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

Active substanceIsoniazid + Pyrazinamide + Rifampicin + EthambutolIsoniazid + Pyrazinamide + Rifampicin + Ethambutol

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Dosage form: & nbspcoated tablets

Composition:

Each film-coated tablet contains:

Active substances:

Isoniazid 60 mg or 75 mg or 150 mg.

Pyrazinamide 300 mg or 400 mg or 750 mg.

Rifampicin 120 mg or 150 mg or 225 mg.

Etambutol hydrochloride 225 mg or 275 mg or 400 mg.

Excipients:

Dosage "60 mg + 300 mg + 120 mg + 225 mg":

starch (44.00 mg), shellac (gold) (6.15 mg), isopropanol (not found in the finished product), talc (25.00 mg), povidone K-30 (1.50 mg), silicon dioxide colloid (6.50 mg), crospovidone (100.00 mg), magnesium stearate (15.00 mg).

Shell composition: hypromellose (18.00 mg), isopropanol (not detectable in the finished product), dichloromethane (not found in the finished product), castor oil (4.87 mg), diethyl phthalate (1.50 mg), titanium dioxide (7.50 mg), the colorant sunny sunset is yellow (0.243 mg).

Dosage "75 mg + 400 mg + 150 mg + 275 mg":

starch (222.25 mg), shellac (gold) (7.50 mg), isopropanol (not found in the finished product), talc (34.25 mg), povidone K-30 (2.00 mg), silicon dioxide colloid (5.75 mg), crospovidone (29.00 mg), magnesium stearate (10.50 mg).

Shell composition: hypromellose (12.00 mg), isopropanol (not detected in the finished product), dichloromethane (not found in the finished product), castor oil (4.87 mg), diethyl phthalate (1.50 mg), titanium dioxide (7.50 mg), the colorant sunny sunset is yellow (0.243 mg).

Dosage "150 mg + 750 mg + 225 mg + 400 mg":

starch (12.00 mg), shellac (gold) (10.00 mg), isopropanol (not found in the finished product), talc (40.50 mg), povidone K-30 (2.50 mg), silicon dioxide colloid (7.50 mg), crospovidone (35.00 mg), magnesium stearate (14.00 mg).

Shell composition: hypromellose (16.50 mg), isopropanol (not found in the finished product), dichloromethane (not found in the finished product), castor oil (6.50 mg), diethyl phthalate (1.50 mg), titanium dioxide (10.00 mg), the colorant sunny sunset is yellow (0.324 mg).

Description:

The tablets are biconvex, capsular, covered with a film shell of orange color with a pink tinge.

Pharmacotherapeutic group:Anti-tuberculosis drug combined

ATX: & nbsp

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

Pharmacodynamics:

Isoniazid:

Isoniazid has a bactericidal effect mainly 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 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 various strains of Mycobacterium tuberculosis to pyrazinamide depends on the activity of this enzyme, which can be measured in vitro, thereby assessing the sensitivity of a particular strain. At acidic pH values, the MIC of pyrazinamide In vitro is 20 mg / L. Pyrazinamide does not affect atypical mycobacteria. 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.

Ethambutol:

Etambutol is a bacteriostatic drug that is effective against Mycobacterium tuberculosis resistant to other antituberculosis drugs. Ethambutol 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 nontuberculous mycobacteria (M. kansasii).

Pharmacokinetics:

Isoniazid

After taking the drug Kombitub ® 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.

Excreted by the kidneys in the first 24 hours. Less than 10% of the dose taken is excreted by the intestine. The main products of excretion in urine are N-acetylisoiniazide, monoacetylhydrazine and isonicotinic acid.

Pyrazinamide

After taking the drug Kombitub ® in healthy adults, the maximum concentration of pyrazinamide in plasma reaches 24.13 μg / ml after 3 hours. The half-life of pyrazinamide 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 is excreted by the kidneys in the form of pyrazinic acid and 3.4% in the form of unchanged pyrazinamide.

Rifampicin

After taking the drug Kombitub ® in healthy adults, the maximum concentration of rifampicin in plasma reaches 7.84 mcg / ml. When taken together with food, the absorption of rifampicin, which is part of Combbituba®, 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 plasma of the mother) and in breast milk (breast-fed children 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 metabolized in the liver to deacetyltrifampicin, this metabolite is active. Rifampicin is excreted from the body by the kidneys (up to 30% of the dose taken).

Ethambutol

After taking Combbitub® with 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 elimination half-life is 4 hours and then 10 hours. Approximately 50-70% of the dose administered is excreted by the kidneys unchanged, and the rest - in the form of adelgic 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 by the kidneys. In patients with impaired renal function, ethambutol elimination is slowed down.

Indications:

Combbitube® is indicated for the treatment of the initial stage of pulmonary tuberculosis.

It is also shown in the initial stages of extrapulmonary tuberculosis.

Contraindications:

Combbitub® 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 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;

- Children under 13 years.

Carefully:

- In pregnancy and lactation;

- with psychosis, old age.

