Proteb-Lome - instructions for use, doses, side effects, contraindications

Active substanceIsoniazid + Lomefloxacin + Pyrazinamide + Etambutol + PyridoxineIsoniazid + Lomefloxacin + Pyrazinamide + Etambutol + Pyridoxine

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Protub® Lome

pills inwards

FARMASINTEZ, JSC (Irkutsk) Russia

Dosage form: & nbspTfilm-covered abeys.

Composition:

Each film-coated tablet contains:

Active substances:	Isoniazid	135 mg	135 mg
	Lomefloxacin hydrochloride in terms of lomefloxacin	200 mg	200 mg
	Pyrazinamide	370 mg	370 mg
	Ethambutol hydrochloride	325 mg	325 mg
	Pyridoxine hydrochloride	10 mg	15 mg

Excipients:

Core: sorbitol (sorbitol), middle molecular povidone (polyvinylpyrrolidone middle molecular, kollidon 25), microcrystalline cellulose, potato starch, magnesium stearate, magnesium silicate (talc), Aerosil (colloidal silicon dioxide), crospovidone (Kollidon CL).

Shell: 15 hydroxypropylmethylcellulose (hypromellose E15), propylene glycol, magnesium silicate (talc), titanium dioxide, dye tropeolin 0.

Description:

Tablets containing 135 mg Isoniazid 200 mg lomefloxacin, pyrazinamide 370 mg, 325 mg ethambutol hydrochloride and 10 mg of pyridoxine hydrochloride: from yellow to yellow-orange color, capsular, with a risk on one side. On a cross-section a tablet from white to white with kremovatym or yellowish shade of color.

Tablets containing 135 mg of isoniazid, 200 mg of lomefloxacin, 370 mg of pyrazinamide, 325 mg of ethambutol hydrochloride and 15 mg of pyridoxine hydrochloride: from orange to dark orange, capsular, with a risk on one side. On a cross-section a tablet from white to white with kremovatym or yellowish shade of color.

Pharmacotherapeutic group:antituberculous agent combined

ATX: & nbsp

J.04.A.M Combinations of antituberculous drugs

Pharmacodynamics:

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.

Lomefloxacin. Antimicrobial bactericide of broad spectrum of action from the group of fluoroquinolones. Affects the bacterial enzyme DNA-gyrase, which provides supercoiling, forms a complex with its tetramer (subunit of gyrase A2B2) and disrupts transcription and replication of DNA, leads to the death of the microbial cell.Beta-lactamases, produced by pathogens, do not affect the activity of lomefloxacin.

Highly active for gram-negative aerobic microorganisms: Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Salmonella spp., Shigella spp., Moraxella catarrhalis, Morganella morganii, Haemophilus influenzae and parainfluenzae, Legionella pneumophila, Pseudomonas aeruginosa.

Moderately sensitive to the preparation: Staphylococcus aureus, Staphylococcus epidermidis, Serratia liquefaciens and marcescens, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Chlamydia trachomatis, Hafnia alvei, Citrobacter freundii, Aeromonas hydrophila, Proteus mirabilis and Proteus stuartii, Providencia rettgeri and Providencia alcalifaciens, Klebsiella oxytoca, Klebsiella ozaenae, Enterobacter aerogenes, Enterobacter agglomerans.

Stable to the preparation: Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria.

It acts both on the outside and on the intracellularly located Mycobacterium tuberculosis, reduces the time of their isolation from the body, provides a faster resolution of infiltrates. Most microorganisms act at low concentrations (the concentration necessary to control the growth of 90% of strains, usually not more than 1 μg / ml). Resistance is rare.

Pyrazinamide. Pyrazinamide has bactericidal action at acidic pH values. Well penetrates into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. It is subjected to enzymatic conversion into the active form - pyrazinic acid.At acidic pH values, the minimum inhibitory concentration of pyrazinamide in vitro is 20 mg / l. On non-tuberculosis pathogens does not work.

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.

Pyridoxine. Vitamin product. Participates in the metabolism. It is necessary for the normal functioning of the central and peripheral nervous system. With tuberculosis infection, there is a deficiency of pyridoxine. In this regard, the daily dose of vitamin increases to 60 mg. With the simultaneous administration of pyridoxine inwards with isoniazid, lomefloxacin, pyrazinamide and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels.Reduces the neurotoxicity of anti-tuberculosis drugs.

