Levofloxacin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEFLOCIN® (LEFLOCIN)

Composition:

active substance: levofloxacin;

1 ml of solution contains levofloxacin hemihydrate, calculated as 100 % substance, 5 mg;

excipients: sodium chloride, hydrochloric acid concentrated*, sodium hydroxide*, water for injections.

* For adjusting the pH of the preparation to the required values.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: yellow or yellowish-green clear solution.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones, the S-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (C_max) or area under the pharmacokinetic curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance

Resistance to levofloxacin develops through a stepwise process of mutations in the target sites of both types of topoisomerase II: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as reduced permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance has been established between levofloxacin and other fluoroquinolones.

Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.

Breakpoints

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended MIC breakpoints for levofloxacin, which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant) and intermediate from resistant organisms, are presented in Table 1 of MIC testing (mg/L).

EUCAST clinical MIC breakpoints for levofloxacin (version 10.0, 01.01.2020): Table 1

The prevalence of resistance may vary geographically and over time for individual species. Local information on microbial resistance should be sought, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence is such that the benefit of the drug, at least for some types of infections, is questionable.

* Methicillin-resistant Staphylococcus aureus is highly likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Oral levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations (Cmax) are reached within 1–2 hours after administration. Absolute bioavailability is approximately 99–100%. Food has minimal effect on the absorption of levofloxacin. Steady-state concentrations are achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after single and multiple 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into tissues and body fluids

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

Biotransformation

Levofloxacin undergoes minimal metabolism. The metabolites are 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

Following both 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 systemic clearance of levofloxacin after a single 500 mg dose is 175 ± 29.2 mL/min.

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

Linearity

Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 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 (see Table 2).

Pharmacokinetics in renal impairment after a single 500 mg dose of levofloxacin

Table 2

Geriatric patients

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

Gender differences

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

Clinical characteristics.

Indications.

Levofloxin® is indicated for the treatment of the following infections in adults (see sections "Special instructions for use" and "Pharmacological properties"):

• community-acquired pneumonia;
• complicated skin and soft tissue infections;

(for the above-mentioned infections, the medicinal product should be used only when other antibacterial agents, usually recommended for initial treatment of these infections, are inappropriate or impossible to use);

• acute pyelonephritis and complicated urinary tract infections (see section "Special instructions for use");
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment (see section "Special instructions for use").

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

Contraindications.

• Hypersensitivity to levofloxacin or to other quinolones, or to any of the excipients of the medicinal product;
• epilepsy;
• history of tendon-related adverse reactions following previous use of quinolones;
• children and adolescents;
• pregnancy;
• breastfeeding.

Special precautions.

The solution should be used immediately (within 3 hours) after perforation of the rubber stopper to prevent bacterial contamination. Protection from light during infusion is not required. The medicinal product is intended for single use only.

The solution should be inspected visually before use. Only clear solution free of particles should be used.

As with all other medicinal products, any unused medicinal product should be disposed of in accordance with local requirements.

The product is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose solution for injection;
• 2.5% glucose in Ringer's solution;
• combined solutions for parenteral nutrition (amino acids, glucose, electrolytes).

Issues related to incompatibility are discussed in the section "Incompatibility".

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on Levofloxin®

Theophylline, fenbufen or similar non-steroidal anti-inflammatory medicinal products

No pharmacokinetic interaction between levofloxacin and theophylline has been demonstrated. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. Levofloxacin concentrations in the presence of fenbufen were approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is because both drugs are capable of blocking tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical significance. Levofloxacin should be used with caution in combination with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

In clinical pharmacology studies, it has been demonstrated that no clinically significant effect on the pharmacokinetics of levofloxacin occurs when levofloxacin is administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of Levofloxin® on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (prothrombin time/international normalized ratio) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section "Special instructions for use").

Medicinal products that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics) [see section "Special instructions for use" (QT interval prolongation)].

Other information

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

Special precautions for use.

The use of levofloxacin should be avoided in patients with a history of serious adverse reactions associated with quinolone- and fluoroquinolone-containing medicinal products (see section "Adverse Reactions"). Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful benefit-risk assessment (see also section "Contraindications").

Resistance risk

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections where MRSA is known or suspected, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin (and typically when use of recommended anti-MRSA antibacterial agents is considered inappropriate).