Pregnancy and lactation:Use during pregnancy and during breastfeeding is possible only if the intended benefit to the mother exceeds the potential risk to the fetus and the baby.

Dosing and Administration:

Adults and children over 13 years of age.

Each film-coated tablet contains:

Isoniazid 60 mg

Pyrazinamide 300 mg

Rifampicin 120 mg

Etambutol hydrochloride 225 mg

taken inside 1 hour before meals. Dosed according to rifampicin, 10 mg / kg body weight, no more than 5 tablets per day for one dose.

Each film-coated tablet contains:

Isoniazid 75 mg

Pyrazinamide 400 mg

Rifampicin 150 mg

Ethambutol hydrochloride 275 mg

taken inside 1 hour before meals. Dosed according to rifampicin, 10 mg / kg body weight, no more than 4 tablets per day for one dose.

Each film-coated tablet contains:

Isoniazid 150 mg

Pyrazinamide 750 mg

Rifampicin 225 mg

Ethambutol hydrochloride. 400 mg

taken inside 1 hour before meals. Dosed according to rifampicin, 10 mg / kg body weight, no more than 2 tablets per day for one dose.

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 with the drug Kombitub ® 2-3 months.

Side effects:

Side effects in the treatment of the drug Kombitub ® are determined by the active ingredients that make up its composition.

Isoniazid

From the nervous system: headache, dizziness, excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of the limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, mood changes, depression. Seizures can occur in patients with epilepsy.

From the side of 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: gynecomastia, menorrhagia, tendency to bleeding and hemorrhage.

Pyrazinamide

From the digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, liver damage and fulminant hepatitis, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow atrophy of the liver), exacerbation of peptic ulcer.

From the central nervous system: dizziness, headache, sleep disturbances, increased excitability, depression; in some cases - hallucinations, convulsions, confusion.

On the part of the organs of hematopoiesis and the system of hemostasis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

From the side of the musculoskeletal system: arthralgia, myalgia.

From the urinary system: dysuria, interstitial nephritis. Allergic reactions: skin rash, hives.

Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.

Rifampicin

From the digestive systemNausea, vomiting, diarrhea, erosive gastritis, pseudomembranous colitis, heartburn, epigastric discomfort, anorexia, increased activity of "liver" enzymes in the serum, hyperbilirubinemia, hepatitis.

Allergic reactions: itching, urticaria, eosinophilia, Quincke edema, bronchospasm, fever.

From the nervous system: disorientation, headache, ataxia, dizziness, confusion, visual disorders.

From the urinary system: nephronecrosis, interstitial nephritis.

Other: Leukopenia, dysmenorrhea, induction of porphyria, muscle weakness, hyperuricemia, worsening of gout, sore throat and sore tongue, arthralgia.

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.In men, toxic liver damage is observed, which usually develops in the first two weeks after the start of treatment.

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, increased activity of "liver" transaminases, peripheral neuropathy, as well as gastrointestinal disturbances such as "metallic "taste in the mouth, nausea, vomiting, anorexia and abdominal pain. Possible hyperuricemia, exacerbation of gout, as well as allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

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:

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 the 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), reduce the absorption of rifampicin. Antacids reduce the absorption of isoniazid. Isoniazid reduces the effectiveness of oral hypoglycemic drugs, theophylline, tolazomide, vitamin B1 (enhances its excretion); reduces the content of zinc in the blood (increase its excretion).

Pyrazinamide

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

Rifampicin

Rifampicin accelerates the metabolism of phenytoin, quinidine, oral anticoagulants and antifungal drugs. Antacids, opiates reduce the bioavailability of rifampicin. Reduces the activity of oral hypoglycemic drugs, oral hormonal contraceptives, digitalis preparations, 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 isoenzymes of the cytochrome P-450 system. Rifampicin reduces the antimicrobial activity of lomefloxacin (maxachvin) and ofloxacin.

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 eye examination of the patient be performed before starting 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 the drug Kombitub®, control of the condition of the kidneys, liver and blood is necessary.

When appointing Combbituba®, it should be borne in mind that urine, faeces, 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 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 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 concentration of uric acid and exacerbation of gouty arthritis, the treatment is canceled.

Effect on the ability to drive transp. cf. and fur:During the treatment period, care must be taken when operating vehicles and mechanisms,that the drug may have side effects from the nervous system.

Form release / dosage:

Film-coated tablets.

Dosages "60 mg + 300 mg + 120 mg + 225 mg", "75 mg + 400 mg + 150 mg + 275 mg", "150 mg + 750 mg + 225 mg + 400 mg."

Packaging:

Primary packaging:

- 10 tablets are placed in the alpine-polyethylene / al-polyethylene.

Secondary packaging:

- 4, 6 or 10 strips are placed in a cardboard box with instructions for medical use.

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:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N012243 / 01

Date of registration:08.04.2009 / 21.05.2014

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: & nbsp31.01.2018

Illustrated instructions

Instructions

Combatub (Combitub)