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

Active substanceIsoniazid + Levofloxacin + Pyrazinamide + Rifampicin + [Pyridoxine]Isoniazid + Levofloxacin + Pyrazinamide + Rifampicin + [Pyridoxine]

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Levofloripin®

pills inwards

M. J. Biofarm Pvt. Ltd. India

Dosage form: & nbspfilm-coated tablets

Composition:

Each film-coated tablet contains:

active substances: isoniazid 75.0 mg, levofloxacin hemihydrate in terms of levofloxacin 200.0 mg, pyrazinamide 400.0 mg, rifampicin 150.0 mg and pyridoxine hydrochloride 10.0 mg;

Excipients: corn starch 140.0 mg, cellulose microcrystalline 75.2 mg, silicon colloidal dioxide 30.0 mg, magnesium stearate 30.0 mg, talc 50.0 mg, sodium carboxymethyl starch 70.0 mg, croscarmellose sodium 34.0 mg;

ready mix "Opadry Brown" 20.0 mg (hypromellose 62.50%, iron oxide red 18.60%, macrogol-400 6.25%, titanium dioxide 5.15%, iron oxide yellow 4.50%, iron oxide black 3.00%) .

Description:The tablets covered with a film cover, dark brown color, the oval form, biconcave. On the cross-section the tablet is reddish-brown in color with white patches.

Pharmacotherapeutic group:Anti-tuberculosis combination drug

ATX: & nbsp

J.04.A.M Combinations of antituberculous drugs

Pharmacodynamics:

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-transfer 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 components 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 slowly and rapidly growing atypical mycobacteria.

Levofloxacin

Fluoroquinolone, a broad-spectrum antimicrobial bactericide. It blocks DNA-gyrase (topoisomerase II) and topoisomerase IV, disrupts supercoiling and cross-linking of DNA gaps, inhibits DNA synthesis, causes profound morphological changes in the cytoplasm, cell wall and bacterial membranes. It is active in vitro against Mycobacterium tuberculosis.

Pyrazinamide

It acts on intracellularly located mycobacteria. The target gene is pyrazinamide synthase 1 mycobacterial fatty acid involved in the biosynthesis mikolievoy 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 in vitro pyrazinamide MPK is 20 mg / l. On non-tuberculosis pathogenic microorganisms do 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 anti-tuberculosis agent I series.

At low concentrations, it has a 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. Active with respect to intracellular and extracellular location 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 B₆. 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:

Isoniazid

Taking isoniazid in together with the drugs that make up Levofloripin does not affect the rate of its absorption from the gastrointestinal tract. 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_ma_x) - 1-2 hours, the maximum concentration of the drug in the blood (C_m_Oh) 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 formation inactive products. In the liver acetylated N-acetyltransferase with formation of N-acetylisoiniazide, which is then converted to isonicotinic acid and monoacetylhydrazium, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 at N- hydroxylation of the active intermediate metabolite. The rate of acetylation genetically is deterministic; 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 failure T_1/2 can increase to 6.7 hours. T_1/2 for children aged 1.5 to 15 years - 2.3-4.9 h, and in newborns - 7.8 - 19.8 h (which is due to the imperfection of the processes of acetylation in newborns.) Despite the fact that the T_1/2 varies considerably in depending on the individual intensity of acetylation processes, average value T_1/2 is 3 hours (reception inside 600 mg) and 5.1 h (900 mg). When repeated appointments T_1/2 shortened up to 2-3 hours. It is mainly excreted by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites - N-acetylisiniazide and isonicotinic acid. At the same time, "fast acetylators" contain N-acetylisiniazide content of 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 up to 73%.

Levofloxacin

Absorption

After oral administration levofloxacin quickly and almost completely is absorbed into the blood from the gastro-intestinal tract. Eating small affects the speed and completeness of absorption. Absolute bioavailability in admissioninside is 99-100%. Maximum concentration in the plasma is achieved through 1-2 hours and for a dose of levofloxacin 250 mg, 500 mg and 750 mg equals 2.8 μg / ml, 5.2 μg / ml and 8.0 μg / ml, respectively.

The pharmacokinetics of levofloxacin is linear in the range of 50 to 1000 mg.

After receiving a single or multiple dose amount of absorbed drug in direct proportion to the dose.

Distribution

Average volume of distribution Levofloxacin varies from 74 to 112 liters. Binding to plasma proteins is 30-40%. It penetrates well into organs and tissues: bronchial mucosa, fluid

epithelial lining, alveolar macrophages (concentration in the lung tissue in 2-5 times the concentration in the plasma), pulmonary tissue, bone tissue, organs genitourinary system, polymorphonuclear white blood cells.

Metabolism

Levofloxacin is metabolized in of an insignificant degree (5% accepted dose). Its metabolites are demethyllevofloxacin and N-oxide levofloxacin, which are excreted kidneys. Levofloxacin is an stereochemically stable and not is subjected to chiral transformations.

Excretion

After oral administration levofloxacin relatively slowly derived from plasma (the half-life of 6-8 hours).