Resistance of Escherichia coli, the most common pathogen causing urinary tract infections, to fluoroquinolones varies across different countries of the European Union. When prescribing levofloxacin, physicians should take into account the local prevalence of fluoroquinolone resistance in Escherichia coli.

Pulmonary anthrax

Clinical experience is based on in vitro susceptibility data for Bacillus anthracis, as well as animal experimental data and limited human data. Physicians should refer to established national and/or international guidelines for the treatment of anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions

Rare, prolonged (several months or years), disabling, and potentially irreversible serious adverse reactions affecting multiple body systems (musculoskeletal, nervous and psychiatric systems, sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or presence of risk factors. At the first sign or symptom of any serious adverse reaction, levofloxacin should be discontinued immediately and medical advice sought.

Duration of infusion

The recommended duration of infusion is at least 60 minutes for the 500 mg levofloxacin infusion solution (Levofloxacin®). With ofloxacin, tachycardia and transient decrease in blood pressure have been observed during infusion. In rare cases, circulatory collapse may occur as a result of sudden hypotension. If marked hypotension occurs during administration of levofloxacin (l-isomer of ofloxacin), infusion should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, and occasionally even several months after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in patients receiving levofloxacin at a daily dose of 1000 mg, elderly patients, patients with renal impairment, patients after solid organ transplantation, and patients receiving concomitant corticosteroids. Concomitant use of corticosteroids and fluoroquinolones should be avoided. If early signs of tendinitis (e.g., painful swelling or joint inflammation) occur, treatment with levofloxacin should be discontinued immediately and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent and/or hemorrhagic diarrhea, during or after treatment with Levofloxacin® (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD ranges from mild to life-threatening. The most severe form of this condition is pseudomembranous colitis (see section "Adverse Reactions"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, infusion of Levofloxacin® should be stopped immediately and appropriate treatment initiated promptly. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures.

Levofloxacin infusion solution is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant medications that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur (see section "Adverse Reactions"), treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions when treated with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in such patients, with close monitoring for risk of hemolysis.

Patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Posology and method of administration").

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) in individual cases after administration of the first dose (see section "Adverse Reactions"). If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin reactions

Cases of severe skin adverse reactions, which may be fatal, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients receiving levofloxacin (see section "Adverse Reactions"). When prescribing levofloxacin, patients should be informed about signs and symptoms of severe skin reactions and closely monitored. At the first sign or symptom suggestive of such reactions, levofloxacin should be discontinued immediately and alternative therapy considered. If a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome occurs during treatment with levofloxacin, re-administration of levofloxacin in this patient is absolutely contraindicated.

Blood glucose fluctuations

As with other quinolones, disturbances in blood glucose levels, including cases of hyperglycemia and hypoglycemia, have been reported, more frequently in elderly patients, especially in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. In patients with diabetes mellitus, careful monitoring of blood glucose levels is recommended (see section "Adverse Reactions").

If a patient reports fluctuations in blood glucose levels, levofloxacin should be discontinued immediately and alternative antibacterial therapy with a non-fluoroquinolone agent considered.

Phototoxicity prevention

Cases of phototoxicity have been reported with levofloxacin (see section "Adverse Reactions"). To prevent phototoxicity, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., sunlamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists

Due to possible increases in coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding in patients taking Levofloxacin® in combination with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored when these medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In rare cases, these progressed to suicidal ideation and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse Reactions"). If such reactions occur, levofloxacin should be discontinued immediately at the first sign or symptom, and the patient should be advised to consult their treating physician. Alternative antibacterial therapy with a non-fluoroquinolone agent should be considered and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or psychiatric conditions in their medical history.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups [see sections "Posology and method of administration" (Elderly patients), "Interaction with other medicinal products and other forms of interaction", "Overdose", "Adverse Reactions"].

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral polyneuropathy have been reported in patients receiving quinolones or fluoroquinolones, leading to paresthesia, hypaesthesia, dysesthesia, or weakness. Patients receiving levofloxacin should be instructed to inform their physician before continuing treatment if symptoms of neuropathy occur, including pain, burning, tingling, numbness, and/or weakness, to prevent development of potentially irreversible conditions (see section "Adverse Reactions").

Hepatobiliary disorders

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

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including fatal cases and conditions requiring respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or ocular adverse reactions occur during levofloxacin therapy, immediate consultation with an ophthalmologist is required (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse Reactions").

