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

Excipients: starch, shellac (gold), isopropyl alcohol, RUR K 30. colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate, purified talc.

Description:

Yellowish-pink oval biconvex tablets, covered with a shell. Color of the tablet on the break: red-brown color with light inclusions.

Pharmacotherapeutic group:Anti-tuberculosis drug combined

ATX: & nbsp

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

Pharmacodynamics:

Combination is a combined preparation containing fixed amounts of rifampicin, isoniazid, pyrazinamide and ethambutol.

The combined use of active substances included in the drug reduces the risk of developing resistance, which develops with monotherapy.

Pharmacodynamics

Rifampicin:

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

Isoniazid:

Isoniazid has a bactericidal effect on the actively dividing cells of 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 arises quickly.

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.

At acidic pH values, the maximum inhibitory concentration of pyrazinamide in vitro is 20 mg / l. Pyrazinamide does not affect atypical mycobacteria.

Ethambutol:

Etambutol 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 active against virtually all strains of Mycobacterium tuberculosis and M. bovis. as well as against mycobacteria, for example M. kansasii.

Pharmacokinetics:

Rifampicin

After taking Combatub 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 the Combbitub, is reduced by 30%.

The maximum concentration of rifampicin in plasma reaches 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 the plasma of the fetus - 33% of the concentration in the plasma of the mother) and in breast milk (breastfed babies receive no more than 1% of the therapeutic dose of the drug). 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 pharmacologically active deacetyltrifampicin, is excreted from the body with urine (up to 30% of the dose taken).

Isoniazid

After taking Combatub in healthy adults, the maximum concentration of isoniazid in plasma reaches 4.75 μg / ml after 2 hours. The half-life of isoniazid from 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. The apparent volume of isoniazid distribution is 61% of body weight. Isoniazid is present in effective concentrations in many tissues and biological fluids, including cerebrospinal fluid (CSF). Up to 95% of the dose of isoniazid is excreted in the urine in the first 24 hours, the rest is excreted with feces. The main products of urinary excretion are N-acetylisosodium and isonicotinic acid.

Pyrazinamide

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

Ethambutol

After taking Combatub in healthy adults, the maximum 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. Ethambutol it penetrates well into tissues and organs (into the cerebrospinal fluid only with meningitis). Approximately 50-70% of the accepted dose is excreted in the urine unchanged, and the rest - 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. A small portion of the dose taken is metabolized in the liver and possibly in other tissues and the metabolite is excreted in the urine. In patients with impaired renal function, ethambutol elimination is slowed down.

Indications:The initial stage of pulmonary tuberculosis and extrapulmonary tuberculosis.

Contraindications:

- With increased sensitivity to any ingredient in this drug;

- patients with visual impairment (diabetic retinopathy, optic nerve damage, inflammatory eye diseases);

- Epilepsy and propensity 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:

- In pregnancy and lactation;

- children under 13 years;

- with psychosis, gout, old age.

Dosing and Administration:

Each tablet, film-coated, containing:

Rifampicin 150 mg, Isoniazid 75 mg, Pyrazinaltda 400 mg, Ethambutol 275 mg

taken inside 1-2 hours before meals 4 tablets per day, single patients whose body weight does not exceed 50 kg, for two months.

Each film-coated tablet contains:

Rifampicin 225 mg, Isoniazine 150 mg, Pyrazinamide 750 mg, Ethambutol 400 mg

taken inside 1-2 hours before meals 2 tablets per day, single patients whose body weight is not less than 60 kg, for two months.

It is possible to use the drug in combination with other anti-tuberculosis drugs, such as streptomycin, etc.

Side effects:

Side effects in the treatment of the drug Combbitub determined by its active ingredients.

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's edema, bronchospasm, arthralgia, fever.

From the nervous system: disorientation.

From the urinary system: nephronecrosis, interstitial nephritis.

Other: leukopenia, dysmenorrhea, induction of porphyria, muscle weakness. With irregular therapy or with the resumption of treatment after a break, flu-like syndrome (fever, chills, headache, dizziness, myalgia), skin reactions, hemolytic anemia, thrombocytopenic purpura, acute renal failure are possible.

Isoniazid

Long-term use of isoniazid causes periphyrical neuropathy in 3.5-17% of patients. Headache, dizziness, nausea, vomiting. Medicinal 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 in a network of lesions of the liver 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 effect of ethambutol is retrobulbar neuritis,manifested by a decrease in visual acuity, a narrowing of the field of vision, a central or periphyric scotoma, and a violation of 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 impairment of liver function, periphyrical neuropathy, as well as gastrointestinal disturbances like, metallic taste in the mouth, nausea. Vomiting, anorexia and abdominal pain.

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 bicarbonate in the development of metabolic acidosis.

Interaction:

Rifampicin

Rifampicin accelerates the metabolism of phenytoin, quinidine, oral anticoagulants and antifungal agents. Antacids, opiates reduce the bioavailability of rifampicin.Reduces the activity of oral hypoglycemic drugs, oral hormonal contraceptives, drugs of the digitalis, antiarrhythmics (disopyramide, mexiletine), glucocorticosteroids, dapsone, hydantoin (fentonin), hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporin A, beta adrenoblockers, enalapril and cimetidine.

Isoniazid

Isoniazid enhances the effects of phenytoin, such as drowsiness and ataxia.

Prednisolone can significantly reduce the concentration of isoniazid in the blood plasma 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 disease. PASK preparations containing bentonite (aluminum hydrosilicate) are prescribed 4 hours after rifampicin intake. Antacids reduce the absorption of isoniazid. Isoniazid reduces the effectiveness of oral contraceptives, oral hypoglycemic drugs, theophylline, tolazomide,vitamin B1 (enhances its excretion); reduces the excretion of triazolam; reduces the content of zinc in the blood (increase its excretion).

Ethambutol

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

Pyrazinamide

Pyrazinamide slightly reduces the concentration of isoniazid in the blood serum, especially in slow acetylators.

Special instructions:

Before the beginning of treatment it is recommended to conduct a complete ophthalmological examination of the patient, which includes the determination of visual acuity, color vision, visual fields and ophthalmoscopy. Such an action on the part of the organ of vision 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. When prescribing the drug, it should be borne in mind that urine, faeces, saliva and tears can be painted in 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 must be corrected to obtain accurate results of the study. 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 developing toxic effects. 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, cutaneous, 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, 120 mg / 60 mg / 300 mg / 225 mg.

Packaging:

Primary packaging:

- 10 tablets are placed in strips of aluminum foil.

- 10 tablets are placed in PVC blisters / Al.

Secondary packaging:

- 10 strips together with instructions for use are placed in a cardboard box;

- 10 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:In a dry, dark place, out of reach of children at a temperature not exceeding 18 ° C.

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

Terms of leave from pharmacies:On prescription

Registration number:П N012243 / 02-2003

Date of registration:08.04.2009

Expiration Date:Unlimited

The owner of the registration certificate: Simpex Pharma Pvt Ltd. Simpex Pharma Pvt Ltd. India

Manufacturer: & nbsp

SIMPEX PHARMA, Pvt. Ltd. India

Representation: & nbspKORAL-MED, CJSCKORAL-MED, CJSC

Information update date: & nbsp01.02.2018

Illustrated instructions

Instructions

Combatub (Combitub)