Flexin - instructions for use, doses, side effects, contraindications

Excipients: lactose monohydrate, povidone, sodium carboxymethyl starch, talc, silicon dioxide colloidal anhydrous, croscarmellose sodium, glyceryl dibehenate.

Sheath: hypromellose, giprolose, macrogol 6000, iron oxide yellow, iron oxide red, titanium dioxide, talc.

Description:Light orange-pink octagonal, biconvex tablets, film-coated, with a risk on both sides (dosage of 250 mg) or on one side (500 mg dosage).

Pharmacotherapeutic group:Antimicrobial agent - fluoroquinolone

ATX: & nbsp

J.01.M.A Fluoroquinolones

J.01.M.A.12 Levofloxacin

Pharmacodynamics:

Levofloxacin is a broad-spectrum antimicrobial bactericide that blocks DNA-gyrase and topoisomerase IV, suppresses the synthesis of DNA. Below are summarized data on the activity of levofloxacin based on in vitro studies and the results of clinical studies.

Sensitive microorganisms (minimal suppressive concentration (MIC) <2 mg / ml)

Aerobic Gram-positive microorganisms: Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus spp., Listeria monocytogenes, Staphylococcus coagulase-negative methi-S (I) (coagulase-negative methicillin-sensitive / moderately sensitive), Staphylococcus aureus methi-S (methicillin-sensitive), Staphylococcus epidermidis methi-S methicillin-sensitive), Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans streptococci.

Aerobic Gram-negative microorganisms: Acinetobacter baumannii, Acinetobacter spp., Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter spp., Escherichia coli, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella spp., Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella spp, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa (hospital infections caused by Pseudomonas aeruginosa, may require a combined treatment), Pseudomonas spp., Salmonella spp., Serratia marcescens, Serratia spp.

Anaerobic microorganisms: Bacteroides fragilis. Bifidobacterium spp., Fusobacterium spp., Propionibacterium spp, Veilonella spp, Gardnerella vaginalis.

Other microorganisms: Bartonella spp., Chlamydophila pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp., Mycobacterium leprae, Micobacterium tuberculosis, Mycoplasma pneumoniae, Rickettsia spp., Ureaplasma urealyticum.

Moderately sensitive microorganisms (IPC = 4 mg / l)

Aerobic Gram-positive microorganisms: Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R (methicillin-resistant), Staphylococcus haemolyticus methi-R.

Aerobic gram-negative microorganisms: Burkholderia cepacia, Campilobacter jejuni/coli.

Anaerobic microorganisms: Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Prevotella spp., Porphyromonas spp., Peptostreptococcus, Clostridium perfringens.

Resistant to levofloxacin microorganisms (MIC> 8 mg / l)

Aerobic Gram-positive microorganisms: Corynebacterium jeikeium, Staphylococcus aureus methi- R, Staphylococcus coagulase-negative methi-R.

Aerobic gram-negative microorganisms: Alcaligenes xylosoxidans, Burkholderia cepacia.

Anaerobic microorganisms: Bacteroides thetaiotaomicron, Bacteroides fragilis.

Other microorganisms: Mycobacterium avium, Mycoplasma hominis.

Resistance

Resistance to levofloxacin develops as a result of a phased process of gene mutation, encoding both topoisomerases of type II: DNA gyrase and topoisomerase IV (modification of the target of action). Other mechanisms of resistance, such as the mechanism of influence on the penetration barriers of a microbial cell (a mechanism characteristic of Pseudomonas aeruginosa) and the mechanism of efflux (active excretion of the antimicrobial from the microbial cell), can also reduce sensitivity microorganisms to levofloxacin. There is observed between levofloxacin and other fluoroquinolones cross-resistance. In connection with the mechanism of action, cross-resistance between levofloxacin and other antibacterial groups preparations, as a rule, do not happen.

Clinical efficacy (efficacy in clinical studies in the treatment of infections caused by the following microorganisms)

Aerobic Gram-positive microorganisms: Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae Streptococcus pyogenes.

Aerobic Gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella (Branhamella) catarrhal is, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

Other: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Pharmacokinetics:

Suction

Ingestion levofloxacin quickly and almost completely absorbed from the gastrointestinal tract, the bioavailability of the drug is approximately 99-100%. The maximum concentration in the blood plasma is reached within 1-2 hours. The intake of food has practically no effect on the absorption of levofloxacin.

Distribution

The connection with plasma proteins is 30-40 %. After single dose 500 mg levofloxacin volume distribution of levofloxacin is approximately 100 liters, which indicates a good penetration of the drug into human organs and tissues. The equilibrium concentration is reached within 48 hours after taking levofloxacin in a dose of 500 mg 1 or 2 times a day.