Excreted from the body mainly kidneys by glomerular filtration and tubular secretion. Unchanged the kidneys deduce 70% of the taken internally dose for 24 hours and 87% for 48 hours 4% taken inside the dose is excreted by the intestine within 72 hours.

Pharmacokinetics in selected patient groups

The pharmacokinetics of levofloxacin in men and women do not differ. In renal failure pharmacokinetics Levofloxacin varies. As the kidney function decreases, excretion through the kidneys and kidney clearance decreases, and the elimination half-life increases. Pharmacokinetics in elderly patients does not differ from that in young patients, except for differences related to creatinine clearance.

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_m_Oh) - 1-2 hours Well penetrates into tissues and organs. Metabolised in the liver, where the active metabolite pyrazinic acid is first formed, which later turns into an inactive metabolite - 5-hydroxypyrazinoic 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.

Rifampicin

Absorption - fast, food intake reduces absorption of the drug. When ingestion on an empty stomach 600 mg the maximum concentration of the drug in blood (FROM_ma_x) - 10 μg / ml, and (TS_ma_x) - 2-3 hours. The connection with plasma proteins is 84-91%. Quickly distributed to organs and tissues (the highest concentration in the liver and kidneys), penetrates into the bone tissue, concentration in the saliva - 20% of plasma, the apparent volume distribution - 1.6 l / kg in adults and 1.1 l / kg in children. Through the blood-brain barrier (BBB) penetrates only in case of inflammation meninges. Penetrates through placenta (concentration in fetal plasma - 33% of the concentration in the mother plasma) and excreted in breast milk (breast-fed children receive no more than 1% of therapeutic dose of the drug). Metabolized in the liver with education pharmacologically active metabolite - 25-O-deacetyltrifampicin. Is an autoinducer - accelerates its metabolism in the liver, resulting in system clearance - 6 l / h after taking first dose, increases to 9 l / h after repeated reception. Ingestion the induction of wall enzymes is also probable intestines. T_1/2 after oral administration of 300 mg - 2.5 h, 600 mg - 3-4 hours, 900 mg - 5 hours. After a few days of repeated admission bioavailability decreases, and T_1/2 after multiple intake 600 mg is shortened to 1-2 hours. It is excreted mainly with bile, 80% - in the form of a metabolite; kidneys - 20%. After taking 150-900 mg of the drug the amount of rifampicin withdrawn kidneys in an unchanged form, depends on the of the accepted dose and is 4-20 %. In patients with impaired excretory kidney function T_1/2 lengthened only in those cases where doses of rifampicin exceed 600 mg. Displays when peritoneal dialysis and hemodialysis. In patients with impaired liver function increased concentrations of rifampicin in plasma and elongation T_1/2.

Pyridoxine

Absorbed quickly all over small intestine, more absorbed in the jejunum. Metabolized in the liver with education pharmacologically active metabolites (pyridoxal-5-phosphate and pyridoxamino phosphate). Pyridoxal-5- phosphate 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, It is secreted with breast milk. Period plasma elimination half-life - 15-20 days. It is excreted by the kidneys, and also during hemodialysis.

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.

Contraindications:

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

- pregnancy, lactation period;

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

- peptic ulcer of stomach and duodenal ulcer 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);

- pulmonary heart failure of II-III degree;

- chronic renal failure (CRF);

- gout;

- thrombophlebitis;

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

- violations of the liver function;

- simultaneous use with protease inhibitors: amprenavir, saquinavir, atazanavir, darunavir, fosamprenavir, tipranavir, indinavir, lopinavir, nelfinavir with or without ritonavir;

- Hyperuricemia;

- pseudo-paralytic myasthenia gravis (myasthenia gravis).

Carefully:

Alcoholism; liver failure; peripheral neuropathy; HIV infection; decompensated diseases of the cardiovascular system (chronic heart failure (CHF), coronary heart disease (CHD), arterial hypertension, myocardial infarction, bradycardia); hypothyroidism; elderly age (risk of concomitant decline in kidney function); electrolyte imbalance (eg, hypokalemia, hypomagnesemia); syndrome of congenital extension of the QT interval; simultaneous use of drugs that extend the QT interval; deficiency of glucose-6-phosphate dehydrogenase (increased risk of hemolytic reactions in the treatment of quinolones); porphyria; predisposition to the development of seizures (in patients with previous lesions of the central nervous system(CNS), in patients simultaneously receiving drugs that reduce the threshold of convulsive brain readiness, such as fenbufen, theophylline) (see "Interaction with other medicinal products"); diabetes mellitus, when administered orally to hypoglycemic agents, for example, glibenclamide or insulin (the risk of developing hypoglycemia increases).

Pregnancy and lactation:

The use of the drug during pregnancy and during breastfeeding is contraindicated.

Dosing and Administration:

Inside, regardless of food intake 1 time per day, preferably in the first half of the day. Levofloripin® is dosed by 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 assigned isoniazid in the evening (total daily dose of isoniazid up to 10 mg / kg). According to indications, Levofloripin ® is combined with kanamycin, capreomycin (intramuscularly at a dose of 15 mg / kg once a day for 3 months).