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_mOh) - 1-2 hours, the maximum concentration of the drug in the blood (FROM_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 all tissues and fluids, including cerebrospinal, pleural, ascites; 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 insufficiency 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_1/2significantly varies depending on the individual intensity of the acetylation processes, the average value of 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.

It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites - N-acetylisonic acid and isonicotinic acid. At the same time, "fast acetylators" contain N-acetylisiniazide 93%, while "slow" - not more than 63%.

Small 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.

Lomefloxacin

Active components included in the Proteb®-Lomé, do not affect the rate of absorption of Lomefloxapine from the gastrointestinal tract. Bioavailability of Lomefloxacin is more than 90%. The drug after intake is rapidly absorbed from the gastrointestinal tract. The maximum concentration is 5.1 mg / l, the time to reach is 1-1.5 hours. The body circulates for a long time: the half-life is 8-9 hours.

The connection with blood proteins is insignificant - 10%. Well penetrates into various organs and tissues, where concentrations are created, 9-13 times higher than serum. In small amounts, biotransformation is carried out in the liver with the formation of 5 metabolites, which have little antimicrobial activity.

In 80% is excreted by the kidneys, in 20% with feces, then with saliva. Hepatic failure does not affect the biotransformation of lomefloxacin.

Pyrazinamide

After oral administration, it is quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 10-20%. Time to reach the maximum concentration of the drug in the blood TS_mOh - 1-2 hours. It penetrates well into tissues and organs.

Metabolised in the liver, where an active metabolite, pyrazinic acid, is first formed, which is then converted into an inactive metabolite, 5-hydroxypyrazinic acid.Half-life of blood T_1/2- 8-9 hours.

It is excreted by the kidneys: in unmodified form - 3%, in the form of pyrazinic acid - 33%, in the form of other metabolites - 36%. Removed during hemodialysis.

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_1/2- 3-4 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% (unchanged ). It is excreted in hemodialysis and peritoneal dialysis.

Pyridoxine

Absorbed rapidly throughout the small intestine, a larger amount is absorbed in the jejunum.Metabolised in the liver with the formation of pharmacologically active metabolites (giridoksalfosfat and pyridoxamino phosphate). Pyridoxalphosphate with plasma proteins binds to 90%. It penetrates well into all tissues; accumulates mainly in the liver, less - in the muscles and central nervous system. Penetrates through the placenta, is secreted with breast milk. The half-life is 15-20 days. It is excreted by the kidneys.

Indications:

- Acute progressive course of tuberculosis;

- tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora, sensitive to lomefloxacin.

Contraindications:

- Hypersensitivity to lomefloxacin, isoniazid, pyrazinamide, ethambutol, pyridoxine;

- pregnancy, lactation;

- children's age to 18 years (period of formation and growth of the skeleton);

- peptic ulcer of stomach and duodenum;

- ulcerative colitis;

- acute hepatitis, cirrhosis;

- diseases of the central nervous system (epilepsy and other diseases with a tendency to convulsive seizures);

- diseases of the organs of vision (inflammation of the optic nerve, cataracts, diabetic retinopathy, inflammatory diseases of the eyes);

- gout;

- thrombophlebitis.

Dosing and Administration:

Dosing regimen: Inside, regardless of food intake 1 time per day, preferably in the first half of the day.

Proteb®-Lome is dosed by Lomfloxacin 13.2 mg / kg body weight, but not more than 5 tablets.

Duration of treatment - 3 months.

With a large body weight of 80 kg is additionally assigned isoniazid in the evening (total daily dose of isoniazid up to 10 mg / kg).

According to indications Proteb®-Lome is combined with streptomycin (intramuscularly at a dose of 16 mg / kg once a day for 3 months).

Side effects:

Isoniazid

From the central nervous system (CNS): headache, dizziness; rarely excessive 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 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: very rarely - gynecomastia, menorrhagia, a tendency to bleeding and hemorrhage.

Lomefloxacin

From the digestive systemnausea, vomiting, dry mouth, gastralgia, abdominal pain, diarrhea or constipation, flatulence, pseudomembranous enterocolitis, dysphagia, discoloration of the tongue, decreased appetite or bulimia, taste distortion, dysbiosis, increased activity of "liver" transaminases (alanine aminotransferase (ALT) ), aspartate aminotransferase (ACT), alkaline phosphatase).

