Glevo (Tablets) Instructions for Use

Marketing Authorization Holder

Glenmark Pharmaceuticals, Ltd. (India)

Contact Information

GLENMARK IMPEX LLC (Russia)

ATC Code

J01MA12 (Levofloxacin)

Active Substance

Levofloxacin (Rec.INN registered by WHO)

Dosage Form

Glevo

Film-coated tablets, 500 mg: 5, 10, or 25 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light orange in color, biconvex, capsule-shaped, with a score on one side.

Excipients: microcrystalline cellulose (avicel pH101), povidone (kollidon K-30), crospovidone (kollidon CL), magnesium stearate.

Shell composition: hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 6000), dibutyl phthalate, talc (purified), titanium dioxide, iron oxide red dye, iron oxide yellow dye.

5 pcs. – blister packs (1) – cardboard packs.
5 pcs. – blister packs (2) – cardboard packs.
5 pcs. – blister packs (5) – cardboard packs.

Clinical-Pharmacological Group

Antibacterial drug of the fluoroquinolone group

Pharmacotherapeutic Group

Antimicrobial agent – fluoroquinolone

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.

Susceptible microorganisms (MIC ≥2 mg/L; inhibition zone ≥17 mm)

• aerobic gram-positive microorganisms: Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp. (including Enterococcus faecalis), Listeria monocytogenes, Staphylococcus coagulase-negative methi-S(I) [coagulase-negative, methicillin-susceptible/-moderately susceptible)], Staphylococcus aureus methi-S (methicillin-susceptible), Staphylococcus epidermidis methi-S (methicillin-susceptible), Staphylococcus spp. CNS (coagulase-negative), Streptococcaceae groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae peni I/S/R (penicillin-moderately susceptible/-susceptible/-resistant), Streptococcus pyogenes, Streptococcus viridans peni-S/R (penicillin-susceptible/-resistant);
• aerobic gram-negative microorganisms: Acinetobacter spp. (including Acinetobacter baumannii), Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter spp. (including Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae ampi-S/R (ampicillin-susceptible/-resistant), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca), Moraxella catarrhalis β+/β- (β-lactamase-producing and non-producing), Morganella morganii, Neisseria gonorrhoeae non PPNG/PPNG (non-penicillinase-producing and penicillinase-producing), Neisseria meningitidis, Pasteurella spp. (including Pasteurella multocida, Pasteurella dagmatis, Pasteurella canis), Proteus mirabilis, Proteus vulgaris, Providencia spp. (including Providencia rettgeri, Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa [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, 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.

Moderately susceptible microorganisms (MIC= 4 mg/L; inhibition zone 16-14 mm)

• aerobic gram-positive microorganisms: Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R (methicillin-resistant), Staphylococcus haemolyticus methi-R (methicillin-resistant);
• aerobic gram-negative microorganisms: Campylobacter jejuni, Campylobacter coli;
• anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Microorganisms resistant to levofloxacin (MIC ≥8 mg/L; inhibition zone ≥13 mm)

• aerobic gram-positive microorganisms: Staphylococcus aureus methi-R (methicillin-resistant), Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant), Corynebacterium jeikeium;
• aerobic gram-negative microorganisms: Alcaligenes xylosoxidans;
• anaerobic microorganisms: Bacteroides thetaiotaomicron;
• other microorganisms: Mycobacterium avium.

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.

Clinical efficacy (efficacy in clinical studies in the treatment of 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.

Pharmacokinetics

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration; food intake has little effect on its absorption. The absolute bioavailability after oral administration is 99-100%. After a single dose of 500 mg, C_max of levofloxacin in plasma is reached within 1-2 hours and is 5.2±1.2 µg/ml. The pharmacokinetics of levofloxacin is linear in the dose range from 50 to 1000 mg. C_ss of levofloxacin in plasma when taken at a dose of 500 mg once or twice a day is reached within 48 hours.

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

On the 10th day of oral administration of levofloxacin at a dose of 500 mg twice a day, C_max was 7.8±1.1 µg/ml, and C_min was 3.0±0.9 µg/ml.

