Novox

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

Composition:

Active substance: levofloxacin;

100 ml of solution contain 500 mg of levofloxacin hemihydrate calculated as anhydrous 100% levofloxacin;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow to yellowish-green liquid. Theoretical osmolarity — 300 mOsmol/L.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.

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.

Mechanism of action.

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

Pharmacokinetic/pharmacodynamic relationship.

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

Mechanism of resistance.

The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists 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.

Breakpoint values.

The breakpoint MIC values for levofloxacin recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from intermediate susceptible (moderately resistant) organisms, and intermediate susceptible from resistant organisms, are presented in the MIC testing table below (mg/l).

EUCAST clinical breakpoint MIC values for levofloxacin

Table 1

The prevalence of resistance of individual species may vary geographically and over time, so it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, advice from a specialist should be sought when local resistance prevalence renders the benefit of the drug at least questionable for certain types of infections.

Generally susceptible species

Aerobic Gram-positive bacteria:

Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci group C and G*, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.*

Aerobic Gram-negative bacteria:

Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, 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 problematic

Aerobic Gram-positive bacteria:

Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Coagulase-negative Staphylococcus spp.

Aerobic Gram-negative bacteria:

Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria:

Bacteroides fragilis.

Naturally resistant strains

Aerobic Gram-positive bacteria

Enterococcus faecium

*The resistance mechanism of Staphylococcus aureus is likely associated with cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

There is no significant difference between the pharmacokinetics of levofloxacin after intravenous and oral administration.

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 serum. The mean volume of distribution of levofloxacin is about 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into tissues and body fluids.

Levofloxacin has the ability to penetrate into bronchial mucosa, alveolar epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle fluid), prostate tissue, and urine. However, penetration into cerebrospinal fluid is poor.

Biotransformation.

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

Elimination.

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). The mean total systemic 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 between intravenous and oral administration, indicating interchangeability of these routes.

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 decreased renal function, renal excretion and clearance are reduced, and elimination half-lives are prolonged, as shown in the table below.

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

Clinical characteristics.

Indications.

For use in adults for the treatment of infections caused by microorganisms sensitive to the drug:

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections;

(For the above-mentioned infections, levofloxacin should be used only when other antibacterial agents typically recommended for initial treatment of these infections are inappropriate or not feasible);

• Acute pyelonephritis, complicated urinary tract infections;
• Chronic bacterial prostatitis;
• Pulmonary form of anthrax — post-exposure prophylaxis and treatment.

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

Contraindications.

Hypersensitivity to levofloxacin or to other quinolones, epilepsy, tendon-related adverse reactions following prior administration of quinolones. Pediatric use (under 18 years of age). Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other drugs on the medicinal product NOVOKS®.

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

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. Levofloxacin does not affect the pharmacokinetics of theophylline, which is a substrate of the CYP1A2 enzyme; therefore, levofloxacin is not considered to be an inhibitor of CYP1A2. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, NSAIDs, and other agents that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen compared to administration of levofloxacin 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% with probenecid, as both drugs can block tubular secretion of levofloxacin. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Other information.

Clinical pharmacology studies have demonstrated that there was no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of the medicinal product NOVOKS® on other drugs.

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), increased values in coagulation tests (prothrombin time (PT)/international normalized ratio (INR)) and/or bleeding events, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists require monitoring of coagulation parameters.

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, antipsychotics).

Concomitant use of levofloxacin with alcohol is not recommended.

Concomitant use with glucocorticoids increases the risk of tendon rupture.

Special precautions for use.

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

An aneurysm and dissection of the aorta and cardiac valve regurgitation/insufficiency.

Epidemiological data suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and of 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 assessment of the benefit-risk ratio and consideration of alternative therapeutic options in patients with a personal or family history of aortic aneurysm or congenital heart valve defects, in patients with a confirmed diagnosis of aortic aneurysm and/or dissection, and in patients with heart valve disease or 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 receiving systemic corticosteroids concomitantly.

