Tavanic^® (Tablets, Solution) Instructions for Use

ATC Code

J01MA12 (Levofloxacin)

Active Substance

Levofloxacin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antibacterial drug of the fluoroquinolone group

Pharmacotherapeutic Group

Systemic antibacterial agents; quinolone derivatives; fluoroquinolones

Pharmacological Action

A synthetic broad-spectrum antibacterial drug from the fluoroquinolone group, containing Levofloxacin as the active substance – the levorotatory isomer of ofloxacin. Levofloxacin blocks DNA gyrase and topoisomerase IV, disrupts DNA supercoiling and cross-linking of breaks, inhibits DNA synthesis, and causes profound morphological changes in the cytoplasm, cell wall, and membranes of microbial cells.

Levofloxacin is active against most strains of microorganisms, both in vitro and in vivo.

In vitro susceptible (MIC ≤ 2 mg/ml; inhibition zone ≥17 mm) aerobic gram-positive microorganisms Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp. (including Enterococcus faecalis), Listeria monocytogenes, Staphylococcus spp. (coagulase-negative, methicillin-susceptible/methicillin-intermediate strains), Staphylococcus aureus methi-S (methicillin-susceptible strains), Staphylococcus epidermidis methi-S (methicillin-susceptible strains), Staphylococcus spp. CNS (coagulase-negative), Streptococcus spp. groups C and G (including Streptococcus agalactiae, Streptococcus pneumoniae peni I/S/R (penicillin-susceptible/intermediate/resistant strains), Streptococcus pyogenes, Streptococcus viridans (penicillin-susceptible/resistant strains); aerobic gram-negative microorganisms Acinetobacter baumannii, Acinetobacter spp., Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter spp. (including Enterobacter cloacae, Enterobacter aerogenes), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae ampi-S/R (ampicillin-susceptible/resistant strains), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Moraxella catarrhalis β+/β- (β-lactamase-producing and non-producing strains), Morganella morganii, Neisseria gonorrhoeae non PPNG/PPNG (penicillinase-producing and non-producing strains), Neisseria meningitidis, Pasteurella spp. (including Pasteurella canis, Pasteurella dagmatis, Pasteurella multocida), Proteus mirabilis, Proteus vulgaris, Providencia spp. (including Providencia rettgeri, Providencia stuartii), Pseudomonas spp. (hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy), Salmonella spp., Serratia spp. (including Serratia marcescens); anaerobic microorganisms Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus spp., Propionibacterium spp., Veillonella spp.; other microorganisms: Bartonella spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp. (including Mycobacterium leprae, Mycobacterium tuberculosis), Mycoplasma hominis, Mycoplasma pneumoniae, Rickettsia spp., Ureaplasma urealyticum.

Levofloxacin is moderately active (MIC = 4 mg/l; inhibition zone 16-14 mm) against aerobic gram-positive microorganisms Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R (methicillin-resistant strains), Staphylococcus haemolyticus methi-R (methicillin-resistant strains); aerobic gram-negative microorganisms Campylobacter jejuni, Campylobacter coli; anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Resistant to levofloxacin (MIC ≥ 8 mg/l; inhibition zone ≤ 13 mm) aerobic gram-positive microorganisms: Staphylococcus aureus methi-R (methicillin-resistant strains), Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant strains); aerobic gram-negative microorganisms Alcaligenes xylosoxidans; anaerobic microorganisms Bacteroides thetaiotaomicron; other microorganisms Mycobacterium avium.

Clinical efficacy

In clinical studies, the drug was effective in treating infections caused by the microorganisms listed below.

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) catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

Other Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Resistance

Resistance to levofloxacin develops as a result of a stepwise process of mutations in the genes encoding both type II topoisomerases: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as the mechanism affecting the penetration barriers of the microbial cell (a mechanism characteristic of Pseudomonas aeruginosa) and the efflux mechanism (active removal of the antimicrobial agent from the microbial cell), can also reduce the sensitivity of microorganisms to levofloxacin.

Due to the peculiarities of the mechanism of action of levofloxacin, cross-resistance between levofloxacin and other antimicrobial agents is usually not observed.