From the nervous system: fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, convulsions, hyperkinesia, tremor, paresthesia, nervousness, anxiety, depression, agitation.

From the genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria, urethral bleeding, crystalluria, hematuria, urinary retention, edema; in women - vaginitis, leukorrhea, intermenstrual bleeding, pain in the perineum, vaginal candidiasis; in men - orchitis, epididymitis.

From the side of metabolism: hypoglycemia, gout.

From the side of the musculoskeletal system: arthralgia, vasculitis, calf muscle cramps, back and chest pain.

On the part of the organs of hematopoiesis and the system of hemostasis: bleeding from the digestive tract, thrombocytopenia, purpura, increased fibrinolysis, epistaxis, lymphadenopathy.

From the respiratory system: dyspnoea, respiratory infections, bronchospasm, cough, hypersecretion of phlegm, influenza-like symptoms.

From the sense organs: visual impairment, pain and noise in the ears, pain in the eyes.

From the side of the cardiovascular system: lowering blood pressure, tachycardia, bradycardia, extrasystole, arrhythmias, progression of heart failure and angina pectoris, pulmonary embolism, myocardiopathy, phlebitis.

Allergic reactions: itching, hives, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

Influence on the fetus: in the experiment fetotoxic action (arthropathy) is described.

Other: Candidiasis, increased sweating, chills, thirst, superinfection.

Pyrazinamide

From the digestive systemNausea, vomiting, diarrhea, "metallic" aftertaste in the mouth, liver dysfunction (loss of appetite, liver pain, hepatomegaly, jaundice, yellow atrophy of the liver); exacerbation of peptic ulcer.

From the side of the central nervous system: headache, sleep disturbance, 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.

Ethambutol

From the nervous system and sense organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, impaired color perception,mostly green and red flowers, 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.

Pyridoxine

Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the limbs - a symptom of "stocking" and "gloves"; rarely - skin rash, itching of the skin.

Overdose:

Isoniazid

Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, abnormal liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, convulsions (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).

Lomefloxacin

Treatment: induction of vomiting or gastric lavage, adequate hydration, symptomatic therapy. Hemo- and peritoneal dialysis with an overdose is ineffective (less than 3% is output).

Pyrazinamide

Symptoms: a violation of liver function, an increase in the severity of side effects from the central nervous system.

Treatment: symptomatic

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.

Reduces metabolic transformations and increases the concentration in the blood of alfentanil.

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).

Lomefloxacin

Does not affect the pharmacokinetics of isoniazid.

Does not interact with theophylline, caffeine.

Increases the activity of oral anticoagulants and increases the toxicity of non-steroidal anti-inflammatory drugs.

Forms chelated compounds with antacid medicines and sucralfate, which reduces its bioavailability.

In the treatment of patients with tuberculosis lomefloxacin are used in conjunction with isoniazid, pyrazinamide, streptomycin and ethambutol.

Drugs that block tubular secretion, slow down its excretion.

There is no cross-resistance with penicillins, cephalosporins, aminoglycosides, co-trimoxazole, metronidazole.

Vitamins with mineral supplements should be used 2 hours before or 2 hours after the application of Lomefloxacin.

Pyrazinamide is compatible with other antituberculous drugs: in chronic destructive forms pyrazinamide it is recommended to combine with rifampicin or ethambutol (better tolerability than when combined with rifampicin, but weaker effect). The likelihood of developing a hepatotoxic effect increases when combined with rifampicin.

When used simultaneously with drugs that block tubular secretion, it is possible to reduce their excretion and enhance toxic reactions.

Strengthens the anti-tuberculosis effect of ofloxacin and lomefloxacin.

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.

Pyridoxine

It reduces the effect of levodopa when combined.

Pyridoxine reduces the risk of developing toxic effects of anti-tuberculosis drugs on the central and peripheral nervous system.

Special instructions:

Treatment of patients with a multicomponent drug reduces the medical burden on the patient by 3 times, which contributes to the improvement of drug tolerance.

Form release / dosage:

Tablets coated with a film coat, 135 mg + 200 mg + 370 mg + 325 mg + 10 mg and 135 mg + 200 mg + 370 mg + 325 mg + 15 mg

Packaging:

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

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

Storage conditions:

In a dry, dark place, three temperatures are not higher than 25 ° C.

Keep away from children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:For hospitals

Registration number:LSR-004061/09

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

Protub® Lome (Protub®-Lome)