Levofloxacin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN-DARNITSA (LEVOFLOXACIN-DARNITSA)

Composition:

Active substance: levofloxacin;

1 ml of solution contains levofloxacin hemihydrate equivalent to 5 mg of levofloxacin;

Excipients: sodium chloride, diluted hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow liquid with a greenish tint, practically free from particles.

Pharmacotherapeutic group.

Antibacterials for systemic use. Antibacterials of the quinolone group. Fluoroquinolones. Levofloxacin. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA gyrase/DNA topoisomerase IV complex. The primary mechanism of resistance results from mutations in the gyr-A genes.

In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones.

Breakpoints.

The minimal inhibitory concentration (MIC) breakpoints for levofloxacin recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from moderately resistant ones and moderately resistant from resistant organisms, are presented in Table 1 of MIC testing (mg/L).

EUCAST clinical MIC breakpoints for levofloxacin:

Table 1

1 The breakpoint values for levofloxacin refer to high-dose therapy.

2 A low level of resistance to fluoroquinolones may be possible (MIC of ciprofloxacin 0.12–0.5 mg/L), but evidence that such resistance has clinical significance in respiratory tract infections caused by Haemophilus influenzae is lacking.

3 Isolates with MIC values exceeding the breakpoint between susceptible and intermediate-resistant strains are very rare or have not yet been reported. Testing for identification and antimicrobial susceptibility on any such isolates should be repeated, and if confirmed, the isolate should be sent to an authorized laboratory. As long as data indicate clinical response for confirmed isolates with MIC above the current resistant breakpoint, they must be reported as resistant.

4 Breakpoint values for oral and intravenous doses range from 500 mg once daily to 500 mg twice daily.

Antibacterial spectrum.

The prevalence of resistance among individual species may vary geographically and over time. Local resistance data should be obtained, especially when treating severe infections.

Generally susceptible species.

Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci – groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria: Peptostreptococcus.

Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species for which acquired (secondary) resistance may be a problem.

Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Staphylococcus coagulase spp.

Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria: Bacteroides fragilis.

Naturally resistant strains.

Aerobic gram-positive bacteria: Enterococcus faecium.

* Methicillin-resistant S. aureus may exhibit resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed; Cmax is reached within 1–2 hours after administration. Absolute bioavailability is approximately 99–100%. Food has almost no effect on the absorption of levofloxacin. Steady state is achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating extensive distribution into body tissues.

Penetration into tissues and body fluids

Levofloxacin has demonstrated penetration into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

After oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). It is primarily excreted by the kidneys (over 85% of the administered dose).

The mean total body clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that these routes of administration are interchangeable.

Linearity

Levofloxacin exhibits linear pharmacokinetics in the dose range of 50–1000 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-life increases, as shown in Table 2.

Table 2

Geriatric patients

There are no significant differences in the pharmacokinetics of levofloxacin between younger and elderly patients, except for differences related to creatinine clearance.

Gender differences

Separate analysis of female and male patient groups demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender-related pharmacokinetic differences are clinically significant.

Clinical characteristics.

Indications.

Levofloxacin-Darnitsia is indicated in adults for the treatment of the following infections caused by microorganisms sensitive to levofloxacin:

− Community-acquired pneumonia*;

− Complicated skin and soft tissue infections*;

− Acute pyelonephritis and complicated urinary tract infections;

− Chronic bacterial prostatitis;

− Pulmonary form of anthrax: post-exposure prophylaxis and definitive treatment.

*Regarding the above-mentioned infectious diseases, levofloxacin should be prescribed only when other antibacterial agents, typically used as first-line therapy for these infections, have shown insufficient efficacy.

Official recommendations on the appropriate use of antibacterial agents should be taken into account.

Contraindications.

− Hypersensitivity to levofloxacin, other quinolones, or any component of the medicinal product.

− Tendon-related adverse reactions following prior use of quinolones.

− Epilepsy.

− Pediatric age (under 18 years).

− Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs).

Concomitant administration of quinolones with theophylline, NSAIDs, or other substances that lower the seizure threshold may substantially reduce the seizure threshold. The concentration of levofloxacin in the presence of fenbufen is approximately 13% higher than when levofloxacin is administered alone.

Probenecid and cimetidine.

Probenecid and cimetidine significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 34% in the presence of probenecid and by 24% with cimetidine. This is because both medicinal products can block tubular secretion of levofloxacin. Levofloxacin should be used with caution in combination with medicinal products affecting renal tubular secretion (probenecid and cimetidine), especially in patients with impaired renal function.

Cyclosporine.

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists.

When used concomitantly with vitamin K antagonists (e.g., warfarin), coagulation test parameters (prothrombin time/INR) may increase. Severe bleeding may occur. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concurrently.

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotic medicinal products).

Theophylline.