Distribution

Binding to serum proteins is 30-40%. After single and repeated administration of 500 mg of levofloxacin, the V_d of levofloxacin averages 100 L, indicating good penetration of levofloxacin into the organs and tissues of the human body.

Penetration into the bronchial mucosa, epithelial lining fluid, alveolar macrophages. After a single oral dose of 500 mg, C_max of levofloxacin in the bronchial mucosa and epithelial lining fluid was reached within 1 hour or 4 hours and was 8.3 µg/g and 10.8 µg/ml, respectively. The penetration coefficients into the bronchial mucosa and epithelial lining fluid, compared to the concentration in plasma, are 1.1-1.8 and 0.8-3.0, respectively. After 5 days of oral administration of the drug at a dose of 500 mg, the average 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.

Penetration into lung tissue. C_max of levofloxacin in lung tissue after oral administration of the drug at a dose of 500 mg was reached after 4-6 hours and was approximately 11.3 µg/g with penetration coefficients of 2.0-5.0 compared to the concentration in plasma.

Penetration into alveolar fluid. After 3 days of taking the drug at a dose of 500 mg once or twice a day, C_max of levofloxacin in alveolar fluid was reached after 2-4 hours and was 4.0 and 6.7 µg/ml, respectively, with a penetration coefficient of 1.0 compared to plasma concentrations.

Penetration into bone tissue. Levofloxacin penetrates well into cortical and cancellous bone tissue, both in the proximal and distal parts of the femur, with a penetration coefficient (bone tissue/plasma) of 0.1-3.0. C_max of levofloxacin in the cancellous bone tissue of the proximal femur after taking the drug at a dose of 500 mg was approximately 15.1 µg/g (2 hours after taking the drug).

Penetration into cerebrospinal fluid. Levofloxacin poorly penetrates into the cerebrospinal fluid.

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

Urine concentrations. Average urine concentrations 8-12 hours after oral administration of 150, 300, and 600 mg doses 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), mainly through the kidneys (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.

The absence of significant differences in the pharmacokinetics of levofloxacin during its intravenous administration and oral administration confirms the fact that oral and intravenous routes of administration are interchangeable.

Pharmacokinetics in special patient groups

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

The pharmacokinetics in elderly patients does not differ from that in young patients, except for pharmacokinetic differences associated with changes in CC.

In renal insufficiency, the pharmacokinetics of levofloxacin changes. As renal function deteriorates, renal excretion and renal clearance (ClR) decrease, and T_1/2 increases.

Pharmacokinetics in renal insufficiency after a single oral dose of 500 mg levofloxacin

Indications

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

• Complicated urinary tract infections and pyelonephritis;
• Chronic bacterial prostatitis;
• For 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 only as an alternative to other antimicrobial drugs

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections;
• Acute bacterial sinusitis;
• Exacerbation of chronic bronchitis;
• Uncomplicated cystitis.

When using the drug Glevo, official national recommendations on the appropriate use of antibacterial drugs, as well as the sensitivity of pathogenic microorganisms in a particular country, should be taken into account (see section “Special Instructions”).

ICD codes

Dosage Regimen

The drug is taken orally 1-2 times a day. The tablets should be swallowed whole, without chewing, and washed down 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 drugs containing magnesium and/or aluminum, iron, zinc, or sucralfate.

Considering that the bioavailability of levofloxacin when taking Glevo tablets is 99-100%, when transferring a patient from intravenous infusion of levofloxacin to taking tablets, treatment should be continued at the same dose that was used during intravenous infusion.

Missing one or more doses of the drug

If a dose is accidentally missed, the next dose should be taken as soon as possible and then continued according to the recommended dosage regimen.

Doses and duration of treatment

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.

Patients with normal renal function (CC >50 ml/min)

Complicated urinary tract infections 1 tablet of 500 mg once a day (respectively 500 mg of levofloxacin) – 7-14 days.