When administered orally 500 mg levofloxacin: maximum concentrations in the bronchial mucosa and bronchial secretion are reached approximately 1 hour after and make up 8,3 μg / g and 10.8 μg / ml, respectively; the maximum the concentration in the lung tissue is reached 4-6 hours after the administration of the drug and is about 11.3 μg / g. The concentration of the drug in the lungs exceeds the concentration in the blood plasma.

Levofloxacin poorly penetrates into the cerebrospinal fluid.

Metabolism

Levofloxacin in an insignificant amount is metabolized with the formation of desmethyl-levofloxacin and levofloxacin-N- oxide. These metabolites account for less than 5% of the dose, released through the kidneys.

Excretion

The half-life of levofloxacin (T_1/2) is 6-8 hours. Removal of the drug is mainly carried out by the kidneys (more than 85% of the dose taken). The total clearance of levofloxacin after a single dose of 500 mg is 175 ± 29.2 ml / min.

Have patients with renal insufficiency the pharmacokinetics of levofloxacin varies. As the kidney function worsens, excretion through the kidneys and kidney clearance (ClR) decrease, and T_1/2 increases. Pharmacokinetics for renal insufficiency after a single oral administration of 500 mg of Flexid ®:

Creatinine clearance (CK) (ml / min)

<20

20-49

50-80

ClR

(ml / min)

T 1/2

In elderly patients (over 65 years of age) kinetics of levofloxacin does not differ from that in patients of other age groups, except for differences in pharmacokinetics, related to the change in the clearance of creatinine (CC).

Indications:

Infections caused by sensitive to levofloxacin strains of microorganisms:

- Infections of ENT organs (acute sinusitis);

- infection of the lower respiratory tract (exacerbation of chronic bronchitis, community-acquired pneumonia);

- urinary tract infections;

- chronic bacterial prostatitis;

- infections of the skin and soft tissues;

- as part of complex therapy of drug-resistant forms of tuberculosis.

Contraindications:

- hypersensitivity to levofloxacin or other quinolones, and / or to other components of the drug;

- epilepsy;

- lesions of tendons that occurred with previous treatment with fluoroquinolones;

- rare hereditary forms of lactose intolerance, lactase deficiency or impaired absorption of glucose / galactose (because the composition contains lactose);

- children and adolescence (up to 18 years);

- pregnancy and the period of breastfeeding;

- myasthenia gravis gravis.

Carefully:

Carefully levofloxacin should be used in patients with renal insufficiency; with a deficiency of glucose-6-phosphate dehydrogenase (increased risk of hemolytic anemia); with diabetes mellitus; with psychoses and other mental disorders in the anamnesis; with known risk factors for prolonging the QT interval (congenital syndrome of the extended QT interval, simultaneous administration of drugs that can prolong the QT interval (for example, antiarrhythmics of Classes IA and III, tricyclic antidepressants, macrolides, neuroleptics), older patients and women may be more sensitive to drugs , extending the interval QT); with uncorrected electrolyte disorders (eg, hypomagnesemia, hypokalemia, hyponatremia); in elderly patients; patients with heart disease (eg, heart failure, myocardial infarction, bradycardia); with a predisposition to convulsive reactions (atherosclerosis of cerebral vessels, cerebral circulatory disorders (in anamnesis), organic diseases of the central nervous system); hepatic porphyria; while taking medications that reduce the threshold of convulsive brain readiness (fenbufen and other non-steroidal anti-inflammatory drugs (NSAIDs) similar to it, theophylline); with simultaneous administration of drugs that affect tubular secretion (eg, probenecid and cimetidine).

Dosing and Administration:

Inside.

FLEXID® tablets should be Take one or two times a day, regardless of food intake, without chewing and washing down with a sufficient amount of liquid.

FLEXID® tablets can also be used to continue therapy in those patients who experienced an improvement in the initial / primary treatment with levofloxacin intravenously; Considering bioequivalence of the parenteral and oral form of the drug, it is possible to use the drug in the same dosage.

The drug should be taken at least 2 hours before or 2 hours after taking antacid preparations containing magnesium and / or aluminum, iron salts, zinc salts, sucralfate or didanosine (only didanosine preparations that contain magnesium and aluminum as auxiliary substances).

The dose of the drug and the duration of treatment depend on the indication for use and the severity of the course of the disease.

When selecting Dose pill can be divided into parts by dividing risk. Treatment with the drug Flexi ® should continue at least another 48-72 hours after the disappearance symptoms of the disease.