Side effects:

Isoniazid

From the nervous system: headache, dizziness, paresthesia, numbness of the extremities, peripheral neuropathy; rarely excessive fatigue or weakness, irritability, euphoria, sleep disturbances, optic neuritis, polyneuritis, toxic psychosis, emotional lability, depression, convulsions, toxic neuropathy, memory impairment.

From the cardiovascular system (SSS): palpitation, angina, increased blood pressure (BP).

From the digestive system: nausea, vomiting, gastralgia, increased activity of "hepatic" transaminases, bilirubinemia, hyperbilirubinemia, jaundice; rarely - toxic hepatitis, including fatal.

On the part of the organs of hematopoiesis and the system of hemostasis: eosinophilia, thrombocytopenia, hemolytic, sideroblastic or aplastic anemia, agranulocytosis.

Allergic reactions: itching and hyperemia of the skin, skin rash (cortex, maculopapular, exfoliative, purpura), fever, arthralgia, lymphadenopathy, vasculitis.

From the side of metabolism: hypovitaminosis B₆, pellagra, hyperglycemia, metabolic acidosis, gynecomastia.

Other: menorrhagia, a tendency to bleeding and hemorrhage.

Levofloxacin

Heart Disease:

rarely: sinus tachycardia, palpitations;

frequency unknown (postmarketing data): interval lengthening QT, ventricular arrhythmias, ventricular tachycardia, ventricular pirouette tachycardia, which can lead to cardiac arrest.

Violations from the blood and lymphatic system:

infrequently: leukopenia (a decrease in the number of leukocytes in the peripheral blood), eosinophilia (an increase in the number of eosinophils in peripheral blood);

rarely: neutropenia (a decrease in the number of neutrophils in the peripheral blood), thrombocytopenia (a decrease in the number of platelets in the peripheral blood);

frequency unknown (postmarketing data): pancytopenia (decrease in the number of all elements in the peripheral blood), agranulocytosis (absence or sharp decrease in the number of granulocytes in the peripheral blood), hemolytic anemia.

Impaired nervous system:

often: headache, dizziness;

infrequently: drowsiness, tremor, dysgeusia (perversion of taste); rarely: paresthesia, convulsions;

frequency unknown (postmarketing data): peripheral sensory neuropathy, peripheral sensory-motor neuropathy, dyskinesia,extrapyramidal disorders, agesia (loss of taste sensations), parosmia (odor disorder, especially subjective sense of smell, objectively absent), including loss of smell; fainting, benign intracranial hypertension.

Disorders from the side of the organ of vision:

rarely: visual impairments, such as the vagueness of the visible image;

frequency is unknown (post-marketing data): transient loss of vision, uveitis.

Violations from the organ of hearing and labyrinthine disorders:

infrequently: Vertigo (feeling of rejection or circling or own body or surrounding objects);

rarely: tinnitus;

frequency unknown (post-marketing data): hearing loss, hearing loss.

Disturbances from respiratory system, chest organs and mediastinum:

infrequently: dyspnea;

frequency is unknown (post-marketing data): bronchospasm, allergic pneumonitis.

Disorders from the gastro-intestinal tract:

often: diarrhea, vomiting, nausea;

infrequently: abdominal pain, indigestion, flatulence, constipation;

frequency is unknown (post-marketing data): hemorrhagic diarrhea, which in Very rare cases can be sign of enterocolitis, including pseudomembranous colitis.

Infringements from kidneys and urinary tract:

infrequently: increase in concentration serum creatinine;

rarely: acute renal failure (for example, due to the development of interstitial nephritis).

Disturbances from the skin and subcutaneous fabrics:

infrequently: rash, itching, hives, hyperhidrosis;

frequency is unknown (post-marketing data): toxic epidermal Necrolysis, Stevens-Johnson syndrome, exudative erythema multiforme, photosensitivity reaction (increased sensitivity to solar and ultraviolet radiation), leukocytoclastic vasculitis, stomatitis.

Reactions from the skin and mucous membranes shells can sometimes develop even after taking the first dose of the drug.

Disorders from the side of the skeletal- muscular system and connective fabric:

infrequently: arthralgia, myalgia;

rarely: defeat of tendons, including tendonitis (eg, Achilles tendon), muscle weakness, which can be especially dangerous in patients with pseudo-paralytic myasthenia gravis (myasthenia gravis);

frequency is unknown (post-marketing data): rhabdomyolysis, tendon rupture (for example, the Achilles tendon. a side effect can be observed in within 48 hours after initiation of treatment and can be of a two-sided nature) ligament rupture, muscle rupture, arthritis.

Disorders from the metabolism and nutrition:

infrequently: anorexia;

rarely: hypoglycemia, especially in patients with diabetes mellitus (possible signs of hypoglycemia: "wolfish" appetite, nervousness, sweating, trembling);

frequency is unknown: hyperglycemia, hypoglycemic coma.

Infectious and parasitic diseases:

infrequently: fungal infections, development resistance of pathogenic microorganisms.

Vascular disorders:

rarely: lowering of blood pressure.

General disorders:

infrequently: asthenia;

rarely: pyrexia (fever body);

frequency is unknown: Pain (including pain in the back, chest and limbs).

Immune system disorders:

rarely: angioedema;

frequency is unknown (post-marketing data): anaphylactic shock, anaphylactoid shock.