Pyelonephritis 1 tablet of 500 mg once a day (respectively 500 mg of levofloxacin) – 7-10 days.

Chronic bacterial prostatitis 1 tablet of 500 mg once a day (respectively 500 mg of levofloxacin) – 28 days.

Complex treatment of drug-resistant forms of tuberculosis 1 tablet of 500 mg 1-2 times a day (respectively 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 (respectively 500 mg of levofloxacin) once a day for up to 8 weeks.

Community-acquired pneumonia 1 tablet of 500 mg 1-2 times a day (respectively 500-1000 mg of levofloxacin) – 7-14 days.

Complicated skin and soft tissue infections 1 tablet of 500 mg 1-2 times a day (respectively 500-1000 mg of levofloxacin) – 7-14 days.

Acute bacterial sinusitis 1 tablet of 500 mg once a day (corresponding to 500 mg of levofloxacin) – 10-14 days.

Exacerbation of chronic bronchitis 1 tablet of 500 mg once a day (corresponding to 500 mg of levofloxacin) – 7-10 days.

Uncomplicated cystitis 1/2 tablet of Glevo 500 mg once a day (corresponding to 250 mg of levofloxacin) – 3 days.

Patients with impaired renal function (CrCl ≤50 ml/min)

Levofloxacin is eliminated primarily by the kidneys, therefore, when treating patients with impaired renal function, a dose reduction of the drug is required (see table below).

¹ No additional doses are required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Patients with impaired hepatic function

No dosage adjustment is required in patients with impaired hepatic function, since Levofloxacin is only minimally metabolized in the liver.

Elderly patients

No dosage adjustment is required for elderly patients, except in cases where CrCl decreases to 50 ml/min or lower.

Adverse Reactions

The adverse effects listed below are presented according to the following frequency gradations: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000, including isolated reports), frequency not known (cannot be estimated from the available data).

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

Infections and infestations uncommon – fungal infections, development of resistance of pathogenic microorganisms.

Blood and lymphatic system disorders uncommon – leukopenia (decrease in the number of leukocytes in peripheral blood), eosinophilia (increase in the number of eosinophils in peripheral blood); rare – neutropenia (decrease in the number of neutrophils in peripheral blood), thrombocytopenia (decrease in the number of platelets in peripheral blood); frequency not known (post-marketing data) – pancytopenia (decrease in the number of all formed elements in peripheral blood), agranulocytosis (absence or sharp decrease in the number of granulocytes in peripheral blood), hemolytic anemia.

Immune system disorders rare – angioedema; frequency not known (post-marketing data) – anaphylactic shock, anaphylactoid shock. Anaphylactic and anaphylactoid reactions may sometimes develop even after the first dose of the drug.

Endocrine disorders rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders uncommon – anorexia; rare – hypoglycemia, especially in patients with diabetes mellitus (possible signs of hypoglycemia: “ravenous” appetite, nervousness, sweating, tremor); frequency not known – hyperglycemia, severe hypoglycemia, up to hypoglycemic coma (especially in elderly patients, in patients with diabetes mellitus taking oral hypoglycemic agents or receiving insulin therapy) (see section “Special Precautions”).

Psychiatric disorders common – insomnia; uncommon – feeling of restlessness, anxiety, confusion; rare – mental disorders (e.g., hallucinations, paranoia), depression, agitation, sleep disorders, nightmares; frequency not known (post-marketing data) – psychiatric disorders with behavioral disturbances causing self-harm, including suicidal thoughts and suicide attempts, nervousness, memory impairment, delirium (including attention disturbances, disorientation).

Nervous system disorders common – headache, dizziness; uncommon – drowsiness, tremor, dysgeusia (taste distortion); rare – paresthesia, seizures (see section “Special Precautions”); frequency not known (post-marketing data) – peripheral sensory neuropathy, peripheral sensorimotor neuropathy (see section “Special Precautions”), dyskinesia, extrapyramidal disorders, ageusia (loss of taste sensation), parosmia (disorder of smell sensation, especially a subjective sensation of a smell that is objectively absent), including loss of smell; syncope, increased intracranial pressure (benign intracranial hypertension, pseudotumor cerebri).