When levofloxacin is used in patients with normal kidney function (SC more than 50 ml / min)

Indication	The daily dose (depending on severity)	Duration of treatment
Acute Sinusitis	500 mg once a day	10-14 days
Exacerbation of chronic bronchitis	500 mg once a day	7-10 days
Community-acquired pneumonia	500 mg 1-2 times a day	7-14 days
Uncomplicated urinary tract infections	250 mg once a day	3 days
Complicated urinary tract infections	500 mg once a day	7-14 days
Pyelonephritis	500 mg once a day	7-10 days
Chronic bacterial prostatitis	500 mg once a day	28 days
Infections of the skin and soft tissues	500 mg 1-2 times a day	7-14 days
As part of the complex treatment of drug-resistant forms of tuberculosis	500 mg 1-2 times a day	Up to 3 months

The maximum daily dose of 1000 mg

Patients with impaired function of the nights need an individual dose selection (creatinine clearance <50 ml / min).

Creatinine clearance (CC)

Doses depending on the nosology and severity of the condition

The first dose of 250 mg / 24 h

First dose of 500 mg / 24 h

The first dose of 250 mg / 12 h

50-20

ml / min

then:

125

mg / 24 h

then:

250

mg / 24 h

then:

250

mg / 12 h

19-10

ml / min

then:

125

mg / 48 h

then:

125

mg / 24 h

then:

125

mg / 12 h

<10 ml / min (including

hemodialysis and CAPD *)

then:

125

mg / 48 h

then:

125

mg / 24 h

then:

125

mg / 24 h

* after hemodialysis or permanent Outpatient peritoneal dialysis (CAPD) for additional doses is not required.

Doses for patients with impaired liver function

If there is a violation of liver function A special dose selection is required, since levofloxacin not is subject to significant metabolism in the liver. Individual dose selection for elderly patients (over 65 years of age) It is not required (however, it is necessary to control the QC).

Side effects:

According to the World Health Organization (WHO) undesirable reactions are classified according to their frequency of development as follows: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

From the gastrointestinal tract (GIT)

often: nausea, diarrhea, vomiting; infrequently: abdominal pain, indigestion, flatulence, constipation; frequency is unknown: diarrhea with an admixture of blood, which in very rare cases can be a sign of enterocolitis, including pseudomembranous colitis, pancreatitis, stomatitis.

From the liver and biliary tract

often: increased activity of "hepatic" transaminases, increased activity of alkaline phosphatase (APP) and gamma-glutamyl transferase (GGT); infrequently: increased bilirubin concentration in blood plasma; frequency is unknown: severe hepatic insufficiency, including cases of acute hepatic insufficiency, sometimes fatal, mainly in patients with severe underlying disease (eg, in patients with sepsis), hepatitis, jaundice.

From the nervous system

often: headache, dizziness, insomnia; infrequently: vertigo, drowsiness, increased excitability, confusion, anxiety, tremor, anxiety; rarely: "nightmarish" dreams, paresthesia, convulsions, depression, agitation, disorientation, psychotic reactions (eg, hallucinations, paranoia); frequency is unknown: extrapyramidal disorders and other disorders of coordination, dyskinesia, peripheral sensory neuropathy, peripheral sensory-motor neuropathy, violation of the psyche with violation of behavior with self-harm, suicidal thoughts, suicidal attempts, fainting, benign intracranial hypertension.

From the sense organs

infrequently: dysgeusia taste sensitivity); rarely: visual impairment (visual impairment), "ringing" in the ears; frequency is unknown: transitory loss of vision, hearing loss (in the city of hearing loss), parosmia (violation smell), including anosmia (loss of smell), agevzia (loss of taste sensitivity).

From the side of the cardiovascular system

rarely: sinus tachycardia, lowering blood pressure, heart palpitations; frequency is unknown: elongation interval QT, ventricular arrhythmias and ventricular tachycardia of the "pirouette" type (torsades de pointes) predominantly in patients with risk factors for lengthening interval QT, ventricular tachycardia, which can lead to cardiac arrest.

From the musculoskeletal system

infrequently: arthralgia, myalgia; rarely: tendonitis, muscle weakness (is of particular importance for myasthenia patients); frequency is unknown: rhabdomyolysis, tendon rupture (eg, Achilles tendon), ligament rupture, muscle rupture, arthritis.

From the urinary system

infrequently: hypercreatininaemia; rarely: acute renal insufficiency (for example, due to development interstitial nephritis).

From the respiratory system

infrequently: dyspnea; frequency is unknown: bronchospasm, allergic pneumonitis.