Pharmacokinetics

Absorption

After oral administration, Levofloxacin is rapidly and almost completely absorbed from the gastrointestinal tract. Food intake has little effect on its absorption. The absolute bioavailability after oral administration is 99-100%.

After a single dose of levofloxacin 500 mg, C_max in blood plasma is reached within 1-2 hours and is 5.2±1.2 µg/ml.

The pharmacokinetics of levofloxacin are linear in the dose range from 50 to 1000 mg.

C_ss of levofloxacin in plasma when taking 500 mg of levofloxacin 1 or 2 times/day is reached within 48 hours.

On the 10th day of oral administration of Tavanic^® at a dose of 500 mg once/day, the C_max of levofloxacin in plasma was 5.7±1.4 µg/ml, and the C_min of levofloxacin (concentration before the next dose) in plasma was 0.5±0.2 µg/ml.

On the 10th day of oral administration of Tavanic^® at a dose of 500 mg twice/day, the C_max of levofloxacin in plasma was 7.8±1.1 µg/ml, and the C_min of levofloxacin (concentration before the next dose) in plasma was 3.0+0.9 µg/ml.

Distribution

Plasma protein binding is 30-40%.

After single and repeated administration of levofloxacin at a dose of 500 mg, the V_d of levofloxacin averages 100 L, indicating good penetration of levofloxacin into the organs and tissues of the human body.

After a single oral dose of levofloxacin 500 mg, the C_max of levofloxacin in the bronchial mucosa and epithelial lining fluid was reached within 1 hour and 4 hours and was 8.3 µg/g and 10.8 µg/ml, respectively, with penetration ratios into the bronchial mucosa and epithelial lining fluid compared to plasma concentration of 1.1-1.8 and 0.8-3.0, respectively.

After 5 days of oral levofloxacin at a dose of 500 mg, the mean concentrations of levofloxacin 4 hours after the last dose in the epithelial lining fluid were 9.94 µg/ml and in alveolar macrophages – 97.9 µg/ml.

C_max in lung tissue after oral administration of levofloxacin 500 mg was approximately 11.3 µg/g and was reached 4-6 hours after drug administration with penetration ratios of 2-5 compared to plasma concentration.

After 3 days of levofloxacin administration at a dose of 500 mg once or twice/day, the C_max of levofloxacin in alveolar fluid was reached 2-4 hours after drug administration and was 4.0 and 6.7 µg/ml, respectively, with a penetration ratio compared to plasma concentrations of 1.

Levofloxacin penetrates well into cortical and cancellous bone tissue, both in the proximal and distal parts of the femur, with a penetration ratio (bone tissue/plasma) of 0.1-3. C_max of levofloxacin in the cancellous bone tissue of the proximal femur after oral administration of the drug at a dose of 500 mg was approximately 15.1 µg/g (2 hours after drug administration).

Levofloxacin poorly penetrates the cerebrospinal fluid.

After oral administration of levofloxacin at a dose of 500 mg once/day for 3 days, the mean concentration of levofloxacin in prostate tissue was 8.7 µg/g, the mean prostate/plasma concentration ratio was 1.84.

Mean urine concentrations 8-12 hours after oral administration of 150, 300, and 600 mg of levofloxacin were 44 µg/ml, 91 µg/ml, and 162 µg/ml, respectively.

Metabolism

Levofloxacin is metabolized to a small extent (5% of the administered dose). Its metabolites are demethyllevofloxacin and N-oxide Levofloxacin, which are excreted by the kidneys. Levofloxacin is stereochemically stable and does not undergo chiral transformations.

Excretion

After oral administration, Levofloxacin is relatively slowly eliminated from plasma (T_1/2 – 6-8 hours). It is excreted mainly in the urine (more than 85% of the administered dose). The total clearance of levofloxacin after a single dose of 500 mg was 175±29.2 ml/min.

There are no significant differences in the pharmacokinetics of levofloxacin between its intravenous administration and oral administration, confirming that oral and intravenous administration are interchangeable.

Pharmacokinetics in special patient groups

The pharmacokinetics of levofloxacin do not differ between men and women.