Anaphylactic and anaphylactoid reactions can sometimes develop even after taking the first dose of the drug.

Disorders from the liver and bile ducts:

often: increased activity "hepatic" enzymes in the blood (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (ACT)), increased activity of alkaline phosphatase (AP) and gamma glutamyl transferase (GGT);

infrequently: increase in concentration bilirubin in the blood;

frequency is unknown (post-marketing data): severe hepatic Insufficiency, including cases of development acute hepatic insufficiency, sometimes with a fatal outcome, especially in

patients with severe underlying disease (for example, in patients with sepsis), hepatitis, jaundice.

Disorders of the psyche:

often: insomnia;

infrequently: anxiety, anxiety, confusion of consciousness;

rarely: mental disorders (for example, hallucinations, paranoia), depression, agitation (agitation), sleep disturbances, nightmares; frequency is unknown (post-marketing data): mental disorders with behavioral disorders with causing harm, including suicidal thoughts and suicidal attempts.

Other possible undesirable effects related to all fluoroquinolones:

rarely: porphyria attacks (very rare metabolic disease) in patients with porphyria.

Pyrazinamide

From the digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, liver function disorder (decreased appetite, liver soreness, hepatomegaly, jaundice, yellow atrophy liver), exacerbation of peptic ulcer.

From the nervous system: dizziness, headache, violation sleep, increased excitability, depression, hallucinations, convulsions, confusion consciousness.

On the part of the organs of hematopoiesis and hemostasis systems: thrombocytopenia, sideroblastic anemia,

vacuolization of erythrocytes, porphyria, hypercoagulation, splenomegaly.

From the side of the locomotor system apparatus: arthralgia, myalgia.

From the urinary system: dysuria, interstitial nephritis.

Allergic reactions: skin rash, hives.

Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increase in the concentration of iron in plasma blood.

Rifampicin

From the digestive system: nausea, vomiting, diarrhea, decreased appetite, erosive gastritis, pseudomembranous colitis, increased activity "hepatic" transaminases, alkaline phosphatase in blood plasma, hyperbilirubinemia, hepatitis, acute pancreatitis.

Allergic reactions: urticaria, eosinophilia, angioedema, bronchospasm, arthralgia, fever.

From the nervous system: headache, decreased visual acuity, ataxia, disorientation.

From the urinary system: nephronecrosis, interstitial nephritis.

Other: thrombocytopenic purpura, thrombocytopenia, leukopenia, bleeding, acute hemolytic anemia, exacerbation of gout.

Pyridoxine

Allergic reactions: hypersecretion of hydrochloric acid, pain in epigastric region, numbness limbs, the appearance of a feeling of squeezing in the limbs - a symptom of "stocking" and "gloves", skin rash, itching of the skin.

Overdose:

Symptoms: pulmonary edema, confusion, dizziness, hallucinations, tremor, convulsions, peripheral polyneuropathy, impaired liver function, nausea, vomiting, impaired vision and hearing, slurred speech,respiratory depression, stupor, coma, erosion of the mucous membrane of the gastrointestinal tract. extension of the QT interval.

Treatment: gastric lavage, the appointment of activated charcoal, symptomatic therapy, forced diuresis, artificial ventilation, for the prevention and treatment of neurotoxic effects, anticonvulsant and sedative drugs, hemodialysis. It is necessary to monitor the electrocardiogram.

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 system of cytochrome P450, which increases the metabolism of paracetamol to toxic products. Ethanol increases the hepatotoxicity of isoniazid and accelerates 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, terizidone and disulfiram increase the risk of side effects of isoniazid from the central nervous system.

Raises the hepatotoxicity of rifampicin.

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

Combination with pyridoxine reduces the risk of peripheral neuritis.

FROM caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs due to the risk of side effects.

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

Glucocorticosteroids accelerate the metabolism of isoniazid 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.

Reduces the metabolism of primidone.

Antacid medicines (especially aluminum-containing) slows down absorption and reduces the concentration of isoniazid in the blood (antacids should be taken no earlier than 1 hour after taking isoniazid).

With simultaneous application with enflurane, isoflurane, sevoflurayom isoniazid can increase the formation of inorganic fluoride metabolite, which has a nephrotoxic effect.

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

Salicylic acid derivatives, pheniramidol, chlorpromazine increase the T_1/2 isoniazid.

Chloroquine, chenodeoxifolic acid can enhance the excretion and attenuation of isoniazid.

Haloperidol increases the activity of isoniazid.

Beta-blockers: possibly reducing the clearance of isoniazid.

Isoniazid increases the concentration of progionamide. Increases the toxicity of atropine.

With simultaneous application with insulin, it is possible to increase or decrease the concentration of glucose in the blood.

Increases the excretion of vitamin B₆; decrease in the concentration of calcium, phosphate and hydroxylated form of vitamin D in plasma.

Inhibitors of monoamine oxidase (MAO) increase the risk of side effects from the central nervous system and the cardiovascular system.

Pyrazinamide increases the concentration of isoniazid in the serum, slowing its excretion. Pyrazinamide enhances the anti-tuberculosis effect of ofloxacin and lomefloxacin.