From the skin and soft tissues

infrequently: itching, skin rash, urticaria, hyperhidrosis; frequency is unknown: syndrome Stevens-Johnson, toxic epidermal necrolysis (Lyell's syndrome), exudative erythema multiforme, leukocytoplastic vasculitis, photosensitivity reaction.

From the immune system

rarely: angioedema, hypersensitivity reactions; frequency is unknown: anaphylactoid shock, anaphylactic shock.

On the part of the blood and lymphatic system

infrequently: eosinophilia, leukopenia; rarely: neutropenia, thrombocytopenia; frequency is unknown: hemolytic anemia, agranulocytosis, pancytopenia.

From the side of metabolism and nutrition

infrequently: anorexia; rarely: hypoglycemia (increase appetite, increased sweating, trembling, especially in patients with diabetes mellitus); rarely: seizures of porphyria (a very rare metabolic disease) in patients already suffering from this disease, as evidenced by the experience of using other quinolones. A similar effect is not excluded when using levofloxacin. frequency is unknown: hyperglycemia (increased blood glucose concentration), hypoglycemic coma.

Other

infrequently: asthenia, fungal infection, superinfection; rarely: pyrexia body temperature); frequency is unknown: pain (including pain in the back, chest and limbs).

Overdose:

Symptoms: nausea, erosion of the mucous membranes of the gastrointestinal tract, confusion, dizziness, loss of consciousness and convulsions.

Treatment: symptomatic; monitoring of ECG parameters; hemodialysis is ineffective; there is no specific antidote.

Interaction:

Iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only those didanosine preparations that contain magnesium and aluminum as auxiliary substances) significantly reduce the absorption of levofloxacin when taken concomitantly. With simultaneous application levofloxacin and iron salts, zinc salts, antacids,containing magnesium or aluminum, didanosine is recommended to prescribe the latter 2 hours after taking levofloxacin (or 2 hours before taking levofloxacin).

Calcium salts have little effect on the oral absorption of levofloxacin.

Sucralfate significantly reduces the bioavailability of levofloxacin. With the simultaneous use of levofloxacin and sucralfate, it is recommended that the latter be administered 2 hours after taking levofloxacin.

There was no pharmacokinetic interaction between levofloxacin and theophylline. However, with simultaneous use of quinolones with theophylline, with NSAIDs and other drugs that reduce the threshold of convulsive readiness, the threshold of convulsive readiness may decrease.

In the presence of fenbufen, concentrations of levofloxacin approximately 13% higher than when applied in the form of monotherapy.

With the concomitant use of levofloxacin T _1/2 cyclosporine increases by 33%.

With simultaneous application with indirect anticoagulants, coumarin derivatives (e.g., warfarin), there is an increase in the coagulability of the blood (prothrombin time / international normalized ratio (INR)) and / or bleeding.

Cimetidine and probenecid, due to blocking of the channel secretion, reduce the renal clearance of levofloxacin by 24% and 34%, respectively, therefore levofloxacin follows from use caution simultaneously with preparations,

affecting tubular secretion (e.g., probenecid and cimetidiumMr.), especially in patients with impaired renal function. Levofloxacin can extend the interval QT, Therefore, use caution when simultaneous application with antiarrhythmic drugs and IA and III classes, tricyclic antidepressants, macrolides and neuroleptics.

Glucocorticosteroids increase the risk of rupture of tendons.

Clinically significant effects on the pharmacokinetics of levofloxacin did not have a concomitant application of calcium carbonate, glibenclamide, ranitidine, digoxin.

Special instructions:

The prevalence of acquired resistance of the sown strains of microorganisms may vary depending on the geographical region and over time. In this regard, information is required on the resistance of microorganisms to the drug in a particular country.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.

There is a high probability that methicillin-resistant Staphylococcus aureus will be resistant to fluoroquinolones, including levofloxacin. therefore levofloxacin is not recommended for the treatment of established or suspected infections caused by methicillin-resistant Staphylococcus aureus in cases where laboratory tests have not confirmed the susceptibility of this microorganism to levofloxacin.

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (angioedema, anaphylactic shock), even with the use of initial doses (see section "Side effect"). Patients should immediately stop taking the drug and consult a doctor.

When taking levofloxacin, there were cases of severe bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (see section "Side effect").In case of any reactions from the skin and mucous membranes, the patient should immediately consult a doctor and do not continue treatment until his consultation.

There have been reports of hepatic necrosis, including the development of fatal liver failure with levofloxacin, mainly in patients with severe underlying diseases, for example, with sepsis (see section "Side effect"). Patients must be warned about the need to stop treatment and urgent referring to a doctor in case signs and symptoms of liver damage, such as anorexia, jaundice, darkening urine, itching and abdominal pain.