Pharmacokinetics in elderly patients do not differ from those in young patients, except for pharmacokinetic differences associated with differences in CrCl.

In renal insufficiency, the pharmacokinetics of levofloxacin change. As renal function declines, renal excretion and renal clearance decrease, and T_1/2 increases.

Pharmacokinetics in renal insufficiency after a single oral dose of Tavanic^® 500 mg

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin

• Community-acquired pneumonia;
• Complicated urinary tract infections and pyelonephritis;
• Chronic bacterial prostatitis;
• Skin and soft tissue infections;
• For the complex treatment of drug-resistant forms of tuberculosis;
• Prevention and treatment of anthrax with airborne infection.

For the treatment of the following infectious and inflammatory diseases, Levofloxacin may be used as an alternative to other antimicrobial drugs

• Acute sinusitis;
• Exacerbation of chronic bronchitis;
• Uncomplicated cystitis.

When using the drug Tavanic^®, official national recommendations on the appropriate use of antibacterial drugs, as well as the sensitivity of microorganisms in a particular country, should be taken into account.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally at 250 or 500 mg 1 or 2 times/day. The tablets should be swallowed without chewing and with a sufficient amount of liquid (from 0.5 to 1 glass). If necessary, the tablets can be broken along the dividing line.

The drug can be taken before meals or at any time between meals, because food intake does not affect the absorption of the drug.

The drug should be taken at least 2 hours before or 2 hours after taking antacid preparations containing magnesium and/or aluminum, zinc, iron salts, or taking sucralfate.

Given that the bioavailability of levofloxacin when using Tavanic^® tablets is 99-100%, when switching a patient from intravenous administration to oral tablets, treatment should be continued at the same dose that was used during intravenous infusion.

The dosage regimen is determined by the nature and severity of the infection, as well as the sensitivity of the suspected pathogen. The duration of treatment varies depending on the course of the disease.

For patients with normal renal function (CrCl >50 ml/min) the following dosage regimen and duration of treatment are recommended.

Acute sinusitis 2 tablets of 250 mg or 1 tablet of 500 mg once/day (corresponding to 500 mg of levofloxacin) – 10-14 days.

Exacerbation of chronic bronchitis: 2 tablets of 250 mg or 1 tablet of 500 mg once/day (corresponding to 500 mg of levofloxacin) – 7-10 days.

Community-acquired pneumonia 2 tablets of 250 mg or 1 tablet of 500 mg 1-2 times/day (corresponding to 500-1000 mg of levofloxacin) – 7-14 days.

Complicated urinary tract infections: 2 tablets of 250 mg once/day (corresponding to 250 mg of levofloxacin) or 1 tablet of 500 mg once/day (corresponding to 500 mg of levofloxacin) – 7-14 days.

Uncomplicated cystitis: 1 tablet of 250 mg once/day (corresponding to 250 mg of levofloxacin) – 3 days.

Pyelonephritis 2 tablets of 250 mg once/day or 1 tablet of 500 mg once/day (corresponding to 500 mg of levofloxacin) – 7-10 days.

Chronic bacterial prostatitis 2 tablets of 250 mg or 1 tablet of 500 mg once/day (corresponding to 500 mg of levofloxacin) – 28 days.

Skin and soft tissue infections: 2 tablets of 250 mg or 1 tablet of 500 mg 1-2 times/day (corresponding to 500-1000 mg of levofloxacin) – 7-14 days.

As part of complex therapy for drug-resistant forms of tuberculosis 1 tablet of 500 mg 1-2 times/day (corresponding to 500-1000 mg of levofloxacin) – up to 3 months.

Prevention and treatment of anthrax with airborne infection 2 tablets of 250 mg or 1 tablet of 500 mg (corresponding to 500 mg of levofloxacin) once/day – up to 8 weeks.

For patients with impaired renal function (CrCl ≤50 ml/min) adjustment of the dosage regimen is required depending on the CrCl value, because Levofloxacin is predominantly excreted by the kidneys.

* After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), no additional doses are required.

For impaired liver function, no dose adjustment is required since Levofloxacin is only minimally metabolized in the liver.

