Universal reference book for medicines
Product name: LEVOFLORIPIN ® (LEVOFLORIPIN)

Active substance: comb.
drug
Type: Anti-TB drug

Manufacturer: MJ BIOPHARM (India)
Composition, form of production and packaging
Tablets covered with a film membrane of
dark brown color, oval, biconvex;
On a cross section - reddish-brown color with white impregnations.
1 tab.

isoniazid 75 mg

levofloxacin (in the form of hemihydrate) 200 mg

pyrazinamide 400 mg

Rifampicin 150 mg

pyridoxine hydrochloride 10 mg

Auxiliary substances: corn starch, microcrystalline cellulose, silicon dioxide colloid, magnesium stearate, talc, sodium carboxymethyl starch, croscarmellose sodium, ready-mixed Opadry Brown (hypromellose, iron oxide red, macrogol-400, titanium dioxide, iron oxide yellow, ferric oxide black) .

50 pcs.
- polypropylene cans.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Levofloripin ® is a combined five-component preparation containing a fixed amount of isoniazid, levofloxacin, pyrazinamide, rifampicin and pyridoxine.

Isoniazid.
It acts bacteriostatically. Is a prodrug; mycobacterial catalase peroxidase metabolizes isoniazid to the active metabolite, which, when bound to the enoyl (acyl-permeating protein) reductase of fatty acid synthase II, disrupts the conversion of delta 2-unsaturated fatty acids into mycolic acid. The latter is a branched chain fatty acid that, when combined with arabinogalactan (polysaccharide), participates in the formation of the components of the cell wall of Mycobacterium tuberculosis.Isoniazid is also an inhibitor of mycobacterial catalase peroxidase, which reduces the protection of the microorganism against reactive oxygen species and hydrogen peroxide.
Isoniazid is also active against a small number of strains of Mycobacterium kansasii (for infections caused by this pathogen, it is necessary to determine the sensitivity to isoniazid before starting treatment).
For mycobacteria tuberculosis, the minimum inhibitory concentration (MIC) is 0.025-0.05 mg / L. Isoniazid has a moderate effect on slow and fast-growing atypical mycobacteria.
Levofloxacin.
Fluoroquinolone, a broad-spectrum antimicrobial bactericide. It blocks DNA-gyrase (toposomerase II) and topoisomerase IV, disrupts supercoiling and cross-linking of DNA gaps, suppresses DNA synthesis, causes profound morphological changes in the cytoplasm, cell wall and bacterial membranes. It is active in vitro against Mycobacterium tuberculosis, Mycobacterium avium.
Pyrazinamide.
It acts on intracellularly located mycobacteria. The pyrazinomide target is the mycobacterial fatty acid synthase gene 1 involved in the biosynthesis of mycolic acid. More effective in an acidic environment.
Well penetrates into the tuberculosis foci.
Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. To manifest the bactericidal activity of pyrazinamide, the preparation is subjected to enzymatic conversion into the active form - pyrazinic acid. At acidic pH values, the MPC of pyrazinamide in vitro is 20 mg / L. On non-tuberculosis pathogens does not work.
Depending on the dose, it has a bactericidal or bacteriostatic effect.

In the course of treatment, the development of resistance is possible, the probability of which decreases when combined with other antituberculous drugs.

Rifampicin.
Semisynthetic broad-spectrum antibiotic, antituberculous drug of the 1st series.
At low concentrations, it shows bactericidal effect on Mycobacterium tuberculosis, Brucella spp., Chlamydia trachomatis, Legionella pneumophila, Rickettsia typhi, Mycobacterium leprae;
in high concentrations - on some gram-negative microorganisms. Characterized by high activity against Staphylococcus spp. (including penicillinase-forming and many strains of methicillin-resistant). Streptococcus spp., Clostridium spp., Bacillus anthracis; Gram-negative coca: Neisseria meningitidis, Neisseria gonorrhoeae. Gram-positive bacteria acts in high concentrations. It is active with respect to intracellular and extracellularly located microorganisms.Suppresses the DNA-dependent RNA polymerase of microorganisms. With rifampicin monotherapy, the selection of rifampicin-resistant bacteria is relatively rapid.Cross-resistance with other antibiotics (with the exception of the other rifamycins) does not develop.
For mycobacteria tuberculosis, the MIC for rifampicin is 2 mg / L.