Eye disorders rare – visual disturbances such as blurred vision; frequency not known (post-marketing data) – transient loss of vision, uveitis.

Ear and labyrinth disorders uncommon – vertigo (sensation of deviation or spinning of one’s own body or surrounding objects); rare – tinnitus; frequency not known (post-marketing data) – hearing impairment, hearing loss.

Cardiac disorders rare – sinus tachycardia, palpitations; frequency not known (post-marketing data) – QT interval prolongation, ventricular arrhythmias, ventricular tachycardia, torsades de pointes, which may lead to cardiac arrest (see sections “Overdose”, “Special Precautions”).

Vascular disorders rare – decreased blood pressure.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea; frequency not known (post-marketing data) – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; frequency not known (post-marketing data) – hemorrhagic diarrhea, which in very rare cases may be a sign of enterocolitis, including pseudomembranous colitis (see section “Special Precautions”), pancreatitis.

Hepatobiliary disorders common – increased activity of liver enzymes in the blood (e.g., ALT, AST), increased activity of alkaline phosphatase and GGT; uncommon – increased concentration of bilirubin in the blood; frequency not known (post-marketing data) – severe hepatic failure, including cases of acute hepatic failure, sometimes with fatal outcome, especially in patients with severe underlying disease (e.g., patients with sepsis) (see section “Special Precautions”); hepatitis, jaundice.

Skin and subcutaneous tissue disorders uncommon – rash, pruritus, urticaria, hyperhidrosis; rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section “Special Precautions”), fixed drug eruption; frequency not known (post-marketing data) – toxic epidermal necrolysis, Stevens-Johnson syndrome, exudative erythema multiforme, photosensitivity reactions (increased sensitivity to sunlight and ultraviolet radiation) (see section “Special Precautions”), leukocytoclastic vasculitis, stomatitis. Reactions from the skin and mucous membranes may sometimes occur after the first dose of the drug.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, myalgia; rare – tendon disorders, including tendinitis (e.g., Achilles tendon), muscle weakness, which may be particularly dangerous in patients with myasthenia gravis (see section “Special Precautions”); frequency not known (post-marketing data) – rhabdomyolysis, tendon rupture (e.g., Achilles tendon. This adverse effect may occur within 48 hours after the start of treatment and may be bilateral (see also section “Special Precautions”)), ligament rupture, muscle rupture, arthritis.

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

General disorders and administration site conditions uncommon – asthenia; rare – pyrexia (increased body temperature); frequency not known – pain (including back pain, chest pain, and limb pain).

Other possible adverse effects related to all fluoroquinolones very rare – porphyria attacks (of a very rare metabolic disease) in patients with porphyria.

Contraindications

• Hypersensitivity to levofloxacin or to other quinolones, as well as to any of the excipients of Glevo;
• Epilepsy;
• Myasthenia gravis (see sections “Adverse Reactions”, “Special Precautions”);
• History of tendon disorders associated with the use of fluoroquinolones;
• Childhood and adolescence up to 18 years (due to incomplete skeletal growth, since the risk of damage to the cartilaginous growth zones cannot be completely excluded);
• Pregnancy (the risk of damage to the cartilaginous growth zones in the fetus cannot be completely excluded);
• Breastfeeding period (the risk of damage to the cartilaginous growth zones in the child cannot be completely excluded).