For elderly patients, no dose adjustment is required, except in cases where creatinine clearance drops to 50 ml/min or below.

Missed dose

If a dose is accidentally missed, the tablet should be taken as soon as possible and then Tavanic^® should be continued according to the recommended dosing regimen.

Solution

The dosing regimen is determined by the nature and severity of the infection, as well as the sensitivity of the suspected pathogen.

The duration of treatment varies depending on the course of the disease. As with the use of other antibiotics, treatment with Tavanic^® is recommended to continue for at least 48-78 hours after normalization of body temperature or confirmed eradication of the pathogen.

Treatment with Tavanic^® should not be interrupted or prematurely discontinued without a doctor’s instruction.

Depending on the patient’s condition, after several days of treatment, it is possible to switch from intravenous infusion to oral administration of the same dose of the drug in tablet form (due to the fact that the bioavailability of levofloxacin when taking Tavanic^® tablets is 99-100%) (see the “Pharmacokinetics” section).

For patients with normal renal function (CrCl >50 ml/min), the drug is recommended in the following doses.

Community-acquired pneumonia 500 mg of levofloxacin 1-2 times/day (daily dose – 500-1000 mg of levofloxacin). Treatment course – 7-14 days.

Complicated urinary tract infections 500 mg of levofloxacin once/day (accordingly, daily dose 500 mg of levofloxacin). Treatment course – 7-14 days.

Pyelonephritis 500 mg of levofloxacin once/day (accordingly, daily dose 500 mg of levofloxacin). Treatment course – 7-10 days.

Uncomplicated cystitis 250 mg of levofloxacin once/day (accordingly, daily dose 250 mg of levofloxacin). Treatment course – 3 days.

Chronic bacterial prostatitis 500 mg of levofloxacin once/day (accordingly, daily dose 500 mg of levofloxacin). Treatment course – 28 days.

Infections of the skin and soft tissues 500 mg of levofloxacin 1-2 times/day (accordingly, daily dose 500-1000 mg of levofloxacin). Treatment course – 7-14 days.

Complex treatment of drug-resistant forms of tuberculosis 500 mg of levofloxacin 1-2 times/day (accordingly, daily dose 500-1000 mg of levofloxacin). Treatment course – up to 3 months.

Prophylaxis and treatment of anthrax with airborne infection 500 mg of levofloxacin once/day (accordingly, daily dose 500 mg of levofloxacin). Treatment course – up to 8 weeks.

For patients with impaired renal function (CrCl ≤50 ml/min), dose adjustment is required depending on the CrCl value, since Levofloxacin is predominantly excreted by the kidneys.

* After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), no additional doses are required.

For impaired liver function, no dose adjustment is required since Levofloxacin is only minimally metabolized in the liver.

For elderly patients, no dose adjustment is required, except in cases where creatinine clearance drops to 50 ml/min or below.

Method of administration

The infusion solution of Tavanic^® is administered 1 or 2 times/day.

The infusion solution of Tavanic^® is administered intravenously by slow drip. The duration of infusion of 1 vial of Tavanic^® solution 500 mg (100 ml with 500 mg levofloxacin) should be at least 60 minutes; when administering half a vial (50 ml with 250 mg levofloxacin), the infusion duration should be at least 30 minutes (see the “Special Precautions” section).

Tavanic^®, infusion solution, 500 mg is compatible with the following infusion solutions: 0.9% sodium chloride solution, 5% dextrose solution, 2.5% Ringer’s solution with dextrose, combined solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Tavanic^® solution 500 mg should not be mixed with heparin or solutions having an alkaline reaction (e.g., sodium bicarbonate solution).

After removal of the vial from the cardboard box, the infusion solution can be stored at room lighting without light protection for no more than 3 days.

Adverse Reactions

Definition of frequency of adverse effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated reports), frequency unknown (cannot be estimated from the available data).

Data obtained from clinical studies and post-marketing use of the drug

From the cardiovascular system rare – sinus tachycardia, palpitations, decreased blood pressure; frequency unknown (post-marketing data) – QT interval prolongation, ventricular arrhythmias, ventricular tachycardia, torsades de pointes, which can lead to cardiac arrest.