With simultaneous use of isoniazid and stavudine / didanosine, the risk of peripheral neuropathy is increased.

Isoniazid inhibits the biotransformation of antidepressants, increases their concentration in the blood and increases their main effect and side effects.

With the simultaneous use of isoniazid and levodopa, isoniazid can reduce the therapeutic effect of levodopa.

With the simultaneous use of isoniazid and halofantrine, isoniazid increases the concentration of halophthrin in the blood and increases its side effects. With the simultaneous use of isoniazid and alosetron, isoniazid increases the concentration of alosetron in the blood and strengthens its main effect. With the simultaneous use of isoniazid and pimozide, isoniazid increases the concentration of pimozide in the blood and increases its side effects. With the simultaneous use of isoniazid and clopidogrel, the main effect of clopidogrel is reduced. With the simultaneous use of isoniazid and leflunomide, the risk of peripheral neuropathy and hepatotoxicity increases. Leflunomide increases hepatotoxicity of isoniazid

Levofloxacin

Interactions requiring caution

With preparations containing magnesium, aluminum, iron and zinc, didanosine

Preparations containing divalent or trivalent cations, such as zinc or iron salts (drugs for the treatment of anemia), magnesium and / or aluminum-containing preparations (such as antacids), didanosine (only dosage forms containing aluminum or magnesium as a buffer), it is recommended to take at least 2 hours before or 2 hours after taking the drug tablets. Calcium salts have a minimal effect on the absorption of levofloxacin when ingested.

With sucralfate

The effect of the drug is significantly weakened by the simultaneous use of sucralfate (a means to protect the gastric mucosa).Patients receiving the drug and sucralfate, it is recommended to take sucralfate 2 hours after taking levofloxacin.

With theophylline, fenbufen or similar drugs from the group of nonsteroidal anti-inflammatory drugs. reducing the threshold of convulsive readiness of the brain

The pharmacokinetic interaction of levofloxacin with theophylline has not been revealed.

However, with the simultaneous use of quinolones and theophylline, non-steroidal anti-inflammatory drugs and other drugs that reduce the threshold of convulsive brain readiness, there may be a marked decrease in the threshold of convulsive readiness of the brain. The concentration of levofloxacin with simultaneous administration of fenbufen is only increased by 13%.

With indirect anticoagulants (vitamin K antagonists)

Patients receiving treatment levofloxacin in combination with indirect anticoagulants (for example, warfarin), there was an increase prothrombin time / international normalized ratio and / or development of bleeding, including, and heavy. Therefore, with simultaneous use of indirect anticoagulants and levofloxacin requires regular blood coagulation monitoring.

With probenecid and cimetidine

With simultaneous application drugs that violate renal tubular secretion, such as probenecid and cimetidine, and levofloxacin should be observed caution, especially in patients with renal insufficiency. Excretion (renal clearance) levofloxacin slows down under the action of cimetidine by 24% and probenecid on 34%. It is unlikely that this can have clinical significance in normal kidney function.

With cyclosporine

Levofloxacin increased T_1/2 cyclosporine by 33%. Since this increase is clinically insignificant, correction of the dose of cyclosporin for its simultaneous use of levofloxacin is not required.

With glucocorticosteroids

Simultaneous reception glucocorticosteroids increases the risk rupture of tendons.

With medicines, extending the interval QT

Levofloxacin, like others fluoroquinolones, should be used with caution in patients receiving drugs that extend the QT interval (e.g., antiarrhythmic agents class IA and III, tricyclic antidepressants, macrolides, neuroleptics).

Other

Clinical and pharmacological research to explore possible pharmacokinetic interactions Levofloxacin with digoxin, Glibenclamide, ranitidine and warfarin showed that pharmacokinetics of levofloxacin in simultaneous application with these drugs does not change in sufficient degree, so that it has a clinical value.

Pyrazinamide

Pyrazinamide is combined with other anti-tuberculosis drugs. The likelihood of developing a hepatoxic action of the drug increases with 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.

When used simultaneously with drugs that block tubular secretion, it is possible to reduce their excretion and increase toxic reactions. Strengthens the antituberculous action of lomefloxacin.

