Levonat

Levonat

levofloxacin

Manufacturer:

Yuria-Pharm

Distributor:

Sannovex
Full Prescribing Info
Contents
Levofloxacin hemihydrate.
Description
Active substance: 1 mL of the solution contains 5 mg of levofloxacin hemihydrate on the 100% basis.
Excipients/Inactive Ingredients: sodium chloride, disodium edetate, water for injections.
Action
Pharmacotherapeutic group: Quinolone antibacterials. Fluoroquinolones. ATC code: J01M A.
Pharmacology: Pharmacodynamics: Levofloxacin is a synthetic antibacterial agent from fluoroquinolone group and is S-enantiomer of racemic mixture of medicinal product ofloxacin.
Mechanism of action: As an antibacterial agent from fluoroquinolone group, levofloxacin has effect on complex of DNA-DNA-gyrase and topoisomerase IV.
Pharmacokinetics/pharmacodynamics ratio: Level of bacterial activity of levofloxacin depends on ratio of peak serum concentration (Сmах) or area under pharmacokinetics curve (AUC) and minimum inhibitory concentration (MIC).
Mechanism of resistance: Main mechanism of resistance is a result of mutation in genes of gyr-A. In vitro there is cross resistance between levofloxacin and other fluoroquinolones. Due to mechanism of action, there is no cross resistance between levofloxacin and other classes of antibacterial agents.
Threshold values: Recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) threshold values of MIC for levofloxacin, that separate sensitive microorganisms from organisms intermediately sensitive to (moderately resistant) and intermediately sensitive from resistant organisms, are given in a table of MIC testing (mg/l) as follows. (See Table 1.)

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Recommended by СLSІ (Clinical and Laboratory Standards Institute, earlier-NCCLS) threshold values of MIC for levofloxacin, that separate sensitive organisms from intermediately sensitive ones, and intermediately sensitive from resistant organisms, are specified in table as follows, for MIC testing (μg/mL) or disk-diffusion method (diameter of zone [mm] with the use of disk with levofloxacin is 5 μg). (See Table 2.)

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Antibacterial spectrum: Spreading of resistance could vary geographically and in course of time, for selected species, and it is advisable to obtain local information concerning resistance, especially for treatment of severe infections. If necessary, a patient should consult a professional, when local occurrence of resistance is such one, that drug utility at least at certain kinds of infections is questionable. (See Table 3.)

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Other data: Hospital acquired infections caused by Р. aeruginosa could require combined therapy.
Pharmacokinetics: Absorption: There is no significant difference in pharmacokinetics of levofloxacin after intravenous and oral administration.
After intravenous administration, drug is accumulated in mucosa of bronchi and bronchial mucous of lung tissue (lung concentration exceeds the one in blood plasma), urine. Levofloxacin penetrates badly into cerebrospinal liquid.
Distribution: Approximately 30-40% of levofloxacin is bound with serum protein. Cumulative effect of levofloxacin at the use of 500 mg once a day multidose administration is practically absent. There is insignificant, but predictable cumulative effect after use of doses of 500 mg twice a day. Steady state is achieved during 3 days.
Penetration into body tissues and fluids: Penetration into mucosa of bronchi, bronchial mucous of lung tissues (BMLT): Maximum concentrations of levofloxacin in mucosa of bronchi and lung bronchial mucous after use of 500 mg orally were 8.3 μg/g and 10.8 μg/mL respectively. These parameters were achieved within one hour after drug administration.
Penetration into lung tissue: Maximum concentrations of levofloxacin in lung tissues after oral administration of 500 mg were approximately 11.3 μg/g and were achieved in 4-6 hours after drug use. The concentration in lungs exceeds the one in blood plasma.
Penetration into bladder content: Maximum concentrations of levofloxacin 4.0-6.7 μg/mL in bladder content were achieved in 2-4 hours after drug administration in 3 days of drug use at doses of 500 mg once or twice a day respectively.
Penetration into cerebrospinal liquid: Levofloxacin penetrates badly into cerebrospinal liquid.
Penetration into prostate tissues: After use of 500 mg of levofloxacin once a day during 3 days, mean concentrations in prostate tissues achieved 8.7 μg/g, 8.2 μg/g and 2.0 μg/g respectively in 2 hours, 6 hours and 24 hours; mean concentration ratio prostate/plasma was 1.84.
Urine concentration: Mean urine concentrations in 8-12 hours after single administration of oral dose 150 mg, 300 mg or 500 mg of levofloxacin were 44 mg/l, 91 mg/l and 200 mg/l respectively.
Biotransformation: Levofloxacin is poorly metabolized, metabolites are desmethyl-levofloxacin and levofloxacin N-oxide.
These metabolites cover less than 5% of drug quantity, eliminated with urine. Levofloxacin is stereochemically stable and is not entitled to inversion of chiral structure.
Elimination: After oral and intravenous administration, levofloxacin is eliminated from blood plasma rather slowly (half-life is 6-8 hours). Generally, it is eliminated by kidneys (over 85% of administered dose).
There is no significant difference regarding pharmacokinetics of levofloxacin after intravenous and oral administration, showing that these routes (oral and intravenous) are interchangeable.
Linearity: Levofloxacin follows linear pharmacokinetics in a range of 50-600 mg.
Patients with renal insufficiency: Renal insufficiency has effect on pharmacokinetics of levofloxacin. In case of nephratonia, renal elimination and clearance is decreased, and half-life periods are increased as it is shown in the table as follows: See Table 4.