Flexid® tablets should be taken 2 hours before or 2 hours after the intake of iron salts, zinc salts, sucralfate or didanosine (only didanosine preparations that contain magnesium and aluminum as auxiliary substances), since absorption may decrease.

In patients who simultaneously take indirect anticoagulants, coumarin derivatives, it is necessary to control the parameters of blood coagulability.

In the rare cases observed during treatment with quinolones,tendonitis can lead to rupture of ligaments, especially the Achilles tendon. This side effect manifests itself within 48 hours after initiation of therapy. For the elderly and patients taking glucocorticosteroids, there is increased risk of development tendonitis. Therefore, during treatment with levofloxacin, careful monitoring of the condition of such patients. If there is a suspicion of tendonitis (it is necessary to inform patients about its symptoms), taking tablets

Flexi® must be discontinued immediately and start appropriate treatment (eg, immobilization).

Diarrhea (especially in cases of severe, persistent and / or blooded impurities) during or after taking Flakeside® tablets may be a symptom of a disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. If available suspicion of pseudomembranous colitis, taking Flexide ® tablets should be immediately stop and conduct symptomatic treatment (eg, vancomycin orally). In this condition, preparations that inhibit peristalsis are contraindicated.

To treat hospital infections, caused by R.aeruginosa, requires combination therapy.

During treatment with Flexiide, direct sunlight and artificial ultraviolet radiation (solarium) to avoid the development of reactions photosensitization.

It should be borne in mind that in patients with a history of brain damage (stroke, severe craniocerebral injury), seizures may develop, with insufficiency of glucose-6-phosphate dehydrogenase - the risk of development of hemolytic reactions.

Since levofloxacin excreted mainly through the kidneys, in patients with impaired renal function, control over the kidney function is required, as well as correction of the dosing regimen.

It was reported on the lengthening of the interval QT in patients who received fluoroquinolones, including levofloxacin. When using fluoroquinolones, including levofloxacin, caution should be exercised in patients with known risk factors for lengthening the interval QT: uncorrected violation of water-electrolyte balance (hypokalemia, hypomagnesemia); congenital lengthening syndrome QT; heart disease (heart failure, myocardial infarction, bradycardia); simultaneous reception medicines capable of lengthening the interval QT.

Older patients and female patients may be more sensitive to drugs that extend the interval QT. Therefore, they should be used with caution in their fluoroquinolones, including Flexi ® tablets.

In patients with diabetes who receive oral hypoglycemic agents, (eg, glibenclamide) or insulin, when applied Levofloxacin increases the risk of hypo- / hyperglycemia.

There have been reports of cases of hypoglycemic coma. Patients with diabetes are required to monitor the concentration of glucose in the blood.

In patients receiving fluoroquinolones, including levofloxacin, was noted sensory and sensory-motor peripheral neuropathy, the beginning of which can be rapid. When a patient develops symptoms of neuropathy, the use of Flexi tablets should be discontinued (minimizes the possible risk of irreversible changes). Tablets Flexide should not be used in patients with pseudo-paralytic myasthenia gravis (myasthenia gravis).

When using quinolones, including levofloxacin, reported on the development of psychotic reactions, which in very rare cases progressed to development suicidal thoughts and behavioral disorders with self-harm (sometimes after taking a single dose of levofloxacin). When developing such reactions, the treatment with Flexid ® tablets should be discontinued and appropriate therapy. Caution should be used to prescribe the drug to patients with psychoses or patients who have a history of mental illness. With the development of any visual impairment, an immediate consultation of the ophthalmologist is necessary.

In severe community-acquired pneumonia caused by Streptococcus pneumoniae, Flikside tablets may not give the optimal therapeutic effect. Levofloxacin can inhibit growth Mycobacterium tuberculosis, therefore a false negative result is possible bacteriological research on tuberculosis.

In patients taking Flexid ® tablets, the definition of opiates in urine can lead to false positive results, which should be confirmed by more specific methods.

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

Care should be taken when driving vehicles and engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Film coated tablets 250 mg, 500 mg.

Packaging:

Primary packaging 5, 7 or 10 tablets in a blister of PVC / TE / PVDC / aluminum.

Secondary packaging 1, 2, 3 or 5 blisters in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

In a place inaccessible to children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006977/08

Date of registration:01.09.2008

The owner of the registration certificate: Lek dd Lek dd Slovenia

Manufacturer: & nbsp

LEK d.d. Slovenia

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp12.10.2015

Illustrated instructions

Instructions

Flexible® (Flexid®)