Pyridoxine.
Vitamin B 6 . Entering the body, it is phosphorylated, converted to pyridoxal-5-phosphate and is part of the enzymes that carry out decarboxylation, transamination and racemization of amino acids, as well as the enzymatic conversion of sulfur-containing and hydroxylated amino acids.
Participates in the exchange of tryptophan (participation in the reaction of biosynthesis of serotonin).
It is necessary for the normal functioning of the central and peripheral nervous system. Reduces the severity of peripheral polyneuropathy caused by antituberculous drugs.
PHARMACOKINETICS

Studies of the pharmacokinetics of the combined drug Levofloripin ® have not been conducted.

INDICATIONS

Tuberculosis (any form, any localization).

It is used in the intensive phase as part of combination therapy in newly diagnosed patients, with recurrence of a disease with a high risk of drug resistance of mycobacterium tuberculosis.

DOSING MODE

Inside, regardless of food intake 1 time per day, preferably in the first half of the day.
Levofloripin ® is dosed on levofloxacin 13.2 mg / kg body weight, but not more than 5 tablets. Duration of treatment - 3 months.
With a body weight of more than 80 kg is additionally prescribed isoniazid in the evening (total daily dose of isoniazid up to 10 mg / kg).
According to indications, Levofloripin ® is combined with kanamycin, amikacin, capreomycin (IM / 15 mg / kg once a day for 3 months).
SIDE EFFECT

From the side of the nervous system: headache, dizziness, paresthesia, numbness of the extremities, peripheral neuropathy;
rare - excessive fatigue or weakness, irritability, euphoria, sleep disturbances, tremor, anxiety, fear, hallucinations, confusion, polyneuritis, toxic psychosis, emotional lability, depression, convulsions, toxic neuropathy, memory impairment, motor disorders.
From the cardiovascular system: palpitation, angina, increased or decreased blood pressure, vascular collapse, tachycardia, prolongation of the QT interval.

On the part of the digestive system : nausea, vomiting, gastralgia, diarrhea (including with blood), digestive disorders, decreased appetite, erosive gastritis, abdominal pain, pseudomembranous colitis, increased activity of "liver" transaminases, hyperbilirubinemia, hepatomegaly, jaundice , yellow atrophy of the liver;
exacerbation of peptic ulcer, dysbiosis; rarely - toxic hepatitis, incl. with a lethal outcome.
On the part of the hematopoiesis and hemostasis system: eosinophilia, thrombocytopenia, hemolytic and sideroblastic anemia, leukopenia, neutropenia, pancytopenia, erythrocyte vacuolization, agranulocytosis, porphyria, hypercoagulation, splenomegaly, hemorrhages.

From the sense organs: visual impairment, optic neuritis, loss of hearing, smell, taste and tactile sensitivity.

From the musculoskeletal system: arthralgia, muscle weakness, myalgia, tendon rupture, tendonitis, rhabdomyolysis.

From the side of the urinary system: dysuria, hypercreatininaemia, interstitial nephritis, acute renal failure.

Allergic reactions: photosensitization, skin pruritus and itching, skin rash (cortex, maculopapular, exfoliative, purpura), urticaria swelling of the skin and mucous membranes, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), bronchospasm, suffocation , anaphylactic shock, angioedema, allergic pneumonitis, fever, arthralgia, lymphadenopathy, vasculitis.

From the side of metabolism: hypovitaminosis B 6 , pellagra, hyperglycemia, metabolic acidosis, gynecomastia.

