Proteb -4 - instructions for use, dose, side effects, contraindications

Excipients: Kernel: lactose (milk sugar), microcrystalline cellulose, polysorbate 80 (Tween 80), povidone (polyvinylpyrrolidone non-molecular media, col l and don 25), silicon dioxide colloid (aerosil brand A -300), carboxy methyl l sodium starch (primogel), magnesium stearate. Sheath: hypromelose E 15, macrogol 6000 (polyethylene glycol 6000), castor oil, trolley dye 0.

Description:The tablets are brown, biconvex, oval, with a risk, covered with a film membrane. A thin shell and a dark brown core with dark and light impregnations are visible on the transverse section.

Pharmacotherapeutic group:Anti-tuberculosis drug.

ATX: & nbsp

J.04.A.M.06 Isoniazid in combination with pyrazinamide, rifampicin and ethambutol

Pharmacodynamics:

Rifampicin

The mechanism of action of rifampicin is the inhibition of DNA-dependent RNA polymerase. Rifampicin has a bactericidal action against both intracellular and extracellular microorganisms.

Isoniazid

Isoniazid has a bactericidal effect mainly 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 Mycobacterium tuberculosis the minimum inhibitory concentration (MIC) of isoniazid is 0.05-0.025 mg / L. Resistance to isoniazid appears slowly.

Pyrazinamide

Pyrazinamide has a bactericidal action at acidic pH values. It is assumed that for the manifestation of the bactericidal activity of this preparation, the enzymatic conversion of pyrazinamide to the active form, pyrazinic acid, is necessary.

The sensitivity of different strains Mycobacterium tuberculosis to pyrazinamide depends on the activity of this enzyme, which can be measured In vitro, thus assessing the sensitivity of a particular strain. At acidic pH values, MIC pyrazinamide In vitro is 20 mg / l. Pyrazinamide does not affect atypical mycobacteria.

Ethambutol

Ethambutol is a bacteriostatic drug that is effective against Mycobacterium tuberculosis, resistant to other anti-TB drugs.

Etambutol suppresses the synthesis of the cell wall, blocking the inclusion of mycolic acids in it. Ethambutol is practically active against all strains Mycobacterium tuberculosis and M. bovis, as well as against non-tuberculous mycobacteria. (M. kansasii)

Pharmacokinetics:

Rifampicin

After taking Protub-4 in healthy adults, the peak concentration of rifampicin in plasma reaches 7.84 μg / ml. In the case of taking with food, the absorption of rifampicin, which is part of Proteb-4, is reduced by 30%.

The maximum concentration of rifampicin in plasma is reached after 2 hours. Rifampicin widely distributed in the body, quickly distributed to organs and tissues (the highest concentration in the liver and kidneys), penetrates into the bone tissue, the concentration in the saliva-20% of the plasma. Through the blood-brain barrier (BBB) penetrates only in case of inflammation of the meninges. Penetrates through the placenta (concentration in fetal plasma-33% of the concentration in the mother's plasma) and in breast milk (breast-fed children receive no more than 1% of the therapeutic dosepreparation). Approximately 80% of the dose is associated with plasma proteins. The half-life of rifampicin averages 3.35 ± 0.66 h. Rifampicin metabolizes in the liver to deacetyltrifampicin, this metabolite is active. Rifampicin is excreted from the body with urine (up to 30% of the dose taken).

Isoniazid

After taking Protub-4 in healthy adults, the peak concentration of isoniazid in plasma reaches 4.75 μg / ml after 2 hours. The half-life of isoniazid from the plasma is 2-6 hours. Isoniazid is subjected to a pronounced pre-systemic metabolism in the wall of the small intestine and liver, as a result of which its plasma concentration in patients with a fast acetylation process is half the concentration in patients with a slow acetylation process.

It is excreted in the urine in the first 24 hours. Less than 10% of the dose is excreted with feces. The main products of excretion in urine are N-acetyl isosine, monoacetylhydrazine and isonicotinic acid.

Pyrazinamide

After taking Protub-4 in healthy adults, the peak concentration of pyrazinamide in plasma reaches 24.13 μg / ml after 3 hours. The half-life of this drug is 10-24 hours, and it is widely distributed in the body, it penetrates well into tissues and biological fluids,including cerebrospinal fluid. Its concentrations in the cerebrospinal fluid are almost identical to those in the blood. In the liver pyrazinamide turns into the main active metabolite-pyrazinic acid. Approximately 30-40% of the dose taken is excreted urine in the form of pyrazinic acid and 3.4% in the form of unchanged pyrazinamide.