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Elderly patients: There are no significant differences in pharmacokinetics of levofloxacin in young patients and elderly patients, except for differences related to creatinine clearance.
Gender differences: Separate analysis regarding female and male patients showed insignificant differences in pharmacokinetics of levofloxacin depending on sex. There is no evidence of the fact that these gender differences are clinically significant.
Indications/Uses
Intravenous administration of levofloxacin (Levonat) is prescribed in adults for treatment of bacterial inflammation processes, if they are caused by bacteria which are sensitive to levofloxacin: pneumonia, complicated urinary infections (including pyelonephritis), skin and soft tissue infections, chronic bacterial prostatitis.
Dosage/Direction for Use
Levofloxacin (Levonat) for intravenous infusion should be used immediately (during 3 hours) after perforation of rubber stopper. Protection from light during infusion is not required.
At room light solution for intravenous infusion can be stored maximum for 3 days not protected from light.
Considering biological equivalence of oral and parenteral dosage forms posology can be the same.
Dosing depends on severity and type of infection.
In adults with unimpaired renal function and creatinine clearance over 50 mL/minute, the following doses are recommended: See Table 5.

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As levofloxacin is primarily eliminated renally, the dose should be decreased in patients with impaired renal function. (See Table 6.)

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Doses for patients with impaired hepatic function: No dose adjustment required, as levofloxacin is metabolized in the liver to insignificantly.
Doses for elderly patients: If the renal function is unimpaired, no adjustment required.
The solution for intravenous administration is infused slowly, by drop infusion, intravenously. The minimum infusion time for one vial of levofloxacin (Levonat).
(100 mL of intravenous solution containing 500 mg of levofloxacin) should be not less than 60 minutes.
Depending on the patient's condition, intravenous administration can be replaced by oral administration after several days, while maintaining the dose.
The therapy duration depends on the progression of the disease. As with other antibacterial drugs, the recommendation is to continue levofloxacin (Levonat).
Treatment during at least 48-72 hours after the body temperature is normalized or after microbiologically proven death of infection agents.
Overdosage
The most important predictable symptoms of overdosing of the drug product levofloxacin (Levonat) belong to the central nervous system (dizziness, impairment of consciousness and seizures).
According to the studies results, prolongation of QT-interval is observed during doses administration which are higher than therapeutic. In cases of overdose, close monitoring of the patient's condition is required, including ECG.
Treatment is symptomatic.
Hemodialysis, including peritoneal dialysis or continuous ambulatory peritoneal dialysis is not effective for elimination of levofloxacin. No specific antidote exists.
Contraindications
Hypersensitivity to levofloxacin or other quinolones, epilepsy, complaints of tendon-related side effects caused by preliminarily used quinolones.
Special Precautions
In the presence of very severe pneumonia, caused by pneumococcus, the drug product levofloxacin (Levonat) may not provide optimal therapeutic effect.
Hospital acquired diseases, caused by P. aeruginosa, may require combined therapy.
Duration of administration: Recommended duration of administration is at least 60 minutes for 500 mg of solution for infusion levofloxacin (Levonat). Concerning ofloxacin, it is known that during infusion, tachycardia and transient increase in blood pressure can occur. Rarely, sudden decrease in blood pressure and circulatory collapse can be observed. If during levofloxacin administration (l-isomer ofloxacin), expressed decrease of blood pressure is observed, administration should be immediately stopped.
