

Active substance:

Isoniazid	150 mg (for tablets 150/400)
	300 mg (for tablets 300/800)
Ethambutol hydrochloride	400 mg (for tablets 150/400)
	800 mg (for tablets 300/800)

Excipients: cellulose microcrystalline, povidone (polyvinylpyrrolidone medium molecular weight, kollidon 25), starch potato cultivar Extra, carboxymethyl starch sodium (sodium starch glycolate), silicon dioxide colloid (aerosil), magnesium stearate, magnesium hydrosilicate (talc).

Description:TAbshetki white or white with a yellowish tinge of color.

Tablets 150/400: Plane cylindrical with a risk and chamfer.

Tablets 300/800: capsular with a risk.

Pharmacotherapeutic group:antituberculous agent combined

ATX: & nbsp

J.04.A.M.03 Isoniazid in combination with ethambutol

Pharmacodynamics:

Protubetam® contains a combination of two antituberculosis drugs.

Isoniazid has a bactericidal effect on actively dividing cells Mycobacterium tuberculosis. The mechanism of its action is the inhibition of the synthesis of mycolic acids, which are a component of the cell wall of mycobacteria. For mycobacteria tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg / l. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

Ethambutol. Bacteriostatic drug, effective against typical and atypical mycobacteria tuberculosis. The mechanism of action of the drug is associated with a violation of the synthesis of RNA in bacterial cells, it suppresses the synthesis of the cell wall, blocking the inclusion of mycolic acids in it. Ethambutol Active against rapidly and slowly growing atypical mycobacteria. The minimum inhibitory concentration of ethambutol is - 0,78-2,0 mg / l. On non-tubercular pathogens ethambutol It does not work.

Pharmacokinetics:

Isoniazid

Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a great influence on the bioavailability index. Time to reach the maximum concentration of the drug in the blood (TS_max) - 1-2 hours, the maximum concentration of the drug in the blood (C_max) after ingestion of a single dose of 300 mg - 3-7 μg / ml. The connection with proteins is insignificant - up to 10%. The volume of distribution is 0.57-0.76 l / kg. Well distributed throughout the body,penetrating into all tissues and fluids, including cerebrospinal, pleural, ascitic; high concentrations are created in the lung tissue, kidneys, liver, muscles, saliva and sputum. Penetrates through the placental barrier and into breast milk.

It is metabolized in the liver by acetylation with the formation of inactive products. In the liver acetylated N-acetyltransferase with formation of N-acetyl isosliniazide, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 at Nhydroxylation of the active intermediate metabolite. The rate of acetylation is genetically determined; in people with "slow" acetylation, little N-acetyltransferase. Is an inhibitor of isoenzymes CYP2C9 and CYP2E1 in the liver. Half-life of blood (T_1/2) for "fast acetylators" - 0.5-1.6 hours; for "slow" - 2-5 hours With renal failure T_1/2can increase to 6.7 hours. T_1/2for children aged 1.5 to 15 years - 2.3-4.9 hours, and in newborns - 7.8-19.8 hours (which is due to the imperfection of the processes of acetylation in newborns).Despite the fact that the indicator T_1/2varies considerably depending on the individual intensity of the acetylation processes, the average value T_1/2is 3 hours (intake of 600 mg) and 5.1 hours (900 mg). With repeated appointments T_1/2shortened to 2-3 hours.

Excreted mainly by the kidneys: within 24 hours 75-95% of the drug is excreted, mainly in the form of inactive metabolites - N-acetylisoiniazide and isonicotinic acid. At the same time, "fast acetylators" contain N-acetyl isosine is up to 93%, while in "slow" - not more than 63%. Small the amounts are excreted with feces. The drug is removed from the blood during hemodialysis; 5 h hemodialysis allows you to remove from the blood to 73% of the drug.

Ethambutol

Absorption is high; bioavailability is 75-80%. After oral administration of a dose of 25 mg the time to reach the maximum concentration of the drug in the blood TS_mOh - 2-4 hours, the maximum concentration of the drug in the blood C_mOh - 1-5 μg / ml. Connection with plasma proteins - 20-30%.

It penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural (in spinal fluid only with meningitis). The greatest concentrations are created in the kidneys, lungs, saliva, urine. Penetrates into breast milk. Do not pass through the intact blood-brain barrier.

Partially metabolized in the liver (15%) with the formation of inactive metabolites. T_1/23-4 hours, with renal dysfunction -8 hours. It is excreted by the kidneys - 80-90% (50% in unchanged form, 15% in the form of inactive metabolites) through the gastrointestinal tract - 10-20% (in unchanged form). It is excreted in hemodialysis and peritoneal dialysis.