Ethambutol

After taking Protub-4 in healthy adults, the peak concentration of ethambutol in plasma reaches 3.45 μg / ml after 2 hours. Further, the concentration decreases in a two-phase manner: at the beginning, the half-life is 4 hours and then 10 hours. Approximately 50-70% of the dose is excreted unchanged in urine, and the rest is in the form of aldehyde and carboxyl metabolites. The average volume of distribution is 3.89 l / kg. About 10-40% of the drug binds to plasma proteins. An insignificant part of the dose is metabolized in the liver. Metabolite is excreted in the urine. In patients with impaired renal function, ethambutol elimination is slowed down.

Indications:Proteb-4 is indicated for the treatment of the initial stage of pulmonary tuberculosis. It is also shown in the initial stages of extrapulmonary tuberculosis.

Contraindications:Proteb-4 is contraindicated:
- with increased sensitivity to any ingredient of this drug,
- patients with visual impairment (diabetic retinopathy, optic nerve damage, inflammatory eye diseases),

- Epilepsy and a tendency to convulsive seizures, in the case of a previous history of poliomyelitis,

- with a violation of the liver and kidneys, gout,

- with jaundice, acute hepatitis

- Thrombophlebitis, severe atherosclerosis.

Carefully:

- during pregnancy and lactation,

- Children under 13 years.

- with psychosis, old age.

Dosing and Administration:

Inside. Adults and children from 13 years. The drug is dosed according to rifampicin 10 mg / kg body weight, but not more than 5 tablets. The drug is taken on an empty stomach for 30-40 minutes before breakfast. The total exchange rate is from 2 to 4 months, depending on the nature of the tuberculosis process. With a body weight> 80 kg is additionally prescribed isoniazid in the evening (the total daily dose of isoniazid - 10 mg / kg). According to indications Proteb-4 is combined with streptomycin (intramuscularly at a dose of 15 mg / kg once a day).

Apply the drug in combination with other anti-tuberculosis drugs, such as streptomycin or kanamycin. Apply the drug with vitamin B6 at least 30 mg per day. The general course of treatment by Proteb-4om is 2-3 months.

Side effects:

Side effects in the treatment with Proteb-4 are determined by the active ingredients included in its composition.

Rifampicin

Rifampicin can cause side effects from the gastrointestinal tract, such as heartburn, epigastric discomfort, anorexia, vomiting, intestinal colic and diarrhea. Some patients experience headache, drowsiness, weakness, ataxia, dizziness, confusion, visual disorders, muscle weakness, fever, pain in the limbs, itching, urticaria, skin rashes and eosinophilia, sore throat and soreness of the tongue. Men occasionally experience toxic liver damage, which usually develops in the first two weeks after the start of treatment.

From the digestive system: erosive gastritis, pseudomembranous enterocolitis.

Allergic reactions: Quincke edema, bronchospasm, arthralgia, fever.

From the nervous system: disorientation.

From the urinary system: nephronecrosis, interstitial nephritis.

Other: leukopenia, dysmenorrhea, induction of Porphyria, muscle weakness.

In therapy or irregular when resuming treatment after a break can grippodobny syndrome (fever, chills, headache, dizziness, myalgia), skin reactions, hemolytic anemia, thrombocytopenic purpura, acute renal failure.

Isoniazid

Long-term use of isoniazid causes periphyrical neuropathy in 3.5-17% of patients. There is a feeling of tingling and numbness in the fingers and toes, some patients have muscle weakness, headache, dizziness, nausea, vomiting, drug-induced hepatitis, gynecomastia in men and menorrhagia in women. Prophylactic and therapeutic use of isoniazid in the form of monotherapy or in combination with anti-tuberculosis drugs is associated with a significant risk of toxic damage to the liver.

Pyrazinamide

Pyrazinamide can cause liver damage and fulminant hepatitis. The likelihood of toxic damage to the liver increases with increasing dose and duration of treatment. At a dose of 3 g per day, signs of liver damage are observed in about 15% of patients.The abolition of pyrazinamide leads to a rapid normalization of liver enzyme levels.

Ethambutol

The most serious side effects of ethambutol are retrobulbar neuritis, which is manifested by decreased visual acuity, narrowing of the field of vision, central or peripheral scotoma, and impaired color perception, especially the ability to distinguish between green and red.

Other side effects include confusion, disorientation, hallucinations, headache, dizziness, general malaise, jaundice or transient liver dysfunction, peripheral neuropathy, as well as gastrointestinal disturbances such as metallic taste in the mouth, nausea, vomiting, anorexia and pain in a stomach.