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2. Therefore, levofloxacin is not considered an inhibitor of CYP1A2.

Glucocorticoids.

The risk of tendon rupture is increased when levofloxacin is used concomitantly with glucocorticoids.

Other information.

No clinically significant effect on the pharmacokinetics of levofloxacin has been observed when administered with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Alcohol consumption is not recommended during treatment with levofloxacin.

Special precautions for use.

The use of the medicinal product should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of such patients with levofloxacin should only be initiated if there are no alternative treatment options and after careful assessment of benefit/risk.

Caution is advised when administering the medicinal product to patients with severe renal function impairment, as well as those with pronounced cerebral atherosclerosis or cerebral circulation disorders.

Renal and hepatic function should be monitored throughout the entire treatment course.

Alcohol consumption should be avoided during treatment with the medicinal product.

In very severe cases of pneumonia caused by pneumococci, levofloxacin may not provide optimal therapeutic efficacy.

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

Methicillin-resistant Staphylococcus aureus (MRSA).

MRSA is likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

Resistance of E. coli.

Resistance of E. coli, the most common causative agent of urinary tract infections, to fluoroquinolones varies across countries of the European Union. When prescribing levofloxacin, physicians should take into account local prevalence rates of E. coli resistance to fluoroquinolones.

Pulmonary form of anthrax.

Clinical practice is based on in vitro susceptibility studies of Bacillus anthracis, as well as experimental animal data together with limited human data. Physicians should refer to nationally and/or internationally agreed guidelines for the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

In patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, very rare cases of prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a physician.

Duration of infusion.

The recommended duration of infusion is at least 60 minutes for the 500 mg infusion solution of the medicinal product. With respect to ofloxacin, tachycardia and transient increases in blood pressure may occur during infusion. In rare cases, a sudden drop in blood pressure or circulatory collapse may occur. If a marked decrease in blood pressure is observed during levofloxacin infusion, the infusion should be stopped immediately.

Aneurysm and aortic dissection, and cardiac valve regurgitation/insufficiency.

Epidemiological studies indicate an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of the aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapies in patients with a personal or family history of aneurysm or congenital heart valve defects, or in patients diagnosed with aortic aneurysm or dissection, or cardiac valve disease, or in the presence of other risk factors, namely:

• risk factors for both aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis;

− risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;

− risk factors for cardiac valve regurgitation/insufficiency: infective endocarditis.

The risk of aortic aneurysm, dissection, and rupture is increased in patients concurrently receiving systemic corticosteroids.

In case of sudden abdominal, chest, or back pain, patients should be advised to seek immediate medical attention at an emergency department.

Patients should be advised to seek immediate medical help if they experience acute shortness of breath, a new episode of palpitations, or the development of abdominal or lower limb edema.

Tendinitis and tendon rupture.

Tendinitis may occur in individual patients. Development of tendinitis and tendon rupture (including, but not limited to, Achilles tendon), sometimes bilateral, may occur as early as within the first 48 hours after initiation of quinolone or fluoroquinolone therapy, and cases have been reported even several months after discontinuation of the medicinal product. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

Levofloxacin should be discontinued immediately at the first signs of tendinitis (e.g., painful swelling, inflammation), and alternative treatment options should be considered. Affected limbs should be appropriately managed (e.g., immobilization of the tendon). Corticosteroids are not recommended in cases of tendonopathy.

Myoclonus.

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment should be initiated.

Clostridium difficile-associated disease.

Diarrhea, especially severe, persistent, or bloody diarrhea during or after treatment with levofloxacin, may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and symptomatic and specific treatment (e.g., vancomycin) should be promptly initiated. Medicinal products that inhibit intestinal peristalsis are contraindicated in this situation.

Patients with seizure predisposition.

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy.

As with other quinolones, the medicinal product should be used with extreme caution in patients predisposed to seizures, such as those with central nervous system disorders, concomitant therapy with fenbufen or similar medicinal products, or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin treatment should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

In patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency, administration of quinolone antibiotics may lead to hemolytic reactions; therefore, levofloxacin should be used with caution in such patients, with monitoring for possible hemolysis.

Patients with renal impairment.

Levofloxacin is primarily eliminated via the kidneys; therefore, dose adjustment is required in patients with renal impairment (see section "Method of administration and dosage").

Hypersensitivity reactions.

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (including angioedema, anaphylactic shock), even after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice should be sought, and appropriate treatment initiated.

Severe bullous reactions.

Severe bullous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (also known as Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with levofloxacin use, which may be life-threatening or fatal. Patients should be informed of the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. Re-administration of levofloxacin is contraindicated in patients with a history of such serious reactions as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome associated with prior levofloxacin use.

Blood glucose alterations.