From the hematopoietic system: uncommon – leukopenia, eosinophilia; rare – neutropenia, thrombocytopenia; frequency unknown (post-marketing data) – pancytopenia, agranulocytosis, hemolytic anemia.

From the nervous system: common – headache, dizziness; uncommon – drowsiness, tremor, dysgeusia (taste disturbance); rare – paresthesia, convulsions; frequency unknown (post-marketing data) – peripheral sensory neuropathy, peripheral sensorimotor neuropathy, dyskinesia, extrapyramidal disorders, ageusia (loss of taste), parosmia (disorder of smell sensation, especially a subjective sensation of an objectively absent smell), including loss of smell, syncope, benign intracranial hypertension.

Mental disorders: common – insomnia; uncommon – feeling of anxiety, confusion; rare – mental disorders (hallucinations, paranoia), depression, agitation, sleep disorders, nightmares; frequency unknown (post-marketing data) – psychiatric disorders with behavioral disorders causing self-harm, including suicidal thoughts and suicide attempts.

From the organ of vision: rare – visual disturbances such as blurred vision; frequency unknown (post-marketing data) – transient loss of vision, uveitis.

From the organ of hearing and labyrinthine disorders: uncommon – vertigo (sensation of deviation or spinning of one’s own body or surrounding objects); rare – tinnitus; frequency unknown (post-marketing data) – hearing impairment, hearing loss.

From the respiratory system uncommon – dyspnea; frequency unknown (post-marketing data) – bronchospasm, allergic pneumonitis.

From the digestive system: common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; frequency unknown (post-marketing data) – hemorrhagic diarrhea, which in very rare cases can be a sign of enterocolitis, including pseudomembranous colitis, pancreatitis.

From the liver and biliary tract: common – increased ALT, AST, ALP, GGT activity; uncommon – increased blood bilirubin concentration; frequency unknown (post-marketing data) – severe liver failure, including cases of acute liver failure (sometimes fatal), especially in patients with severe underlying disease (e.g., sepsis); hepatitis, jaundice.

From the urinary tract: uncommon – increased serum creatinine concentration; rare – acute renal failure (e.g., due to the development of interstitial nephritis).

From the skin and subcutaneous tissues: uncommon – rash, pruritus, urticaria, hyperhidrosis; frequency unknown (post-marketing data) – toxic epidermal necrolysis, Stevens-Johnson syndrome, exudative multiforme erythema, photosensitivity reactions (increased sensitivity to solar and UV radiation), leukocytoclastic vasculitis, stomatitis. Reactions from the skin and mucous membranes can sometimes develop even after the first dose of the drug.

From the immune system rare – angioedema; frequency unknown (post-marketing data) – anaphylactic shock, anaphylactoid shock. Anaphylactic and anaphylactoid reactions can sometimes develop even after the first dose of the drug.

From the musculoskeletal system: uncommon – arthralgia, myalgia; rare – tendon disorders, including tendinitis (e.g., Achilles tendon), muscle weakness, which can be particularly dangerous in patients with myasthenia gravis; frequency unknown (post-marketing data) – rhabdomyolysis, tendon rupture (e.g., Achilles tendon; this side effect can occur within 48 hours after the start of treatment and can be bilateral), ligament rupture, muscle rupture, arthritis.

From metabolism: uncommon – anorexia; rare – hypoglycemia, especially in patients with diabetes mellitus (possible symptoms of hypoglycemia: ravenous appetite, nervousness, sweating, tremor); frequency unknown – hyperglycemia, hypoglycemic coma.

Infectious and parasitic diseases: uncommon – fungal infections, development of resistance of pathogenic microorganisms.

General reactions uncommon – asthenia; rare – pyrexia (increased body temperature); frequency unknown – pain (including back pain, chest pain, limb pain).

Other possible adverse effects related to all fluoroquinolones

Very rare – porphyria attacks in patients already suffering from this disease.