Other: very rarely - dysmenorrhea;
induction of porphyria, persistent fever, development of superinfection, acne, increased serum iron concentration.
CONTRAINDICATIONS

- hypersensitivity to isoniazid, levofloxacin, pyrazinamide, rifampicin, pyridoxine;

- pregnancy, lactation;

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

- Stomach ulcer and 12-intestinal gut in the stage of exacerbation;

- ulcerative colitis in the acute stage;

- drug-induced hepatitis, recently transferred (less than 1 year) infectious hepatitis, jaundice, liver failure, liver disease in the acute stage, cirrhosis;

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

severe pulmonary heart failure;

- chronic renal failure;

- gout;

- thrombophlebitis;

- damage to the tendons during the previous treatment with quinolones.

Carefully.
Alcoholism, hepatic insufficiency, peripheral neuropathy, HIV infection, decompensated diseases of the cardiovascular system (chronic heart failure), IHD, hypertension), hypothyroidism, elderly age (risk of concomitant decline in kidney function), hyperuricemia, glucose-6- phosphate dehydrogenase.
PREGNANCY AND LACTATION

Contraindicated during pregnancy, during lactation.

APPLICATION FOR FUNCTIONS OF THE LIVER

Contraindicated: chronic renal failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindicated: drug hepatitis, recently transferred (less than 1 year) infectious hepatitis, jaundice, liver failure, liver disease in the acute stage, cirrhosis.

With caution: liver failure.

In some cases, fatal drug hepatitis develops during treatment, which may occur even after several months of use.
The risk rises with age (the highest frequency in the age group is 35-64 years), especially with daily consumption of ethanol. Therefore, every month it is necessary to monitor the function of the liver, individuals over 35 years of age, the function of the liver is additionally examined before treatment. In addition to ethanol use, additional risk factors are chronic liver disease, parenteral drug use and the postpartum period; under these circumstances, monitoring of liver function (laboratory and clinical) should be conducted more often. Patients should be informed of the need to report any manifestations of liver damage (unexplained anorexia, nausea, vomiting, darkening of the urine, jaundice, rash, paresthesia of the hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right upper quadrant ).
APPLICATION FOR CHILDREN

Contraindicated in children under 18 years.

APPLICATION IN ELDERLY PATIENTS

With caution: elderly age (risk of concomitant decline in kidney function).

SPECIAL INSTRUCTIONS

Isoniazid.
In some cases, fatal drug hepatitis develops during treatment, which may occur even after several months of use. The risk rises with age (the highest frequency in the age group is 35-64 years), especially with daily consumption of ethanol. Therefore, every month it is necessary to monitor the function of the liver, individuals over 35 years of age, the function of the liver is additionally examined before treatment. In addition to ethanol use, additional risk factors are chronic liver disease, parenteral drug use and the postpartum period; under these circumstances, monitoring of liver function (laboratory and clinical) should be conducted more often. Patients should be informed of the need to report any manifestations of liver damage (unexplained anorexia, nausea, vomiting, darkening of the urine, jaundice, rash, paresthesia of the hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right upper quadrant ).
During the treatment, cheese (especially Swiss or Cheshire), fish (especially tuna, sardine) should be avoided, since the simultaneous use of them with isoniazid may cause reactions (skin hyperemia, itching, sensation of heat or cold, palpitations, increased sweating, chills, headache, dizziness) associated with the suppression of monoamine oxidase (MAO) and diaminoxidase activity and leading to a disruption of the metabolism of tyramine and histamine contained in fish and cheese.

It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria;
tests with copper reduction can be false positive; the drug does not affect the enzymatic glucose tests.
Levofloxacin.
During treatment, sun and artificial UV irradiation should be avoided to avoid damage to the skin (photosensitivity).
When there are signs of tendinitis, pseudomembranous colitis, levofloxacin is immediately withdrawn.

It should be borne in mind that the development of seizures is possible in patients with a history of brain damage (stroke, severe trauma), and the risk of hemolysis is a deficiency in glucose-6-phosphate dehydrogenase.

Pyrazinamide.
With prolonged treatment, it is necessary to monitor the activity of alanine aminotransferase (ALT) and the concentration of uric acid in the blood once a month.
In patients with diabetes, the risk of hypoglycemia increases.