Rifampicin

Reduces the activity of indirect anticoagulants, oral hypoglycemic drugs (LC), hormonal contraceptives, cardiac glycosides, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tokainid), glucocorticosteroid, dapsone, phenytoin, hexobarbital, portriptilina, benzodiazepines, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine, azathioprine, beta adrenoblockers, slow calcium channel blockers, enalapril, cimetidinerifampicin causes the induction of cytochrome P450 isoenzymes, accelerating their metabolism), lamotrigine, amitriptyline, citalopram, mirtazapine, sertraline, aminophylline, cyclooxygenase 2 inhibitors (celecoxib, etorikoksib, Rofecoxib), hypolipidemic agents (fluvastatin, pravastatin, simvastagin), antitumor drugs (imatinib, irinotecan, tamoxifen), ondosegron, antimalarial drugs (mefloquine, Atovaquone), imidapril, spiraprila, alfentanil. diclofenac, fentanyl, methadone, paracetamol, losartan, chloramphenicol, clarithromycin, doxycycline, ciprofloxacin, linezolid, metronidazole, telithromycin, praziquantel, cimetidine, fexofenadine, darifenacin, cinacalcet, leflunomide,sulfasalazine, codeine, levothyroxine, zaleplon, zolpidem, zopiclone, immunosuppressants, ropivacaine, tranquilizers, neuroleptics, vitamin D_3, bunazosin, delavirdine, nevirapine, efavirspza, zidovudine. Antacids, narcotic analgesics (buprenorphine), anticholinergic drugs, ketoconazole, Activated carbon and bentonite is reduced (in the case of simultaneous ingestion) bioavailability of rifampicin. Isoniazid and / or pyrazinamide increase the frequency and severity of liver function disorders to a greater extent than with the appointment of a single rifampicin, in patients with a previous liver disease. The effect of rifampicin increases with simultaneous admission with the following drugs: sulfamethoxazole + trimethoprim, probenecid. With the simultaneous use of rifampicin (600 mg / day), ritonavir (100 mg twice daily) and saquipavir (1000 mg / day), it is possible to develop severe hepatotoxicity. When combined rifampicin significantly reduces plasma concentrations of atazanavir, darunavir, fosamprenavir, saquipavir, indinavir, lopinavir, nelfinavir and tipranavir, which may lead to a decrease in antiviral activity. Rifampicin can slow the excretion from the gallium radiopaque substances used in the study of the gallbladder. Preparations of para-aminosalicylic acid should be administered no earlier than 4 hours after taking the drug, since absorption may be impaired. Rifampicin can reduce the concentration of valproic acid in the blood plasma and lead to a loss of its therapeutic effect. Therefore, it may be necessary to increase the dose of valproic acid with simultaneous application of rifampicin. The results of two clinical studies of drug interactions in adult healthy volunteers show that rifampicin can both accelerate and slow the distribution of caspofungin. In one of the studies rifampicin and caspofungin was administered within 14 days from the first day of treatment. In the second study, rifampicin for 14 days until the equilibrium concentration of the drug was reached in the blood plasma, and then for another 14 days, both drugs were used simultaneously. At the stage of equilibrium concentration of rifampicin, only a slight change in AUC of caspofungin or concentration inthe time of completion of the infusion, but the residual concentration of caspofungin was reduced by approximately 30%.

The reverse effect of rifampicin was observed with simultaneous co-administration of rifampicin and caspofungin from the first day of treatment: there was a transient increase in the concentration of caspofungin in the blood plasma on the first day (AUC increase by approximately 60%). At the same time, when caspofungin was administered against rifampicin monotherapy during 14 days, no effect of rifampicin on the concentration of caspofungin was noted.

Simultaneous application of fluconazole and rifampicin leads to a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. In patients concurrently receiving fluconazole, it is necessary to consider the advisability of increasing the dose of fluconazole.

With simultaneous application voriconazole with rifampicin (inducer of the isoenzyme system CYP450) at a dose of 600 mg per day of c.ms and AUC voriconazole decreased by 93% and 96% respectively. Rifampicin may impair action terbinafine or reduce its concentration in the plasma. Rifampicin increases ground clearance terbinafine by 100%.

With simultaneous application maraviroc in a dose of 100 mg twice a day with rifampicin in a dose of 600 mg once a day C_max and maraviroc AUC decrease by 34% and 37%, respectively. If combination therapy with rifampicin can not be avoided, consider increasing the dose of the drug maraviroc up to 600 mg twice a day. This dose adjustment has not been studied in patients with HIV. With the simultaneous use of rifampicin and bosentan, a significant reduction in the effectiveness of drug treatment bosentan. With the simultaneous use of bosentan at a dose of 125 mg twice daily for 7 days and rifampicin in 9 healthy volunteers, the concentration of bosentan in blood plasma was reduced by 58%, and in individual patients by 90%. Simultaneous use of rifampicin and interferon beta. In the absence of compatibility studies, interferon beta should not be confused with other drugs. With the simultaneous use of raltegravir with rifampicin at a dose of 400 mg per day, scales and ARL raltegravir are reduced by 38% and 40%, respectively. Rifampicin reduces the concentration of raltegravir in blood plasma. If combination therapy with rifampicin can not be avoided, consider increasing the dose of the drug raltegravir in 2 times.

Etravirine should not be used in combination with rifampicin, since this is can cause a significant decrease the concentration of etravirine in plasma and, consequently, to the loss of its therapeutic effect.

The simultaneous use of rifampicin and abacavir can lead to a negligible reduction of abacavir concentration in plasma blood.

The simultaneous use of rifampicin and roflumilast leads to a decrease in total inhibitory activity of phosphodiesterase-4 (PDE4) by about 60% and, consequently, to reduce the therapeutic effect roflumilast.

Pyridoxine

Strengthens the action of diuretics; weakens the activity of levodopa. Isoniazid, penicillamine, cycloserine and estrogen-containing oral croupsTraceptors weaken the effect pyridoxine.

Combined with cardiac glycosides (pyridoxine promotes an increase in the synthesis of contractile proteins in the myocardium), with glutamic acid, potassium and magnesium asparaginate.