Tendinitis and tendons ruptures: Cases of tendinitis can occur rarely. Mostly this concerns Achilles tendon and can cause tendon rupture. Risk of tendinitis and tendon rupture increases in elderly patients and in patients taking corticosteroids. Thus, careful monitoring of these patients is required if they are prescribed levofloxacin (Levonat). Patients should consult a doctor, if they observe tendinitis symptoms. If tendinitis is suspected, treatment with levofloxacin (Levonat) should be immediately discontinued and appropriate treatment should be initiated (e.g., provide tendon immobilization).
Diseases, caused by Clostridium difficile: Diarrhea, especially in severe cases, persistent and/or hemorrhagic diarrhea, during or after treatment with levofloxacin (Levonat), could be a symptom of disease caused by Clostridium difficile, the most severe form of which is pseudomembraneous colitis. If pseudomembraneous colitis is suspected, levofloxacin (Levonat) infusion should be discontinued, and patients should be immediately treated with supportive agents ± specific therapy (e.g., oral administration of vancomycin). Inhibitors of intestinal motility are contraindicated in this clinical situation.
Patients disposed to seizures: Levofloxacin (Levonat) solution for infusion is contraindicated to patients with history of epilepsy. As in cases with other quinolones, it should be used with extreme caution in patients disposed to seizures, such as patients with central nervous system disturbances in history, at concomitant therapy with fenbufen and similar non-steroidal anti-inflammatory medicinal products or medicines that increase seizure activity (lower seizure threshold), such as theophylline (see Interactions). If seizures occur, treatment with levofloxacin should be discontinued.
Patients with glucose-6-phosphatedehydrogenase deficiency: Patients with latent or present defects of glucose-6-phosphatedehydrogenase activity could be disposed to hemolytic reactions at therapy with antibacterial agents of quinolone group, therefore they should use levofloxacin with caution.
Patients with renal insufficiency: As levofloxacin is excreted mainly by kidneys, dose adjustment is required for patients with impaired renal function (renal insufficiency) (see Dosage & Administration).
Hypersensitivity reactions: Sometimes levofloxacin could cause serious potentially fatal reactions of hypersensitivity (e.g., angioedema to anaphylactic shock) after initial dose administration (see Adverse Reactions).
In this case, patients should immediately discontinue the treatment and consult a doctor.
Hypoglycemia: As well as in case with all quinolones, cases of hypoglycemia were reported, especially in patients suffered from diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Careful monitoring of blood glucose levels in patients suffering from diabetes mellitus is recommended (see Adverse Reactions).
Prophylaxis of photosensitivity: Though photosensitivity rarely occurs at administration of levofloxacin, patients are recommended not to be exposed to sunlight or artificial UV radiation in order to avoid it (e.g., lamps of synthetic ultraviolet radiation, solarium).
Patients who obtained vitamin K antagonists: Due to possible increase of coagulation tests parameters (PT/International Normalized Ratio) and/or bleeding in patients taking levofloxacin (Levonat) in combination with vitamin K antagonist (e.g., warfarin), coagulation tests should be monitored if these medicinal products are used concomitantly (see Interactions).
Psychotic reactions: Psychotic reactions were reported in patients who take quinolones, including levofloxacin. Rarely they developed to suicidal ideation and self-destructive behaviour, sometimes after administration of single dose of levofloxacin (see Adverse Reactions). If these reactions occur, administration of levofloxacin should be cancelled and appropriate measures should be taken. Levofloxacin should be used with caution in patients with psychotic disorders or patients with mental disorders in history.
QT interval prolongation: Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT prolongation, such as, e.g.: congenital syndrome of QT prolongation; concomitant use of medicinal products known for ability to prolong QТ interval (e.g., Class ІА or III antiarrhythmic agents, tricyclic antidepressants, macrolides); uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia); elderly patients; heart disease (e.g. heart failure, myocardial infarction, bradycardia) (see Elderly patients under Dosage & Administration, Interactions, Adverse Reactions, and Overdosage).