Contraindications

• Epilepsy;
• Myasthenia gravis;
• Tendon disorders associated with previous use of fluoroquinolones;
• Childhood and adolescence up to 18 years (due to incomplete skeletal growth, as the risk of damage to the cartilage growth zones cannot be completely excluded);
• Pregnancy (the risk of damage to the cartilage growth zones in the fetus cannot be completely excluded);
• Breastfeeding period (the risk of damage to the cartilage growth zones of the bones in the child cannot be completely excluded);
• Hypersensitivity to levofloxacin or to other quinolones, as well as to any of the excipients of the drug.

With caution

• In patients predisposed to the development of seizures (in patients with previous CNS lesions, in patients simultaneously receiving drugs that lower the seizure threshold of the brain, such as fenbufen, theophylline);
• In patients with latent or manifested glucose-6-phosphate dehydrogenase deficiency (increased risk of hemolytic reactions during treatment with quinolones);
• In patients with impaired renal function (mandatory monitoring of renal function is required, as well as dose adjustment);
• In patients with known risk factors for QT interval prolongation: in elderly patients; in female patients; in patients with uncorrected electrolyte disturbances (with hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); with simultaneous use of drugs that can prolong the QT interval (class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics);
• In patients with diabetes mellitus receiving oral hypoglycemic drugs (e.g., glibenclamide) or insulin (increased risk of hypoglycemia);
• In patients with severe adverse reactions to other fluoroquinolones, such as severe neurological reactions (increased risk of similar adverse reactions when using levofloxacin);
• In patients with psychoses or in patients with a history of mental illness;
• In elderly patients, in patients after transplantation, as well as with concomitant use of corticosteroids (increased risk of tendinitis and tendon rupture).

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and in breastfeeding women.

Use in Hepatic Impairment

In case of impaired liver function, no special dose selection is required, since Tavanic^® is metabolized in the liver to an extremely insignificant extent.

Use in Renal Impairment

With caution the drug should be prescribed to patients with impaired renal function (mandatory monitoring of renal function is required, as well as dose adjustment).

Pediatric Use

Contraindicated in childhood and adolescence up to 18 years (due to incomplete skeletal growth, as the risk of damage to the cartilage growth zones cannot be completely excluded).

Geriatric Use

For elderly patients, no dose adjustment is required, except in cases where creatinine clearance drops to 50 ml/min or below.

Special Precautions

Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy.

The prevalence of acquired resistance of isolated microbial strains may vary by geographic region and over time. Therefore, information on drug resistance in a particular country is required. For the treatment of severe infections or in case of treatment failure, a microbiological diagnosis should be established with isolation of the pathogen and determination of its sensitivity to levofloxacin.

There is a high probability that methicillin-resistant strains of 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 strains of Staphylococcus aureus, unless laboratory tests confirm the sensitivity of this microorganism to levofloxacin.

The use of fluoroquinolones, including levofloxacin, has been associated with disability and the development of irreversible serious adverse reactions from various body systems, which may develop simultaneously in the same patient. Adverse reactions caused by fluoroquinolones include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, as well as nervous system side effects (hallucinations, anxiety, depression, insomnia, headaches, and confusion). These reactions can develop from several hours to several weeks after starting levofloxacin therapy. The development of these adverse reactions has been observed in patients of any age and without prior risk factors. At the first signs or symptoms of any serious adverse reactions, the use of levofloxacin should be discontinued immediately. The use of fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced any of these serious adverse reactions.

Like other quinolones, Levofloxacin should be used with great caution in patients predisposed to seizures: in patients with previous CNS lesions, such as stroke, severe traumatic brain injury; in patients simultaneously receiving drugs that lower the seizure threshold of the brain, such as fenbufen and other similar NSAIDs, as well as other drugs that lower the seizure threshold, such as theophylline. If seizures develop, levofloxacin treatment should be discontinued.

Diarrhea that develops during or after treatment with levofloxacin, especially if severe, persistent and/or bloody, may be a symptom of pseudomembranous colitis caused by Clostridium difficile. If pseudomembranous colitis is suspected, levofloxacin treatment should be discontinued immediately and specific antibiotic therapy (vancomycin, teicoplanin, or metronidazole orally) should be started immediately. Drugs that inhibit intestinal peristalsis are contraindicated.