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, people over 35 years of age, the function of the liver is further examined before treatment. In addition to the use of ethanol, additional risk factors include chronic liver disease, parenteral use of the medicinal product and the postpartum period; under these circumstances, monitoring of liver function (laboratory and clinical) should be conducted more often. Patients must be informed about the need to report any manifestations of liver damage (unexplained anorcia, nausea, vomiting, darkening of urine, jaundice, rash, paresthesia of hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right upper quadrant).

During treatment should avoid eating cheese (especially Swiss or Cheshire), fish (especially tuna, sardinella, skipjack), since at 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 activity (MAO) and diaminoksidazy 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

Hospital infections caused by Pseudomonas aeruginosa (Pseudomonas aeruginosa) may require combined treatment. Prevalence acquired resistance of the sown strains of microorganisms may vary depending on the geographic region and over time. In this regard, information about drug resistance in a particular country is required. For the treatment of severe infections or in the ineffectiveness of treatment, a microbiological diagnosis should be made, isolating the pathogen and determining its sensitivity to levofloxacin.

Methicillin-resistant Staphylococcus aureus

There is a high probability that methicillin-resistant Staphylococcus aureus will be resistant to fhorhinolones, including levofloxacin. therefore levofloxacin is not recommended for treatment of established or suspected infections caused by methicillin-resistant Staphylococcus aureus, if laboratory tests did not confirm the susceptibility of this microorganism to levofloxacin.

Patients who are predisposed to develop seizures

Like other quinolones, levofloxacin should be used with great care in patients with a predisposition to convulsions. Such patients include patients with previous lesions central nervous system, such as stroke, severe craniocerebral trauma; patients simultaneously receiving drugs that reduce the threshold convulsive preparedness of the brain, such as fenbufen and others like him nonsteroidal anti-inflammatory drugs or other drugs, lowering the threshold convulsive preparedness, such as theophylline.

Pseudomembranous colitis

Developed during or after treatment levofloxacin diarrhea, especially severe, persistent and / or with blood, can be a symptom of pseudomembranous colitis, caused by Clostridium difficile. AT case of suspected development pseudomembranous colitis treatment levofloxacin should be administered immediately stop and immediately start specific antibiotic therapy (vancomycin, teicoplanin or metronidazole inside). Preparations, inhibiting peristalsis of the intestine, are contraindicated.

Tendonitis

Rarely observed tendonitis with use of quinolones, including levofloxacin, can lead to rupture tendon, including the Achilles tendon. This side effect may develop in 48 hours after initiation of treatment and may be two-sided. Patients elderly age are more predisposed to development of tendonitis. Risk of Gap tendons can increase with simultaneous admission glucocorticosteroids. If suspected on tendonitis should be immediately discontinue drug treatment levofloxacin and start the appropriate treatment of the affected tendon, for example, by providing him with sufficient immobilization.

Hypersensitivity reactions

Levofloxacin can cause serious, potentially fatal, reactions hypersensitivity (angioedema, anaphylactic shock), even with application of initial doses. Patients should immediately stop taking and consult a doctor.

Severe bullous reactions

When taking levofloxacin, we observed cases of severe bullous dermal reactions such as Stevens-Johnson or toxic epidermal necrolysis. If any reactions from the skin or mucous membranes the patient should immediately contact a doctor and do not continue treatment before his consultation.

Disorders from the liver and bile ducts

Cases of development have been reported hepatic necrosis, including development fatal liver failure when using levofloxacin, the main way, in patients with severe major diseases, for example, sepsis. Patients should be warned of the need cessation of treatment and urgent Seek medical advice if signs and symptoms of liver damage, such as anorexia, jaundice, darkening urine, itching and abdominal pain.

Patients with renal disease insufficiency

As levofloxacin excreted, mainly through the kidneys, in patients with impaired renal function required mandatory control of kidney function, and also correction of the dosing regimen. When treatment of elderly patients should be borne in mind that the patients of this groups are often noted violations kidney function.

Preventing the development of reactions photosensitivity

Although photosensitivity when applied levofloxacin develops very rarely, to prevent its development to patients not recommended during treatment and in for 48 hours after the end of treatment levofloxacin to be exposed without special need a strong solar or artificial ultraviolet radiation (for example, to visit the solarium).

Superinfection

As with the application of other antibiotics, the use of levofloxacin, especially during time can lead to increased reproduction insensitive to it microorganisms (bacteria and fungi), which can cause changes in microflora, which is normal is present in humans. As a result, Supinsinfection may develop. Therefore, in during treatment must be conducted reassessment of the patient's condition, and, in case of development during treatment superinfection, should be taken appropriate measures.

Elongation interval QT

Very few cases have been reported prolongation of the QT interval in patients, taking fluoroquinolones, including levofloxacin. When using fluoroquinolones, including levofloxacin, should be observed caution in patients with known risk factors for prolonging the QT interval: in patients with uncorrected electrolyte disorders (with hypokalemia, hypomagnesemia); from the syndrome of congenital lengthening QT interval; with heart disease (heart failure, heart attack myocardium, bradycardia); at simultaneous reception of medicinal drugs that can lengthen the interval QT, such as antiarrhythmics IA and III, tricyclic antidepressants, macrolides, antipsychotics.