Alterations in blood glucose levels (hyperglycemia and hypoglycemia) have been reported during quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glyburide) or insulin. Cases of hypoglycemic coma have occurred. Diabetic patients should monitor their blood glucose levels.

Prevention of photosensitivity reactions.

Photosensitivity reactions have been reported during treatment with levofloxacin. To prevent photosensitivity reactions, patients taking levofloxacin should avoid exposure to sunlight and UV radiation (including tanning beds and artificial UV lamps) during treatment and for 48 hours after discontinuation of levofloxacin.

In patients receiving vitamin K antagonists, coagulation parameters should be monitored during concomitant use of levofloxacin and vitamin K antagonists (warfarin) due to the potential risk of increased coagulation parameters [prothrombin time / international normalized ratio (INR)] and/or bleeding.

Psychotic reactions.

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. Very rarely, these have led to suicidal thoughts and self-destructive behavior, sometimes even after a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used cautiously in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation.

Cases of QT interval prolongation have been reported with fluoroquinolone use. Caution should be exercised when using fluoroquinolones, including levofloxacin, in patients with known risk factors for QT prolongation:

• congenital or acquired QT prolongation syndrome;
• concomitant use of medicinal products that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• electrolyte imbalances (particularly hypokalemia, hypomagnesemia);
• cardiac conditions (heart failure, myocardial infarction, bradycardia).

Elderly patients and women are more sensitive to medicinal products that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups.

Peripheral neuropathy.

Cases of sensory or sensorimotor peripheral neuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients taking fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, to prevent progression to potentially irreversible states.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported in post-marketing experience in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If visual disturbances or other ocular effects occur, immediate consultation with an ophthalmologist is required.

Superinfection.

The use of levofloxacin, particularly over prolonged periods, may lead to overgrowth of microorganisms not susceptible to the medicinal product. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory tests.

In patients receiving levofloxacin, opioid screening in urine may yield false-positive results. Confirmation of positive opioid results may require more specific testing methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative bacteriological test results in patients with tuberculosis.

Hepatobiliary disorders.

Cases of necrotizing hepatitis up to life-threatening liver failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Important information on excipients.

This medicinal product contains 860 mg of sodium per dose. Caution is advised when administering to patients on a sodium-restricted diet.

Blood dyscrasias.

During treatment with levofloxacin, bone marrow suppression may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse reactions"). If any of these disorders are suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Use during pregnancy or breastfeeding.

Due to the absence of adequate studies and the potential for quinolones to damage developing joint cartilage, the medicinal product is contraindicated during pregnancy and breastfeeding. If pregnancy occurs during treatment, the patient should inform her physician.

Levofloxacin did not cause impairment of fertility or reproductive function in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving and from potentially hazardous activities requiring heightened attention and rapid reaction times during treatment with the medicinal product, due to the possibility of nervous system adverse reactions (dizziness, ataxia, somnolence, confusion, visual and auditory disturbances, motor disorders, including gait disturbances).

Administration and Dosage.

Prior to administration, a sensitivity test should be performed.

The solution should be used within 3 hours after vial perforation.

The medicinal product is administered intravenously 1–2 times daily.

The dosage depends on the type and severity of the infection. Dosage recommendations should follow those specified for patients with normal renal function (see Table 3), in whom creatinine clearance is over 50 mL/min.

Table 3

1 The duration of treatment includes both intravenous and oral therapy. The time to switch from initial intravenous administration of levofloxacin to oral administration at the same dosage depends on the patient's condition, but the transition is usually possible within 2−4 days after initiation of treatment.

Since levofloxacin is primarily eliminated via the kidneys, the dose should be reduced in patients with impaired renal function.

Dosage for patients with impaired renal function (see Table 4), in whom creatinine clearance is less than 50 ml/min.

Table 4

1 After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver.

Dosing in elderly patients. If renal function is normal, dose adjustment is not required.

The medicinal product should be administered slowly by intravenous infusion. The duration of infusion should be at least 30 minutes for a 250 mg dose or at least 60 minutes for a 500 mg dose.

Depending on the patient's condition, a switch from intravenous administration to oral levofloxacin at the same dosage may be possible after several days.

The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment with levofloxacin for at least 48–72 hours after normalization of body temperature or until microbiological testing confirms eradication of the causative pathogens.

Mixing with infusion solutions.

The medicinal product is compatible with the following infusion solutions:

0.9% sodium chloride solution, 5% glucose monohydrate solution, 2.5% dextrose in Ringer's solution, multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes).

Method of administration

Do not insert needle(s) into non-designated areas of the polymer vial—only into sterile ports!