Superinfection

The use of levofloxacin, especially over prolonged periods, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection occurs during therapy, appropriate measures should be taken.

Effect on laboratory test results

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

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

Aortic aneurysm and aortic dissection, and valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, as well as regurgitation/insufficiency of aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and valvular 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 significant family history (presence of aneurysm or congenital heart valve defect), diagnosed aortic aneurysm and/or aortic dissection, or valvular heart disease, or in the presence of other risk factors, namely:

• risk factors for both aortic aneurysm and aortic dissection, and valvular regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis;
• risk factors for aortic aneurysm and aortic dissection: vascular diseases such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;
• risk factors for valvular regurgitation/insufficiency: infective endocarditis.

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

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

Patients should be advised to seek immediate medical help if dyspnea, palpitations, or swelling of the abdomen or lower limbs occur.

Acute pancreatitis

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. They should be advised to seek immediate medical help if nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting occur. If acute pancreatitis is suspected, the medicinal product should be discontinued. If the diagnosis is confirmed, levofloxacin should not be re-administered. The medicinal product should be used with caution in patients with a history of pancreatitis (see section "Adverse Reactions").

Sodium content

This medicinal product contains 358 mg of sodium per 100 mL vial and 537 mg of sodium per 150 mL vial, equivalent to 18% and 27%, respectively, of the WHO recommended maximum daily sodium intake for adults (2 g).

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of levofloxacin during pregnancy are limited. Animal studies do not indicate direct or indirect harmful effects with regard to reproductive toxicity. However, due to the lack of human data and experimental evidence indicating a risk of fluoroquinolone-induced damage to the articular cartilage in the growing organism, levofloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin in breast milk, although other fluoroquinolones are known to pass into breast milk. Due to the lack of human data and experimental evidence indicating a risk of fluoroquinolone-induced damage to the articular cartilage in the growing organism, levofloxacin should not be administered to women who are breastfeeding (see section "Contraindications").

Fertility

Levofloxacin does not impair fertility or reproductive function in animals.

Ability to influence reaction rate when driving or operating machinery.

Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

Method of administration and dosage.

The drug should be administered intravenously slowly, 1–2 times daily. The dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the drug. Treatment with levofloxacin, after initial intravenous administration, may be continued with the oral formulation, provided such a switch is appropriate for the individual patient. Due to the bioequivalence of oral and parenteral formulations, the dosage may remain the same.

Dosage

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

Table 3

1 The duration of treatment includes intravenous administration and oral intake of the drug. Depending on the patient's condition, a transition from initial intravenous administration to oral administration at the same dosage is possible after several days (usually within 2–4 days).

Patients with renal impairment (creatinine clearance < 50 mL/min)

Table 4

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

Patients with hepatic impairment

Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Elderly patients

If renal function is normal, dose adjustment is not required.

Method of administration

Levofloxacin intravenous infusion solution (Levofloxacin®) should be administered slowly by intravenous infusion. The duration of infusion of one vial of Levofloxacin®
(100 mL of intravenous solution containing 500 mg of levofloxacin) should be at least 60 minutes.

Incompatibility with other infusion solutions is indicated in the section "Incompatibility", and for compatibility information, see the section "Special precautions".

Children

The use of Levofloxacin® is contraindicated in children and adolescents under 18 years of age, as damage to joint cartilage cannot be excluded.

Overdose

According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic, the most serious signs expected after acute overdose of levofloxacin infusion solution are symptoms related to the central nervous system, such as confusion, dizziness, altered consciousness, seizures, and QT interval prolongation.

During post-marketing surveillance, adverse reactions of the central nervous system such as confusion, convulsions, hallucinations, and tremor have been observed.

Treatment

In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and CAPD, is ineffective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

The adverse reactions listed below are classified by system organ class and frequency of occurrence: 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), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse events are listed in decreasing order of severity.

Infections and infestations

Uncommon: fungal infections, including infections caused by Candida species; pathogenic microorganism resistance.

Blood and lymphatic system disorders

Uncommon: leucopenia, eosinophilia.

Rare: thrombocytopenia, neutropenia.

Frequency not known: pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders

Rare: angioedema, hypersensitivity (see section "Special precautions for use").

Frequency not known: anaphylactic shock¹, anaphylactoid shock¹ (see section "Special precautions for use").

Endocrine disorders

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutritional disorders

Uncommon: anorexia.