When using quinolones, including Levofloxacin, tendinitis is rarely observed, which can sometimes lead to tendon rupture, including the Achilles tendon. This side effect can develop within 48 hours after the start of treatment or several months after completion of fluoroquinolone therapy and can be bilateral. Elderly patients are more predisposed to developing tendinitis; in patients taking fluoroquinolones, the risk of tendon rupture may increase with the simultaneous use of corticosteroids. In addition, patients after transplantation have an increased risk of developing tendinitis, so caution is recommended when prescribing fluoroquinolones to this category of patients.

Patients should be advised to rest at the first signs of tendinitis or tendon rupture and to consult their doctor. If tendinitis is suspected, treatment with Tavanic^® should be discontinued immediately and appropriate treatment of the affected tendon should be initiated, for example, by ensuring sufficient immobilization.

Levofloxacin can cause serious, potentially life-threatening hypersensitivity reactions (angioedema, anaphylactic shock), even when using the drug in initial doses. Patients should immediately discontinue the drug and consult a doctor.

Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, have been observed with the use of levofloxacin. In case of any reactions from the skin or mucous membranes, the patient should immediately consult a doctor and not continue treatment until consultation with a specialist.

Cases of liver necrosis, including the development of fatal liver failure, have been reported with the use of levofloxacin, mainly in patients with severe underlying diseases (e.g., sepsis). The patient should be warned to discontinue treatment and seek immediate medical attention if signs and symptoms of liver damage occur, such as anorexia, jaundice, dark urine, itching, abdominal pain.

Since Levofloxacin is excreted mainly by the kidneys, in patients with impaired renal function, mandatory monitoring of renal function is required, as well as dose adjustment. When treating elderly patients, it should be taken into account that patients in this group often have impaired renal function.

Although photosensitivity occurs very rarely with the use of levofloxacin, to prevent its development, patients are advised to avoid unnecessary strong sunlight or artificial ultraviolet radiation (e.g., visiting a tanning bed) during treatment and for 48 hours after finishing treatment with levofloxacin.

As with the use of other antibiotics, the use of levofloxacin, especially over a long period, may lead to the overgrowth of non-susceptible microorganisms (bacteria and fungi). This can cause changes in the microflora normally present in the human body, potentially resulting in a superinfection. Therefore, the patient’s condition should be re-evaluated during treatment, and if a superinfection develops during therapy, appropriate measures should be taken.

Very rare cases of QT interval prolongation have been reported in patients receiving fluoroquinolones, including Levofloxacin. Caution should be exercised when using fluoroquinolones, including Levofloxacin, in patients with known risk factors for QT interval prolongation: patients with uncorrected electrolyte imbalances (hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); and when taking concomitant medications that can prolong the QT interval, such as Class IA and III antiarrhythmic agents, tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients and female patients may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including Levofloxacin, should be used with caution in these patients.

Patients with latent or manifested glucose-6-phosphate dehydrogenase deficiency have a predisposition to developing hemolytic reactions when treated with quinolones, which should be taken into account when treating with levofloxacin.

As with the use of other quinolones, cases of hyperglycemia and hypoglycemia have been observed with the use of levofloxacin, usually in diabetic patients receiving concomitant treatment with oral hypoglycemic drugs (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose monitoring is required in patients with diabetes mellitus.

Cases of sensory and sensorimotor peripheral neuropathy have been reported in patients receiving fluoroquinolones, including Levofloxacin, the onset of which can be rapid. If a patient develops symptoms of neuropathy, the use of levofloxacin should be discontinued. This minimizes the potential risk of irreversible changes. Patients should be informed of the need to report any symptoms of neuropathy to their treating physician. Fluoroquinolones should not be prescribed to patients with a history of peripheral neuropathy.

Fluoroquinolones, including Levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing adverse reactions, including respiratory failure requiring ventilatory support and fatal outcomes, have been associated with the use of fluoroquinolones in patients with myasthenia gravis. The use of levofloxacin in patients with a diagnosed myasthenia gravis is not recommended.

The use of levofloxacin for the prophylaxis and treatment of anthrax by the inhalational route is based on in vitro susceptibility data for Bacillus anthracis, animal efficacy studies, and limited human use data. The treating physician should refer to national and/or international consensus documents on the management of anthrax.