For infusion therapy, follow this procedure:

1. Remove the tamper-evident plastic cap (if present).
2. Remove protective closure(s) No. 1 as shown in Fig. 1 and Fig. 2 (manufacturers may use different types and materials for protective closures).
3. Remove the needle cap and insert the needle into any of the designated ports No. 2 of the infusion vial (see Fig. 1 and Fig. 2).
4. The other sterile port can be used for adding other medicinal products into the infusion vial (No. 4, see Fig. 3), or, if necessary, to improve flow rate for the air-vent needle (No. 4, see Fig. 3).
5. Hang the solution vial using the special ring No. 3 located at the bottom of the vial (see Fig. 3).

Children.

The medicinal product is contraindicated in children, as damage to joint cartilage cannot be excluded.

Overdose.

Symptoms: dizziness, impaired/deranged consciousness, seizures, myoclonus, hallucinations, tremor, QT interval prolongation, or intensification of other adverse reactions.

Treatment – symptomatic, according to clinical manifestations. In case of overdose, close monitoring of the patient, including ECG, is required. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Eye disorders: rare – visual disturbances such as blurred vision; frequency not known – transient loss of vision, uveitis.

Ear and labyrinth disorders: uncommon – vertigo; rare – tinnitus; frequency not known – hearing disturbances, hearing loss.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea; frequency not known – bronchospasm, allergic alveolitis.

Gastrointestinal disorders: common – diarrhoea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; frequency not known – haemorrhagic diarrhoea, which may indicate enterocolitis, including pseudomembranous colitis; pancreatitis.

Hepatobiliary disorders: common – increased liver enzyme levels (alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase (GGT)); uncommon – increased blood bilirubin; frequency not known – jaundice and severe hepatic reactions, including cases of acute liver failure, mainly in patients with severe underlying diseases, hepatitis.

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

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

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycaemia, especially in diabetic patients, hypoglycaemic coma; frequency not known – hyperglycaemia. Signs of hypoglycaemia may include increased appetite, nervousness, increased sweating, and tremor of extremities.

Nervous system disorders: common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia; rare – convulsions, paraesthesia; frequency not known – peripheral sensory or sensorimotor neuropathy, disturbances in tactile sensation, parosmia including anosmia, dyskinesia, extrapyramidal disorders, other disturbances in motor coordination, including gait disturbances, ataxia, ageusia, loss of consciousness, benign intracranial hypertension, myoclonus.

Psychiatric disorders: common – insomnia; uncommon – anxiety, confusion, irritability, restlessness; rare – psychotic disorders (including hallucinations, paranoia), depression, agitation, pathological dreams, night terrors, feeling of fear; frequency not known – psychotic disorders with self-destructive behaviour, including suicidal ideation or actions, mania (see section "Special precautions").

Cardiac disorders*: common – phlebitis; rare – tachycardia, palpitations, arterial hypotension; frequency not known – ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia and torsade de pointes (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on electrocardiogram, collapse, vasculitis.

Blood and lymphatic system disorders: uncommon – leukopenia, eosinophilia; rare – neutropenia, thrombocytopenia leading to increased tendency to haemorrhage or bleeding; frequency not known – bone marrow failure, including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders: rare – hypersensitivity reactions, angioneurotic oedema; frequency not known – anaphylactic shock, anaphylactoid shock. Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, hyperhidrosis; rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), localised drug eruptions; frequency not known – toxic epidermal necrolysis (Lyell’s syndrome), Stevens–Johnson syndrome, erythema multiforme exudativum, increased sensitivity to sunlight and ultraviolet radiation (photosensitivity reactions), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation. Skin and mucosal reactions may occasionally occur even after the first dose.

Infections and infestations: uncommon – fungal infections, including Candida species, overgrowth of other resistant microorganisms.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia; rare – tendon disorders (see section "Special precautions"), including inflammation (tendinitis, e.g., Achilles tendon), muscle weakness, which may be of particular significance in patients with severe myasthenia gravis; frequency not known – rhabdomyolysis, rupture of tendons, ligaments and muscles, arthritis.

General disorders and administration site conditions: common – reaction at injection site, including erythema, pain; uncommon – asthenia, general weakness; rare – increased body temperature; frequency not known – pain (including back, chest and limb pain), as with other fluoroquinolones, porphyria attacks may occur in patients with porphyria.

Other adverse effects associated with fluoroquinolone use include:

• extrapyramidal symptoms and other disturbances in motor coordination;
• hypersensitivity vasculitis;
• porphyria attacks in patients with porphyria.

* In rare cases, patients receiving quinolones and fluoroquinolones, regardless of the presence of risk factors, have experienced long-term (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems and sensory organs (such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disturbances).

** In patients receiving fluoroquinolones, cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been observed (see section "Special precautions").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of the reach of children.

Incompatibilities.

The solution should not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate), or with other medicinal products except those specified in the section "Dosage and method of administration".

Packaging.

100 ml in a vial; 1 vial per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business operations.

13, Borysplis'ka Street, Kyiv, 02093, Ukraine.