With caution

• In patients predisposed to the development of seizures [in patients with previous CNS lesions; in patients simultaneously taking drugs that lower the seizure threshold of the brain, such as fenbufen, theophylline] (see section “Drug Interactions”);
• 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 dosage adjustment, see section “Dosage and Administration”);
• 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 agents, tricyclic antidepressants, macrolides, antipsychotics) (see sections “Overdose”, “Drug Interactions”, “Special Precautions”).
• In patients with diabetes mellitus receiving oral hypoglycemic drugs (e.g., glibenclamide) or insulin preparations (the risk of hypoglycemia increases);
• In patients with severe adverse reactions to other fluoroquinolones, such as severe neurological reactions (increased risk of developing similar adverse reactions when using levofloxacin);
• In patients with psychoses or in patients with a history of mental illness (see section “Special Precautions”);
• In elderly patients, patients after transplantation, as well as with concomitant use of corticosteroids (increased risk of tendinitis and tendon rupture) (see section “Special Precautions”);
• In patients with a family history of aortic aneurysm, or in patients with diagnosed aortic aneurysm and/or aortic dissection or in the presence of other risk factors or conditions predisposing to the development of aortic aneurysm or aortic dissection (e.g., Marfan syndrome, vascular type Ehlers-Danlos syndrome, Takayasu’s arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, atherosclerosis) (see section “Special Precautions”).

Use in Pregnancy and Lactation

Glevo is contraindicated for use in pregnant and breastfeeding women.

Use in Hepatic Impairment

No dosage adjustment is required in patients with impaired hepatic function.

Use in Renal Impairment

The drug should be prescribed with caution to patients with impaired renal function.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

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

Risk of resistance development

The prevalence of acquired resistance of isolated strains of microorganisms 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.

Methicillin-resistant Staphylococcus aureus

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, unless laboratory tests confirm the sensitivity of this microorganism to levofloxacin.

Disability and potentially irreversible serious adverse reactions associated with fluoroquinolone use

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 occur 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 may develop from several hours to several weeks after starting levofloxacin therapy. The development of these adverse reactions has been observed in patients of all ages and without the presence of 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.

Patients predisposed to seizures

Like other quinolones, Levofloxacin should be used with great caution in patients with a predisposition to seizures. Such patients include patients with previous CNS lesions, such as stroke, severe traumatic brain injury; patients simultaneously taking drugs that lower the seizure threshold of the brain (e.g., theophylline; fenbufen and other NSAIDs (see section “Drug Interactions”).

If seizures develop, treatment with levofloxacin should be discontinued.

Pseudomembranous colitis

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, treatment with levofloxacin should be discontinued immediately and specific antibiotic therapy (vancomycin, teicoplanin or metronidazole orally) should be started immediately. Drugs that inhibit intestinal peristalsis are contraindicated.

Tendinitis and tendon rupture

Tendinitis, which rarely occurs with the use of quinolones, may sometimes lead to tendon rupture, including the Achilles tendon, and may be bilateral. This adverse effect may develop within 48 hours after the start of treatment or several months after completion of fluoroquinolone therapy.

Elderly patients are more predisposed to the development of 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. In patients with impaired renal function, the daily dose should be adjusted based on CrCl.

Patients should be advised to rest at the first signs of tendinitis or tendon rupture and to consult their doctor. If tendinitis or tendon rupture is suspected, treatment with Glevo should be discontinued immediately and appropriate treatment of the affected tendon should be initiated, for example, by ensuring sufficient immobilization (see sections “Contraindications” and “Adverse Reactions”).

Hypersensitivity reactions

Levofloxacin can cause serious, potentially life-threatening hypersensitivity reactions (angioedema, anaphylactic shock) even with the initial doses (see section “Adverse Reactions”). In case of their development, patients should immediately stop taking the drug and consult a doctor.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with the use of levofloxacin (see section “Adverse Reactions”). When prescribing the drug, patients should be informed about the signs and symptoms of severe cutaneous adverse reactions and be under close medical supervision. If signs and symptoms appear that indicate the development of these adverse reactions, Glevo should be discontinued immediately and the possibility of alternative treatment should be considered. If a patient develops a severe cutaneous adverse reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS syndrome, while using levofloxacin, the use of the drug should not be resumed in that patient.

Hepatobiliary disorders

Cases of hepatic necrosis, including the development of fatal hepatic failure, have been reported with the use of levofloxacin, mainly in patients with severe underlying diseases, such as sepsis (see section “Adverse Reactions”). Patients should be warned to discontinue treatment and seek immediate medical attention if signs and symptoms of liver damage appear, such as anorexia, jaundice, dark urine, skin itching and abdominal pain.