In case of sudden abdominal, chest, or back pain, patients should immediately seek 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 swelling.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, have developed prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various organ systems (particularly musculoskeletal, nervous, psychiatric, and sensory organs). The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Resistance.

In severe cases of pneumonia caused by pneumococci, the drug may not provide optimal therapeutic effect. Combination therapy may be required for hospital-acquired infections caused by Ps. aeruginosa and for severe cases of pneumococcal pneumonia. The prevalence of acquired resistance to the drug among specific pathogens may vary depending on the geographical region and may change over time. Therefore, local information on pathogen resistance is necessary; microbiological diagnosis with pathogen isolation and demonstration of its susceptibility to antibiotics is recommended, especially in cases of severe infections or lack of adequate response to therapy.

Methicillin-resistant S. aureus.

For methicillin-resistant Staphylococcus aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory test results confirm pathogen susceptibility to levofloxacin.

Resistance of Escherichia coli (the most common cause of urinary tract infections) to fluoroquinolones varies across countries. Local prevalence of Escherichia coli resistance to fluoroquinolones should be considered when prescribing the drug.

Duration of infusion.

The recommended infusion duration should be at least 30 minutes for 250 mg or 60 minutes for 500 mg of levofloxacin infusion solution. Tachycardia and transient decrease in blood pressure have been reported during ofloxacin infusion. In rare cases, a rapid drop in blood pressure may lead to cardiovascular failure. If a significant decrease in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, administration of the drug should be immediately discontinued.

The sodium content of the medicinal product should be considered when administering to patients on a sodium-controlled diet.

Tendinitis and tendon rupture.

Tendinitis may occur in individual patients. Tendinitis and tendon rupture (particularly of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and, as reported, even several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients with organ transplants, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

Upon first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Myoclonus.

Cases of myoclonus have been reported in patients receiving levofloxacin. The risk of myoclonus is increased in elderly patients and in patients with impaired renal function if the levofloxacin dose is not adjusted according to creatinine clearance. If myoclonus occurs, levofloxacin should be discontinued immediately and appropriate treatment initiated.

Clostridium difficile-associated disease.

Diarrhea, especially severe, persistent, and/or hemorrhagic, during or after treatment with NOVOX® may be a symptom of disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, infusion of the drug should be stopped immediately, and supportive measures and specific therapy (e.g., oral vancomycin) should be initiated promptly. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures.

Quinolones may lower the seizure threshold and provoke seizures.

NOVOX® infusion solution is contraindicated in patients with a history of epilepsy. This drug, like other quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients with central nervous system disorders, those receiving concomitant therapy with fenbufen and similar nonsteroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline. If seizures occur, treatment with levofloxacin should be discontinued. Therefore, if levofloxacin use is necessary in these patients, monitoring for possible hemolysis should be performed.

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be susceptible to hemolytic reactions during treatment with quinolone group antibacterial agents. Therefore, if levofloxacin use is necessary in these patients, monitoring for possible hemolysis should be performed.

Patients with renal impairment.

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency).

Renal and hepatic function should be monitored throughout the course of treatment. If adverse effects occur, especially those affecting the central nervous system (CNS) and allergic reactions, which may occur after the first dose, levofloxacin should be discontinued.

Hypersensitivity reactions.

NOVOX® may cause serious hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose. In such cases, patients should discontinue treatment immediately and consult a physician.

Severe skin adverse reactions.

Severe skin adverse reactions, including toxic epidermal necrolysis (TEN, also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse reactions").

At the time of prescribing, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered.

If a patient develops a serious reaction such as SJS, TEN, or DRESS syndrome during levofloxacin treatment, levofloxacin should never be prescribed again to this patient.

Disturbances in glucose metabolism.

As with other quinolones, changes in blood glucose levels (including hyper- and hypoglycemia) have been reported with levofloxacin use, particularly in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Close monitoring of blood glucose levels is recommended in diabetic patients.

Prevention of photosensitization.

Cases of photosensitivity have been reported with levofloxacin use. To prevent photosensitization, patients are advised to avoid exposure to strong sunlight or artificial UV radiation sources (including UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists.