Overdose:

Symptoms: pulmonary edema, confusion, convulsions, peripheral neuropathy, impaired liver function, nausea, vomiting, impaired vision and hearing, slurred speech, respiratory depression, stupor, coma.

Treatment: gastric lavage, the appointment of activated charcoal; symptomatic therapy, forced diuresis, artificial ventilation of the lungs, intravenous short-acting barbiturates, pyridoxine, osmotic diuretics, sodium bicorbanate in the development of metabolic acidosis.

Interaction:

Rifampicin

Rifampicin accelerates the metabolism of phenytoin, quinidine, oral anticoagents and antifungal drugs. Antacids, opiates reduce the bioavailability of rifampicin. Reduces the activity of oral hypoglycemic drugs, oral hormonal contraceptives, drugs of the digitis, antiarrhythmics (disopyramide, mexiletine), glucocorticosteroids, dapsone, hydantoins (phenytoin), hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporin A, beta adrenoblockers, enalapril and cimetidine. It is known that rifampicin induces some enzymes of the cytochrome P-450 system. Rifampicin reduces the antimicrobial activity of lomefloxacin (maxachvin) and ofloxacin.

Isoniazid

Isoniazid enhances the effects of phenytoin, such as drowsiness and

ataxia. Prednisolone can significantly reduce the concentration of isoniazid in plasma

blood in slow and fast acetylators, but this effect is more pronounced in

slow acetylators. Isoniazid increases the frequency and severity of liver function disorders

in combination with rifampicin in patients with previous liver diseases.

PASK preparations containing bentonite (aluminum hydrosilicate) reduce absorption

rifampicin. Antacids reduce the absorption of isoniazid. Isoniazid reduces

efficacy of oral hypoglycemic drugs, theophylline, tolazomide,

vitamin B1 (enhances its excretion); reduces the content of zinc in the blood (increasing it

excretion).

Pyrazinamide.

Pyrazinamide slightly reduces the concentration of isoniazid in the blood serum,

especially in slow acetylators.

Ethambutol

Aluminum hydroxide disrupts the absorption of ethambutol, and therefore it is necessary to use alternative antacids.

When combined with neurotoxic agents, the neurotoxic effect of ethambutol may be enhanced.

Special instructions:Given that the drug has a side effect on eyesight, it is recommended that a complete ophthalmological examination of the patient is performed before the start of treatment, which includes the definition of visual acuity, color vision, visual fields and ophthalmoscopy.It should be borne in mind that the side effect on the part of the eye is basically reversible after discontinuation of the drug. In rare cases, recovery may be delayed for 1 year or more and may be irreversible. Therefore, patients should be advised to immediately inform the doctor of any change in visual acuity. During treatment with Proteb-4, control of the kidney, liver and blood function is necessary.

When prescribing Protub-4a, it should be borne in mind that urine, feces, saliva and tears can be colored orange.

Do not interrupt (accidentally or intentionally) taking the drug without consulting a doctor. Women during the treatment period are recommended to use non-hormonal methods of contraception.

During the treatment period, microbiological methods are used to determine the concentration of folic acid and cyanocobalamin in the blood serum. Progressive deterioration of visual acuity during therapy should be considered a side effect. If corrective glasses were used before the treatment, they should be worn during the assessment of visual acuity. During 1-2 years of therapy, a refractive error may develop,which should be corrected to obtain accurate research results. The study of visual acuity through the stenopathic opening eliminates the error of refraction .. Caution should be used when using in elderly patients, due to the increased risk of development of toxic phenomena.

To avoid the development of a hepatotoxic effect during treatment, ethanol should be avoided.

The use of certain types of cheese (Swiss, Cheshire) or fish (tuna, sardines) during eating can lead to pruritus of the skin, palpitation, chills and headache (inhibition of MAO and plasma diamino oxidase by isoniazid, which affects the metabolism of tyramine and histamine , found in fish and cheese).

Pyrazinamide worsens the course of gout and diabetes, requires monitoring of kidney function, uric acid. In the case of a persistent increase in the level of acid and exacerbation of gouty arthritis, treatment is canceled.

Form release / dosage:

Tablets coated with a coating, 75 mg + 400 mg + 150 mg + 275 mg.

Packaging:10 tablets per contour cell pack.
For 5, 10 contour cell packs, along with instructions for medical use, are placed in a cardboard box.
For hospitals: 100, 500 or 1000 tablets per can of polymeric material or low-pressure polyethylene or high pressure. Banks are placed in a group package.

Storage conditions:

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

In a place inaccessible to children.

Shelf life:2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000728/09

Date of registration:05.02.2009

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

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp19.05.2016

Illustrated instructions

Instructions

Protub®-4 (Protub®-4)