Rifampicin.
Against the backdrop of treatment, the skin of sputum, sweat, cat, lacrimal fluid, urine acquire an orange-red color. Can persistently stain soft contact lenses.
Women of reproductive age during treatment should use reliable methods of contraception (oral hormonal contraceptives and additional non-hormonal methods of contraception).
With prolonged use, a systematic control of the peripheral blood picture and liver function is shown. During the treatment period, it is impossible to apply microbiological methods for determining the concentration of folic acid and vitamin B 12 in the blood serum.
Pyridoxine.
When determining urobilinogen using Ehrlich's reagent, it can distort the results.
During the treatment with Levofloripin ® , care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

OVERDOSE

Cases of overdose with Levofloripin ® have not been registered to date.

DRUG INTERACTION

Taking levofloxacin together with isoniazid, rifampicin and, especially, pyrazinamide, significantly increases antimicrobial activity against sensitive and resistant MBT.

Isoniazid.
When combined with paracetamol, hepatotoxicity and nephrotoxicity increase; isoniazid induces a cytochrome P450 system, 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 increase the adverse central effects of isoniazid.

Increases hepatotoxicity of rifampicin.

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.

Enhances the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, theophylline, as it reduces their metabolism due to the activation of cytochrome P450 isoenzymes.

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

Suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and increased toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with slow acetylation of isoniazid);
should be considered when administered as an anticonvulsant with an overdose of isoniazid.
Antacid drugs (especially aluminum-containing drugs) slow down absorption and reduce the concentration of isoniazid in the blood (antacids should be taken no earlier than 1 hour after taking isoniazid).

When used simultaneously with enflurane, isoniazid can increase the formation of an inorganic fluoride metabolite, which has a nephrotoxic effect.

When taken together with rifampicin reduces the concentration of ketoconazole in the blood.

Increases the concentration of valproic acid in the blood (monitoring of valproic acid concentration is required, correction of the dosing regimen may be required).

Levofloxacin.
Increases T 1/2 cyclosporine.
The effect is reduced drugs that depress intestinal motility, sucralfate, aluminum and magnesium-containing antacid drugs and iron salts (a break between intake of at least 2 hours is necessary).

Non-steroidal anti-inflammatory drugs (NSAIDs), theophylline, quinolone derivatives increase the risk of seizures, glucocorticosteroids increase the risk of rupture of tendons.

When used simultaneously with indirect anticoagulants - coumarin derivatives, monitoring of the International Normalized Ratio (MHO) is necessary.

Cimetidine and drugs that block tubular secretion slow down excretion.

Pyrazinamide.
Pyrazinamide is combined with other anti-tuberculosis drugs.
The likelihood of developing a hepatoxic effect of the drug is increased when combined with rifampicin.

Possible development of hypoglycemia in patients with diabetes mellitus.
With simultaneous application with probenecid, a decrease in excretion and, consequently, an increase in toxic reactions is possible.
Rifampicin.
Reduces the activity of anticoagulants, oral hypoglycemic drugs, hormone contraceptives, cardiac glycosides, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tocainide), corticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, theophylline, chloramphenicol, ketoconazole, itraconazole , cyclosporine, azathioprine, beta-blockers, blockers "slow" calcium channel (BCCI), enalapril, cimetidine (rifampicin causes induction of isoenzyme a cytochrome P450, accelerating their metabolism). Antacids, narcotic analgesics, anticholinergic drugs reduce and ketoconazole (in the case of simultaneous ingestion) bioavailability of rifampicin. Isoniazid and / or pyrazinamide increased incidence and severity of liver dysfunction in a greater degree,than in the appointment of rifampicin in patients with previous liver disease.
Pyridoxine. It enhances the effect of diuretics; It weakens the activity of levodopa.
Isoniazid, penicillamine, cycloserine and estrogen-containing oral contraceptives weaken the effect of pyridoxine.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

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 expiration date.
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