Patients with impaired renal function

Since Levofloxacin is excreted mainly by the kidneys, in patients with impaired renal function, mandatory monitoring of renal function is required, as well as dosage adjustment (see section “Dosage and Administration”). When treating elderly patients, it should be taken into account that patients in this group often have impaired renal function (see section “Dosage and Administration”).

Prevention of Photosensitivity Reactions

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

Superinfection

As with the use of other antibiotics, the use of levofloxacin, especially over a prolonged period, may lead to the overgrowth of non-susceptible microorganisms (bacteria and fungi), which can alter the normal human microflora. As a result, a superinfection may develop. Therefore, it is essential to repeatedly assess the patient’s condition during treatment, and if a superinfection develops during therapy, appropriate measures should be taken.

QT Interval Prolongation

There have been very rare reports of QT interval prolongation in patients taking fluoroquinolones, including Levofloxacin.

Caution should be exercised when using fluoroquinolones, including Levofloxacin, in patients with known risk factors for QT interval prolongation: in patients with uncorrected electrolyte imbalances (with hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); when used concomitantly with drugs that can prolong the QT interval, such as Class IA and III antiarrhythmic agents, tricyclic antidepressants, macrolides, 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 (see sections “With Caution”, “Dosage Regimen”, “Adverse Reactions” and “Overdose”, “Drug Interactions”).

Patients with Glucose-6-Phosphate Dehydrogenase Deficiency

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.

Dysglycemia (Hypo- and Hyperglycemia)

As with the use of other fluoroquinolones, cases of hyperglycemia and hypoglycemia have been observed with the use of levofloxacin. During therapy with levofloxacin, dysglycemia developed more frequently in elderly patients and in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic drugs (e.g., glibenclamide) or insulin. When using levofloxacin in such patients, the risk of developing hypoglycemia, up to hypoglycemic coma, increases. Patients should be informed about the symptoms of hypoglycemia (confusion, dizziness, ravenous appetite, headache, nervousness, palpitations or rapid pulse, pale skin, sweating, tremors, weakness). If a patient develops hypoglycemia, treatment with levofloxacin should be stopped immediately and appropriate therapy initiated. In such cases, it is recommended to switch to therapy with another antibiotic, not a fluoroquinolone, if possible. When treating with levofloxacin in elderly patients and patients with diabetes mellitus, careful monitoring of blood glucose levels is recommended.

Peripheral Neuropathy

Cases of sensory and sensorimotor peripheral neuropathy have been reported in patients taking 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 developing irreversible changes.

Patients should be informed of the need to report any symptoms of neuropathy to their healthcare provider. Fluoroquinolones should not be prescribed to patients with a history of peripheral neuropathy.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including Levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. During the post-marketing period, adverse reactions, including respiratory failure requiring assisted ventilation and fatal outcomes, have been observed, associated with the use of fluoroquinolones in patients with myasthenia gravis. The use of levofloxacin in a patient with an established diagnosis of myasthenia gravis is not recommended (see section “Adverse Reactions”).

Use for Inhalational Anthrax

The use of levofloxacin in humans for this indication is based on in vitro susceptibility data for Bacillus anthracis and experimental animal studies, as well as limited data on the use of levofloxacin in humans. Healthcare providers should refer to national and/or international documents reflecting the consensus view on the treatment of anthrax.

Psychotic Reactions

Psychotic reactions, including suicidal thoughts/attempts, have been noted in patients taking fluoroquinolones, including Levofloxacin, sometimes after a single dose. In the event of any CNS adverse effects, including mental disorders, treatment with levofloxacin should be stopped immediately and appropriate therapy initiated. In such cases, it is recommended to switch to therapy with another antibiotic, not a fluoroquinolone, if possible. The drug should be prescribed with caution to patients with psychosis or patients with a history of mental illness (see section “With Caution”).