Peripheral neuropathy: Sensory or sensomotor peripheral neuropathy with potential for rapid development was reported in patients who obtained fluoroquinolones, including levofloxacin. Administration of levofloxacin should be discontinued in order to prevent occurrence of irreversible state if neuropathy symptoms are observed in patient.
Opiates: Determination of urine opiates may provide false-positive result in patients who obtained levofloxacin.
It might be necessary to confirm positive results for opiates by means of specific methods.
Hepatobiliary disorders: Cases of necrotic hepatitis to life-threatening hepatic failure were reported at administration of levofloxacin, mainly in patients with severe basic diseases, e.g. sepsis (see Adverse Reactions).
Patients should be recommended to discontinue therapy and contact their doctor, if liver disease manifestations and symptoms as anorexia, jaundice, black urine, itching or abdominal pains occur.
Effects on ability to drive and operate machines: Patients who drive and operate vehicles and machines should consider possible side effect on nervous system (dizziness, numbness, drowsiness, confused consciousness, vision disorders and acoustic disturbance, coordination disturbance, also during walking).
Use in Children: Application of medicinal product levofloxacin (Levonat) is contraindicated to children and adolescence (under the age of 18), as damage of articular cartilage is possible.
Use In Pregnancy & Lactation
Due to the absence of studies and possible damage of articular cartilage in the body that grows by quinolones, levofloxacin (Levonat) cannot be indicated to pregnant and lactating women. If during the treatment with the drug product levofloxacin (Levonat) pregnancy is diagnosed, this fact should be informed to the doctor.
Adverse Reactions
Infections and invasions: mycoses (and proliferation of other resistant microorganisms).
Blood and lymphatic system disorders: leucopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia.
Immune system disorders: anaphylactic shock (see Precautions), anaphylactic and anaphylactoid reactions may sometimes appear after the first dose administration, increased sensitivity (hypersensitivity) (see Precautions).
Metabolic and nutrition disorders: anorexia, hypoglycemia, especially in patients with diabetes (see Precautions).
Mental disorders: insomnia, nervousness, psychotic disorders, depression, confused consciousness, anxiety, agitation, alarm, psychotic reactions with self-destructive behavior, including suicidal ideation or action (see Precautions), hallucinations.
Nervous system disorders: dizziness, headache, drowsiness. Rare: convulsions, tremor, paresthesia, sensor or sensomotor peripheral neuropathy, disgeusia (subjective taste disorder), including ageusia (loss of the sense of taste), parasomia (smell disorder), including anosmia (absence of the sense of smell).
Sight disorders: visual disturbances.
Hearing and ear labyrinth disorders: vertigo, acoustic disturbance, tinnitus.
Heart disorders: tachycardia, prolongation of the QT interval on the electrocardiogram (see prolongation of the QT interval under Precautions and Overdosage).
Vascular disorders: hypotension.
Respiratory, thoracic and mediastinal disorders: bronchial spasms, dyspnea, allergic pneumonitis.
Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pains, dyspepsia, abdominal distention, constipation, hemorrhagic diarrhea, which in rare cases may indicate enterocolitis, including pseudomembranous colitis.
Hepatobiliary disorder: increased liver enzyme levels (ALT, AST, alkaline phosphatase, gamma-glutaminetransferase). Infrequent: increased blood serum bilirubin, hepatitis, cases of jaundice and heavy liver injury, including cases of acute liver insufficiency have been reported during levofloxacin administration, predominantly in patients with heavy main diseases (see Precautions).
Skin side effects and general hypersensitivity reactions: rash, itching, urticaria, angioneurotic edema, hypersensitivity to sunlight and ultraviolet emission, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exudative multiform erythema, hyperhidrosis. Sometimes skin and mucosal reactions may occur after the first dose administration.