Due to the risk of increased coagulation test parameters (PT, international normalized ratio) and/or bleeding with concomitant use of levofloxacin and vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored in patients.

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only one 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.

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

QT interval prolongation.

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

• congenital long QT syndrome;
• concomitant use of medicinal products capable of prolonging the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women are more sensitive to drugs 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 polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician to prevent the development of potentially irreversible conditions.

Hepatobiliary disorders.

Cases of necrotic hepatitis up to life-threatening hepatic 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.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal cases and conditions requiring respiratory support, have occurred in patients with myasthenia gravis during post-marketing use of fluoroquinolones. NOVOX® is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If any visual disturbances or adverse reactions affecting the eyes occur during levofloxacin use, patients should seek medical advice immediately.

Superinfection.

The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms resistant to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Acute pancreatitis.

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued, and if confirmed, treatment with levofloxacin should not be resumed. Caution is advised when administering to patients with a history of pancreatitis.

Blood disorders.

During treatment with levofloxacin, bone marrow suppression may occur, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis. If any of these blood disorders are suspected, blood parameters should be monitored. If abnormalities are detected, discontinuation of levofloxacin therapy should be considered.

Effect on laboratory test results.

In patients receiving levofloxacin, opiate screening in urine may yield false-positive results. Confirmation of positive opiate test results obtained by screening tests may be necessary using more specific methods.

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

Pulmonary form of anthrax.

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

Important information on excipients.

The medicinal product contains sodium—caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect reproductive toxicity. However, in the absence of human data and in view of experimental evidence indicating a risk of cartilage damage in the growing organism due to fluoroquinolones, the medicinal product is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding period. Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin into breast milk. However, other fluoroquinolones are excreted into human milk. In the absence of human data and in view of experimental evidence indicating a risk of cartilage damage in the growing organism due to fluoroquinolones, levofloxacin is contraindicated in women who are breastfeeding (see section "Contraindications").

Fertility. Levofloxacin does not impair fertility or reproductive function in animals.

Ability to affect reaction speed when driving or operating machinery.

Patients who drive vehicles or operate machinery should be aware of possible adverse reactions affecting the nervous system (headache, dizziness, numbness, somnolence, confusion, visual and auditory disturbances, motor disorders, including during walking).

Method of Administration and Dosage

Prior to administration, a sensitivity test must be performed. The drug for intravenous use should be administered within 3 hours after perforation of the rubber stopper.

Protection from light during infusion is not required. The intravenous solution may be stored under normal room lighting for up to 3 days without protection from light.

The drug should be administered intravenously slowly, 1 or 2 times daily. Dosage depends on the type and severity of infection, as well as on the susceptibility of the likely causative organism to the drug.

For treatment of adults with normal renal function, in whom creatinine clearance is over 50 mL/min, the following doses are recommended:

Table 3

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

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

Dosing for adult patients with renal impairment with a creatinine clearance of less than 50 ml/min:

Table 4

1 After hemodialysis or chronic 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 not impaired, dose adjustment is not required.

NOVOX® intravenous solution must be administered intravenously slowly by drip infusion. The duration of administration should be at least 30 minutes for a 250 mg dose or at least 60 minutes for a 500 mg dose.

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

Mixing with other infusion solutions.

NOVOX® 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).

Children.

NOVOX® must not be administered to children and adolescents (under 18 years of age), as damage to joint cartilage cannot be excluded.

Overdose.

The most important expected symptoms of overdose with NOVOX® involve the central nervous system (confusion and impaired consciousness, dizziness, seizures, myoclonus, hallucinations, tremor, nausea, erosion of mucous membranes). According to study results, administration of doses higher than therapeutic ones has been associated with QT interval prolongation. In case of overdose, careful patient monitoring, including ECG, should be performed. Treatment is symptomatic.

Hemodialysis, including peritoneal dialysis or CAPD, is not effective for removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions.

The frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, ≤1/100), rare (≥1/10,000, ≤1/1,000), frequency not known (cannot be estimated from the available data).

Infections and infestations.

Uncommon: fungal infections, including infections caused by Candida species. Resistance of pathogenic microorganisms.

Blood and lymphatic system disorders.

Uncommon: leukopenia, eosinophilia.

Rare: thrombocytopenia, neutropenia.

Frequency not known: bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders.

Rare: angioedema, hypersensitivity.

Frequency not known: anaphylactic shock, anaphylactoid reactions (may occasionally occur even after administration of the first dose).

Metabolism and nutrition disorders.

Uncommon: anorexia.

Rare: hypoglycemia, especially in patients with diabetes mellitus.

Frequency not known: hyperglycemia, hypoglycemic coma.

Endocrine system disorders.

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

Psychiatric disorders.*

Common: insomnia.

Uncommon: anxiety, confusion, restlessness.

Rare: psychotic disorders (e.g., with hallucinations, paranoia), depression, agitation, sleep disturbances, nightmares, delirium.

Frequency not known: psychotic reactions with self-destructive behavior, including suicidal thoughts and suicide attempts, mania.

Nervous system disorders.*

Common: headache, dizziness.

Uncommon: somnolence, tremor, dysgeusia.

Rare: seizures, paresthesia, memory impairment.

Frequency not known: sensory or sensorimotor peripheral neuropathy, parosmia including anosmia, dyskinesia, extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension, myoclonus.

Eye disorders.*

Rare: visual disturbances, e.g., blurred vision.

Frequency not known: transient loss of vision, uveitis.

Ear and labyrinth disorders.*

Uncommon: vertigo.

Rare: tinnitus.

Frequency not known: hearing loss, disturbances 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 in patients with risk factors for QT interval prolongation), QT interval prolongation as measured on electrocardiogram.

Vascular disorders.

Common: phlebitis (only for intravenous formulations).

Rare: arterial hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnea.

Frequency not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders.

Common: diarrhea, vomiting, nausea.

Uncommon: abdominal pain, dyspepsia, bloating, constipation.

Frequency not known: hemorrhagic diarrhea, which very rarely may indicate enterocolitis, including pseudomembranous colitis, pancreatitis.

Hepatobiliary disorders.

Common: increased liver enzyme levels (alanine aminotransferase [ALT]/aspartate aminotransferase [AST], alkaline phosphatase, GGT).

Uncommon: increased blood bilirubin levels.

Frequency not known: jaundice and severe liver injury, including fatal cases of acute liver failure, mainly in patients with severe underlying conditions, hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: rash, pruritus, urticaria, hyperhidrosis.

Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), persistent drug eruptions.

Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, photosensitization reactions, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

Musculoskeletal and connective tissue disorders.*

Uncommon: arthralgia, myalgia.

Rare: tendon disorders, including tendinitis (e.g., Achilles tendon), muscle weakness, which may be particularly relevant in patients with myasthenia gravis.

Frequency not known: acute skeletal muscle necrosis (rhabdomyolysis), tendon rupture (e.g., Achilles tendon), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders.

Uncommon: increased serum creatinine levels.

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

General disorders and administration site conditions.*

Common: (applies only to intravenous formulations) infusion site reaction (pain, redness).

Uncommon: asthenia.

Rare: fever.

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

Other adverse effects associated with fluoroquinolone use:

• Extrapyramidal symptoms and other movement coordination disorders;
• Hypersensitivity vasculitis;
• Porphyria attacks in patients with pre-existing porphyria.
• Anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances as potential aspects of prolonged and disabling fluoroquinolone-induced adverse reactions, which may lead to loss of work capacity.

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

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

Reporting of suspected adverse reactions after registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

NOVOX® must 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 administration".

Packaging. 100 ml or 150 ml in a bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and place of business.

Ukraine, 21034, Vinnytsia, Voloshkova St., b. 55

or Ukraine, 23219, Vinnytsia region, Vinnytsia district, village Vinnytski Khutory, Nemirovskе Highway, b. 84A.