Indications:

Treatment of all forms and localizations of tuberculosis caused by sensitive mycobacteria to isoniazid and ethambutol.

It can be used for chemoprophylaxis of tuberculosis and for conducting anti-relapse therapy.

Contraindications:

Patients with hypersensitivity to isoniazid and ethambutol.

Contraindicated in epilepsy and other diseases, accompanied by a tendency to convulsions; with arterial hypertension II-III stage, ischemic heart disease; cirrhosis of the liver, acute hepatitis; miksedeme; with optic neuritis, cataract, diabetic retinopathy; children's age (up to 13 years), pregnancy, lactation.

Carefully:

Prescribe the drug to people with chronic kidney failure.

Dosing and Administration:

The drug Protubetam ® is administered orally 1 to 3 times a day, after meals (at the rate of 5-15 mg / kg / day isoniazid, the maximum dose is 900 mg / day).

The drug is used daily in the intensive care period (3-4 months), in the subsequent time - every other day.

The total course dose of Protubetam® for each individual is dependent on the nature of the disease, the effectiveness of the treatment and the tolerability.

Side effects:

Isoniazid

From the central nervous system (CNS): headache, dizziness; rarely - unusual fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychosis, mood change, depression. Seizures can occur in patients with epilepsy.

From the cardiovascular system: palpitation, angina, increased blood pressure.

From the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.

Allergic reactions: skin rash, itching, hyperthermia, arthralgia.

Other: very rarely - gynecomastia, menorrhagia, a tendency to bleeding and hemorrhage.

Ethambutol

From the nervous system and sense organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression,peripheral neuritis (paresthesia in the extremities, numbness, paresis, pruritus), optic neuritis (decreased visual acuity, violation of color perception, mainly green and red colors, color blindness, scotoma).

From the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function - increased activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase).

Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

Other: hyperuricemia, exacerbation of gout.

Overdose:

Isoniazid

Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, hepatic dysfunction, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, seizures (1-3 hours after drug administration), coma.

Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide; massage, physiotherapy procedures); seizures (in / m pyridoxine hydrochloride - 200-250 mg, in / m 25% solution of magnesium sulfate - 10 ml, diazepam); abnormal liver function (methionine, thioctic acid, cyanocobalamin).

Ethambutol

Symptoms: nausea, vomiting, hallucinations, polyneuritis.

Treatment: symptomatic.

Interaction:

Isoniazid

When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a system of cytochrome P450, which increases the metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and speeds up its metabolism.

Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

Cycloserine and disulfiram strengthens the adverse central effects of isoniazid.

Combination with pyridoxine reduces the risk of peripheral neuritis.

Caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs because of the risk of side effects.

Strengthens the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.

Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.

It suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and an increase in the toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with slow acetylation of isoniazid).

Ethambutol

Aluminum hydroxide reduces the absorption of ethambutol.

The use of ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug.

Etambutol enhances the antimicrobial activity of other antituberculosis drugs.

Special instructions:

During treatment it is necessary to refrain from taking ethanol.

Protubetam may have a hepatotoxic effect, so use with caution in patients with impaired liver function in individuals with chronic alcoholism.

For the prevention and treatment of peripheral neuropathy, an additional appointment of pyridoxine (vitamin AT₆).

In some cases, periodically monitor the level of uric acid in the blood serum.

It is necessary to check the visual acuity of each eye individually and both eyes together. Visual acuity is checked before treatment and periodically during treatment.With any change in visual acuity, patients should immediately consult a doctor. If there is a decrease in visual acuity, the drug is canceled. Vision usually normalizes after a timely withdrawal.

Effect on the ability to drive transp. cf. and fur:When taking in high doses, it is possible to develop adverse reactions from the nervous system, for example, peripheral neuropathy, which affects the ability to drive and work with complex equipment

Form release / dosage:

Tablets, 150 mg + 400 mg and 300 mg + 800 mg.

Packaging:

For 100, 500 or 1000 tablets in a jar of polypropylene or low-density polyethylene, sealed with a lid of polypropylene or high-pressure polyethylene or a can of polyethylene terephthalate for medicines, with a screw cap or with a control of the first opening. Free space from tablets is filled with cotton absorbent medical cotton (for hospitals).

On the bank stick a label from paper label or writing or self-adhesive label.

Banks, together with an equal number of instructions for use, are placed in a group package.

Storage conditions:

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

Keep away from children.

Shelf life:

2 years.

Do not use after the expiration date indicated on the packaging.

Terms of leave from pharmacies:For hospitals

Registration number:LSR-004067/09

Date of registration:25.05.2009

Expiration Date:Unlimited

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC

Information update date: & nbsp16.12.2016

Illustrated instructions

Instructions

Protubetam® (Protubetham®)