Bone, muscle and connective tissues disorders: tendon injury, (see Precautions), including their inflammations (tendinitis) (for example tendinitis of Achilles tendon), arthralgia, myalgia, tendon rupture (see Dosage & Administration). This side effect may appear within 48 hours from the beginning of treatment and impact the Achilles tendon of both legs. Muscular weakness, which may be significant for patients with myasthenia gravis, muscle damage (rhabdomyolysis) are possible.
Kidneys and urinary system disorders: increased level of creatinine in blood serum, acute renal insufficiency (for example, coursed by interstitial nephritis).
Systemic disorders and conditions in the place of drug administration: pain and redness in the place of infusion; phlebitis, asthenia, pyrexia, pain (including pain in a back, chest and limb pain). Among other side effects, associated with fluoroquinolone administration, are the following: extrapyramidal symptoms and other disturbance of movements coordination; hypersensitive vasculitis; attacks of porphyria in patients with porphyria.
Drug Interactions
Effect of other medicinal products on levofloxacin (Levonat): Theophylline, fenbufen or similar non-steroidal anti-inflammatory medicinal products: Pharmacokinetics of interaction between levofloxacin and theophylline was not identified. However significant decrease of seizure threshold is possible at concomitant use of quinolones and theophylline, non-steroidal anti-inflammatory drugs and other agents which reduce seizure threshold. Levofloxacin concentration in the presence of fenbufen was approximately by 13% higher than at administration of levofloxacin alone.
Probenecid and cimetidine: Effect of probenecid and cimetidine on elimination of levofloxacin is statistically significant. Renal clearance of levofloxacin is decreased in the setting of cimetidine by 24%, and probenecid by 34%. It happens as both drugs are able to block tubular secretion of levofloxacin. However, at doses tested in study, it is not probable that statistically significant kinetic differences had clinical significance. Caution should be treated to concomitant use of levofloxacin with medicinal products, effecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal failure.
Other information: Clinical studies of pharmacology have shown no significant clinical effect on pharmacokinetics of levofloxacin at administration of levofloxacin together with the following medicinal products: calcium carbonate, digoxin, glibenclamide, ranitidine.
Effect of levofloxacin (Levonat) on other medicinal products: Cyclosporine: Half-life period of cyclosporine is increased by 33% at concomitant use with levofloxacin.
Vitamin K antagonists: At concomitant use with vitamin K antagonists (e.g., warfarin), elevation of coagulation tests (PT/International Normalized Ratio) and/or bleeding that could be expressed were reported. Taking this fact into account, patients who took concurrent vitamin K antagonists should monitor coagulation factors (see Precautions).
Medicinal products that prolong QT interval: Levofloxacin, as other fluoroquinolones, should be used with caution in patients who obtain medicinal products known for their ability to prolong QT interval (e.g., Class ІА and III antiarrhythmic agents, tricyclic antidepressants and macrolides). (See QT interval prolongation under Precautions).
Caution For Usage
Incompatibilities: Levofloxacin (Levonat) 5 mg/mL solution for infusion should not be mixed with heparin or alkaline solutions (e.g. sodium hydrogen carbonate), with other medicinal products, except for the medicinal products specified in Dosage & Administration.
Mixing with other solutions for infusion: Levofloxacin (Levonat) 5 mg/mL solution for infusion is compatible with the following solutions for infusion: 0.9% solution of sodium chloride, 5% glucose monohydrate, 2.5% dextrose in Ringer's solution, multicomponent solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).
Storage
Store below 30°С in original package. Solution which is not protected from light should be stored not more than 3 days.
Shelf life: 2 years.
MIMS Class
ATC Classification
J01MA12 - levofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.
Presentation/Packing
Soln for infusion 5 mg/mL (transparent, yellow to greenish-yellow liquid) x 100 mL x 1's, 150 mL x 1's.
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