Rare: hypoglycaemia, especially in patients with diabetes mellitus; hypoglycaemic coma (see section "Special precautions for use").

Frequency not known: hyperglycaemia (see section "Special precautions for use").

Psychiatric disorders*

Common: insomnia.

Uncommon: anxiety, confusion, nervousness.

Rare: psychotic reactions (e.g. with hallucinations, paranoia), depression, agitation, sleep disturbances, night terrors, delirium.

Frequency not known: psychotic disorders with behaviour dangerous to the patient, including suicidal thoughts or suicide attempts (see section "Special precautions for use").

Nervous system disorders*

Common: headache, dizziness.

Uncommon: somnolence, tremor, dysgeusia.

Rare: seizures (see section "Special precautions for use"), paraesthesia, memory impairment.

Frequency not known: peripheral sensory neuropathy (see section "Special precautions for use); peripheral sensorimotor neuropathy (see section "Special precautions for use"); parosmia, including anosmia; dyskinesia, extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension.

Eye disorders*

Rare: visual disturbances such as blurred vision (see section "Special precautions for use").

Frequency not known: transient loss of vision (see section "Special precautions for use"), uveitis.

Ear and labyrinth disorders*

Uncommon: vertigo.

Rare: tinnitus.

Frequency not known: hearing loss, worsening of hearing.

Cardiac disorders**

Rare: tachycardia, palpitations.

Frequency not known: ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia and torsades de pointes (mainly observed in patients with risk factors for QT interval prolongation); QT interval prolongation observed on ECG (see sections "Special precautions for use" and "Overdose").

Vascular disorders**

Common: related only to the intravenous formulation: phlebitis.

Rare: arterial hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea.

Frequency not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders

Common: diarrhoea, vomiting, nausea.

Uncommon: abdominal pain, dyspepsia, flatulence, constipation.

Frequency not known: haemorrhagic diarrhoea, which may rarely be a sign of colitis, including pseudomembranous colitis (see section "Special precautions for use"); pancreatitis.

Hepatobiliary disorders

Common: increased levels of liver enzymes (ALT/AST, alkaline phosphatase, GGT).

Uncommon: increased blood bilirubin levels.

Frequency not known: jaundice and severe hepatic injury, including cases of fatal acute liver failure, particularly in patients with severe underlying diseases (see section "Special precautions for use"); hepatitis.

Skin and subcutaneous tissue disorders²

Uncommon: rash, pruritus, urticaria, hyperhidrosis.

Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"), persistent drug eruption.

Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity reactions (see section "Special precautions for use"), leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*

Uncommon: arthralgia, myalgia.

Rare: tendon disorders (see sections "Special precautions for use" and "Contraindications"), including tendinitis (e.g. Achilles tendon); muscle weakness, which may be significant in patients with myasthenia gravis (see section "Special precautions for use").

Frequency not known: acute skeletal muscle necrosis, tendon rupture (e.g. Achilles tendon) (see sections "Special precautions for use" and "Contraindications"), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders

Uncommon: increased blood creatinine levels.

Rare: acute renal failure (e.g. due to interstitial nephritis).

General disorders and administration site conditions*

Common: related only to the intravenous formulation: infusion site reaction (pain, redness).

Uncommon: asthenia.

Rare: pyrexia.

Frequency not known: pain (including back, chest and extremity pain).

¹ Anaphylactic and anaphylactoid reactions may occasionally occur even after administration of the first dose of the drug.

² Mucosal reactions may occasionally occur even after administration of the first dose of the drug.
* There have been reports of rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems (including such reactions as tendinitis, tendon rupture, arthralgia, extremity pain, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, hearing impairment, visual disturbances, taste and smell disturbances) associated with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions for use").

** There have been reports of cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve in patients receiving fluoroquinolones (see section "Special precautions for use").

Other adverse effects associated with fluoroquinolone use include acute porphyria attacks in patients with porphyria.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach and sight of children. Store in the original packaging at a temperature not exceeding 25 °C.

Incompatibilities.

Leflocin® 5 mg/ml infusion 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 "Special precautions for safety".

Packaging.

100 ml, 150 ml in a glass or polymer bottle; 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

LLC "Yuria-Pharm", Ukraine.

Manufacturer's address and location of business activity.

108, Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine.

Tel.: (044) 281-01-01.