Aortic Aneurysm and Dissection

According to epidemiological studies, an increased risk of aortic aneurysm and aortic dissection has been reported following the use of fluoroquinolones, especially in elderly patients. In this regard, fluoroquinolones should be used only after a careful benefit-risk assessment and consideration of other therapeutic options in patients with a family history of aortic aneurysm, or in patients with diagnosed aortic aneurysm and/or aortic dissection, or in the presence of other risk factors or conditions predisposing to aortic aneurysm or dissection (e.g., Marfan syndrome, vascular type Ehlers-Danlos syndrome, Takayasu’s arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, atherosclerosis) (see section “With Caution”).

If sudden abdominal, chest, or back pain occurs, the patient should immediately consult a doctor in the emergency department.

Vision Disorders

If any vision disorders develop, an immediate consultation with an ophthalmologist is necessary (see section “Adverse Reactions”).

Effect on Laboratory Tests

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 Driving and Operating Machinery

Such adverse effects of the drug Glevo as dizziness or vertigo, drowsiness, and visual disturbances (see section “Adverse Reactions”) 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 unstable positions).

Overdose

Symptoms

Based on data from toxicological studies in animals, the most important expected symptoms of acute overdose of Glevo are CNS symptoms (impaired consciousness, including confusion, dizziness, and seizures).

During post-marketing use of the drug, CNS effects, including confusion, seizures, hallucinations, and tremor, have been observed with overdose.

Nausea and erosions of the gastrointestinal mucosa may develop.

In clinical pharmacological studies with doses of levofloxacin exceeding therapeutic doses, QT interval prolongation was observed.

Treatment

In case of overdose, careful observation of the patient is required, including ECG monitoring. Treatment is symptomatic. In case of acute overdose of Glevo, gastric lavage and administration of antacids to protect the gastric mucosa are indicated. Levofloxacin is not removed by dialysis (hemodialysis, peritoneal dialysis, and continuous ambulatory peritoneal dialysis). There is no specific antidote.

Drug Interactions

Interactions Requiring Caution

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

Drugs containing divalent or trivalent cations, such as zinc or iron salts (medicines for the treatment of anemia), magnesium- and/or aluminum-containing drugs (such as antacids), 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 Glevo.

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

With sucralfate

The effect of Glevo is significantly reduced with the simultaneous use of sucralfate (a gastric mucosal protective agent).

Patients receiving Levofloxacin and sucralfate are advised to take sucralfate 2 hours after taking levofloxacin.

With theophylline, fenbufen or other drugs from the NSAID group that lower the seizure threshold of the brain

No pharmacokinetic interaction between levofloxacin and theophylline has been identified. However, with the simultaneous use of quinolones and theophylline, NSAIDs and other drugs that lower the seizure threshold of the brain, a pronounced decrease in the seizure threshold of the brain is possible.

The concentration of levofloxacin when taken concomitantly with fenbufen increases by only 13%.

With indirect anticoagulants (vitamin K antagonists)

In patients treated with levofloxacin in combination with indirect anticoagulants (e.g., warfarin), an increase in prothrombin time/INR and/or the development of bleeding, including severe bleeding, was observed. Therefore, with the simultaneous use of indirect anticoagulants and levofloxacin, regular monitoring of blood coagulation parameters is necessary.

With probenecid and cimetidine

Caution should be exercised when using drugs that impair renal tubular secretion, such as probenecid and cimetidine, and levofloxacin concomitantly, especially in patients with renal failure.

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.

With cyclosporine

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.

With corticosteroids

Concomitant use of corticosteroids increases the risk of tendon rupture.

With drugs that prolong the QT interval

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 agents, tricyclic antidepressants, macrolides, antipsychotics).

Others

Clinical pharmacological studies conducted to investigate possible pharmacokinetic interactions of levofloxacin with digoxin, glibenclamide, ranitidine, and warfarin showed that the pharmacokinetics of levofloxacin when used concomitantly with these drugs do not change to an extent that is clinically significant.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 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.