Patients of advanced age and patients Women can be more sensitive to drugs, extending the interval QT. therefore should be used with caution in them fluoroquinolones. including levofloxacin.

Patients with a deficiency of glucose-6- phosphate dehydrogenase

In patients with latent or a manifest deficiency of glucose-6- phosphate dehydrogenase predisposition to hemolytic reactions in the treatment of quinolones, that should be taken into account when treatment with levofloxacin.

Hypo-and hyperlikemia (dysglycemia)

As with the use of other quinolones, when using levofloxacin there were cases of development hyperglycemia and hypoglycemia, usually in patients with diabetes mellitus, receiving both treatment oral hypoglycemic preparations (e.g., glibenclamide) or insulin preparations. It was reported cases of hypoglycemic coma. In patients with diabetes mellitus monitoring of concentration is required glucose in the blood.

Peripheral Neuropathy

In patients taking fluoroquinolones, including levofloxacin, was noted sensory and sensory-motor peripheral neuropathy, onset which can be fast. If the patient has symptoms neuropathy, the use of levofloxacin must be terminated. it minimizes the possible risk of developing irreversible changes.

Exacerbation of pseudoparalytic myasthenia gravis

Fluoroquinolones, including levofloxacin, characterized by a blocking neuro- muscle activity and can strengthen muscle weakness in patients with pseudo-paralytic myasthenia gravis. AT postmarketing period were observed adverse reactions, including pulmonary insufficiency, which required artificial ventilation lungs, and death, which associated with the application of fluoroquinolones in patients with pseudo-paralytic myasthenia gravis. The use of levofloxacin in a patient with established diagnosis pseudo-paralytic myasthenia gravis recommended.

Application with air-capillary ways of infection with anthrax

The use of levofloxacin in humans by This indication is based on sensitivity to it Bacillus anthracis, obtained in studies in vitro and in experimental research, conducted on animals, as well as on limited application data levofloxacin in humans. Attending physicians should refer to national and / or national international instruments that reflect the common effort point of view on the treatment of anthrax.

Psychotic reactions

When using quinolones, including levofloxacin, reported on the development of psychotic reactions, which in a very rare cases progressed to development of suicidal thoughts and behavioral disorders with self-infliction harm (sometimes after taking a single dose levofloxacin). With the development of such reactions with levofloxacin should be terminate and designate an appropriate therapy. Caution should be exercised prescribe a drug to patients with psychoses or patients with a history mental illness.

Visual disturbances

With the development of any visual impairment immediate consultation is needed ophthalmologist.

Impact on laboratory tests

In patients receiving levofloxacin, the definition of opiates in urine can lead to false positive results, which should be confirmed by more specific methods. Levofloxacin can inhibit growth Mycobacterium tuberculosis and lead in the future to false-negative results of a bacteriological diagnosis of tuberculosis.

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

In the background of treatment, the skin, sputum, sweat, feces, tear 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 B12 in the blood serum.

Pyridoxine

When determining urobilinogen with Using Ehrlich's reagent can distort results.

Patients previously transferred isoniazid hepatitis, appoint alternative anti-tuberculosis medicines. When need for the resumption of therapy, its begin after full resolution clinical and laboratory signs hepatitis followed by a permanent control of liver function. For any signs of relapse the drug immediately cancel. Do not use ethanol and / or alcoholic beverages upon admission preparation. Do not interrupt reception preparation without consulting the doctor. Care should be taken when use of the drug in weakened patients, patients with insufficient body weight and the elderly in connection with increased risk of toxic phenomena. Care should be taken when use of the drug in patients with alcoholism or mental diseases. Need to monitor ALT activity, ACT every 2-4 weeks in process of treatment and before the beginning of treatment, when the level of hepatic enzyme drug is canceled, resume treatment after normalization indicators.

Effect on the ability to drive transp. cf. and fur:

Such side effects as dizziness, drowsiness, and visual disturbances can reduce psychomotor reactions and the ability to concentrate.

During the treatment with Levofloripin ®, caution should be exercised when managing transport or other technical means, engaging in potentially dangerous activities requiring increased attention and rapid psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 75 mg + 200 mg + 400 mg + 150 mg + 10 g.

Packaging:

For 50 or 100 tablets in a can of polypropylene or in a jar of high pressure polyethylene or low pressure polyethylene.

Each bank along with the instruction for use is placed in a pack of cardboard.

For 500 or 1000 tablets per package of polyethylene film unstabilized.

The plastic bag, together with the instruction for use, is placed in a container made of polypropylene or in a container made of high-density polyethylene or low-density polyethylene (for hospital).

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 expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000024

Date of registration:08.11.2010 / 01.11.2016

Expiration Date:Unlimited

The owner of the registration certificate:M. J. Biofarm Pvt. Ltd.M. J. Biofarm Pvt. Ltd. India

Manufacturer: & nbsp

M.J. BIOPHARM, Pvt. Ltd. India

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp06.03.2018

Illustrated instructions

Instructions

Levofloripin® (Levofolripine®)