Psychotic reactions, including suicidal thoughts/attempts, have been observed in patients taking fluoroquinolones, including Levofloxacin, sometimes after a single dose. If such reactions occur, treatment with levofloxacin should be discontinued and appropriate therapy instituted. The drug should be prescribed with caution to patients with psychosis or patients with a history of psychiatric illness.

If any visual disturbances occur, an immediate consultation with an ophthalmologist is necessary.

In patients taking Levofloxacin, urine opiate tests may yield false-positive results, which should be confirmed by more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and subsequently lead to false-negative results in the bacteriological diagnosis of tuberculosis.

Effect on the Ability to Drive and Operate Machinery

Such side effects of the drug Tavanic^® as dizziness or vertigo, drowsiness, and visual disturbances may reduce psychomotor reactions and the ability to concentrate. This may pose a certain risk in situations where these abilities are particularly important (e.g., when driving a car, operating machinery, or working in an unstable position).

Overdose

Symptoms based on data from toxicological studies in animals, the most important expected symptoms of acute overdose of Tavanic^® are CNS symptoms (impaired consciousness, including confusion, dizziness, and seizures). In post-marketing experience, CNS effects, including confusion, seizures, hallucinations, and tremor, have been observed with overdose. Nausea and erosions of the gastrointestinal mucosa are possible. In clinical pharmacological studies with levofloxacin doses exceeding therapeutic levels, QT interval prolongation was demonstrated.

Treatment symptomatic therapy should be administered, with careful patient monitoring, including ECG monitoring. In case of acute overdose of Tavanic^® tablets, gastric lavage and administration of antacids to protect the gastric mucosa are indicated. Levofloxacin is not removed by dialysis (hemodialysis, peritoneal dialysis, or continuous ambulatory peritoneal dialysis). There is no specific antidote.

Drug Interactions

Combinations Requiring Caution

Drugs containing divalent or trivalent cations, such as zinc and iron salts (medicines for treating anemia), antacid preparations containing magnesium and/or aluminum, didanosine (only dosage forms containing aluminum or magnesium as a buffer) are recommended to be taken at least 2 hours before or 2 hours after taking Tavanic^® tablets.

Calcium salts have a minimal effect on the absorption of orally administered levofloxacin.

The effect of Tavanic^® is significantly reduced with the simultaneous use of sucralfate. Patients receiving Levofloxacin and sucralfate are advised to take sucralfate 2 hours after taking levofloxacin.

No pharmacokinetic interaction between levofloxacin and theophylline was identified. The concentration of levofloxacin increases by only 13% with the simultaneous use of fenbufen. However, when quinolones and theophylline, NSAIDs, and other drugs that lower the seizure threshold of the brain are co-administered, a pronounced decrease in the seizure threshold of the brain is possible.

In patients receiving Levofloxacin in combination with indirect anticoagulants (e.g., warfarin), an increase in prothrombin time/INR and/or the development of bleeding, including severe bleeding, has been observed. Therefore, regular monitoring of blood coagulation parameters is necessary when using indirect anticoagulants and levofloxacin concomitantly.

Caution should be exercised when using levofloxacin and drugs that impair the renal tubular secretion of levofloxacin, such as probenecid and cimetidine, especially in patients with renal insufficiency. The elimination (renal clearance) of levofloxacin is slowed by cimetidine by 24% and by probenecid by 34%. This is unlikely to be of clinical significance in normal renal function.

Levofloxacin increased the T_1/2 of cyclosporine by 33%. Since this increase is clinically insignificant, no dose adjustment of cyclosporine is required when used concomitantly with levofloxacin.

Concomitant use of corticosteroids increases the risk of tendon rupture.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs that prolong the QT interval (e.g., Class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics).

Other Combinations

Clinical pharmacological studies conducted to investigate the possible pharmacokinetic interaction of levofloxacin with digoxin, glibenclamide, ranitidine, and warfarin showed that the pharmacokinetics of levofloxacin do not change sufficiently when used concomitantly with these drugs to be of clinical significance.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 5 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.