Ofloxacin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OFLOXACIN-DARNITSA (Ofloxacin-Darnitsa)

Composition:

Active ingredient: ofloxacin;

One tablet contains 200 mg of ofloxacin;

Excipients: potato starch, hydroxypropylcellulose, povidone, sodium croscarmellose, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or off-white tablets, flat cylindrical in shape, bevelled edge and scored.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones. Ofloxacin. ATC code J01MA01.

Pharmacological Properties.

Pharmacodynamics.

The active substance of the medicinal product is ofloxacin, a synthetic fluoroquinolone antimicrobial agent with a broad spectrum of activity.

The bactericidal action mechanism of the drug is associated with inhibition of DNA gyrase activity, leading to termination of bacterial DNA replication.

Ofloxacin is active against most Gram-negative bacteria: Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, Enterobacter, Citrobacter, Providencia, Pseudomonas, Hafnia, as well as Staphylococcus (including microflora resistant to methicillin and other antibiotics). Neisseria, Mycoplasma, Chlamydia, Campylobacter, Brucella, Vibrio, Aeromonas, Plesiomonas, Haemophilus influenzae, Yersinia are also sensitive to ofloxacin.

Variable sensitivity to ofloxacin is observed in: enterococci, streptococci (S. pyogenes, S. pneumoniae, S. viridans), Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter, Mycoplasma (M. hominis, M. pneumoniae), tuberculosis mycobacteria, as well as Mycobacterium fortuitum.

In most cases, the following are resistant to ofloxacin: Ureaplasma urealyticum, Nocardia asteroides, anaerobic bacteria (e.g., Bacteroides spp., peptococci, peptostreptococci, Eubacterium spp., Fusobacterium spp., Clostridium difficile).

Ofloxacin is ineffective against Treponema pallidum.

Pharmacokinetics.

Absorption.

After oral administration, ofloxacin is rapidly and completely absorbed in the gastrointestinal tract. Bioavailability reaches almost 100%.

The time to reach maximum plasma concentration (Tmax) is 0.5–3 hours. The maximum plasma concentration after a single dose of 200–400 mg of the drug (Cmax) is 2 and 5 mg/mL, respectively. Protein binding in plasma is 25%.

Distribution.

Ofloxacin penetrates through the placenta, into breast milk, and into all tissues and organs. The volume of distribution ranges from 1.5 to 2.5 L/kg.

Metabolism.

Ofloxacin is metabolized to a limited extent (up to 5%) in the liver to dimethyl-ofloxacin and ofloxacin-N-oxide. Dimethyl-ofloxacin exerts moderate antimicrobial activity.

Excretion.

Ofloxacin is primarily eliminated from the body via the kidneys through tubular secretion and glomerular filtration: 75–80% of the administered dose is excreted unchanged within 24–48 hours, and less than 5% is excreted as metabolites. 4–8% of the administered dose is excreted in feces.

The elimination half-life (T1/2) is 4–6 hours. Ofloxacin elimination is slowed in patients with severe hepatic insufficiency and in patients with renal impairment (depending on the degree of impairment, up to 15–60 hours).

Clinical characteristics.

Indications.

Infectious and inflammatory diseases caused by microorganisms sensitive to ofloxacin:

• Exacerbations of chronic obstructive pulmonary diseases (including chronic bronchitis)*, community-acquired pneumonia*;
• Uncomplicated acute cystitis*, urethritis*, acute pyelonephritis, and complicated urinary tract infections;
• Complicated skin and soft tissue infections*;
• Gonococcal urethritis and cervicitis caused by sensitive strains of Neisseria*.

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

*Only when other antibacterial agents typically used to treat these infections cannot be applied.

Contraindications.

• Hypersensitivity to the active substance, other components of the medicinal product, or to other fluoroquinolones.
• Epilepsy, central nervous system disorders with reduced seizure threshold (following head trauma, stroke, inflammatory processes of the brain and meninges).
• History of tendinitis.
• Glucose-6-phosphate dehydrogenase deficiency.

The medicinal product must not be used in patients with QT interval prolongation, uncompensated hypoglycemia, or in patients concurrently receiving medicinal products capable of prolonging the QT interval (Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

Interaction with other medicinal products and other forms of interaction.

Potential interactions may occur when the medicinal product is used concomitantly with other medicinal products:

With antacids containing aluminium/magnesium, sucralfate, zinc or iron preparations – reduced absorption of ofloxacin; it should be taken at least 2 hours before these medicinal products;

With medicinal products excreted via tubular secretion (e.g., probenecid, cimetidine, furosemide, methotrexate) – impaired elimination and increased plasma levels of ofloxacin;

With medicinal products capable of prolonging the QT interval (e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) – additional QT interval prolongation; concomitant use is contraindicated;

With nonsteroidal anti-inflammatory drugs and medicinal products capable of lowering the seizure threshold (e.g., theophylline) – additional reduction in central nervous system seizure threshold; if seizures occur, ofloxacin should be discontinued. Ofloxacin is considered not to exhibit pharmacokinetic interaction with theophylline, unlike other fluoroquinolones;

With antidiabetic medicinal products – fluctuations in blood glucose levels (hypo- or hyperglycemia); blood glucose levels should be monitored during concomitant use;

With indirect anticoagulants – prolonged bleeding time; coagulation parameters should be closely monitored during concomitant use;

With glibenclamide – slight increase in plasma levels of the latter; close monitoring of the patient is recommended during concomitant use.

Effect on laboratory test results.

False-positive results in urine tests for opiates or porphyrins may occur during ofloxacin therapy. Confirmation of positive opiate or porphyrin tests using more specific methods may be necessary.

Vitamin K antagonists: close monitoring of coagulation parameters is required in patients receiving vitamin K antagonists due to the potential for enhanced effect of coumarin derivatives.

When ofloxacin is used concomitantly with warfarin or its derivatives, prothrombin time or other appropriate coagulation tests should be monitored.

Ofloxacin may inhibit the growth of Mycobacterium tuberculosis, leading to false-negative results in bacteriological testing for tuberculosis diagnosis.

With high-dose administration of the medicinal product, increased serum concentrations may occur.

Concomitant use of ofloxacin with caffeine, theophylline, cimetidine, cyclosporine, oral anticoagulants, and medicinal products metabolized via cytochrome P450 may increase the risk of adverse effects.

Special precautions for use.

The use of ofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment of these patients with ofloxacin should only be initiated if no alternative treatment options are available and after careful benefit/risk assessment (see also section "Contraindications").

During administration of the medicinal product, patients should drink sufficient amounts of fluid to prevent the development of crystalluria.

Ofloxacin is not a first-line medicinal product for the treatment of community-acquired pneumonia caused by pneumococci or mycoplasma, or acute tonsillitis caused by β-haemolytic streptococci.

During treatment with the medicinal product, exposure to intense sunlight and ultraviolet radiation (mercury-quartz lamps, solariums) should be avoided.

Fluoroquinolones should be used only in patients for whom no alternative treatment options are available for acute bacterial sinusitis, acute exacerbation of chronic bronchitis of bacterial etiology, and uncomplicated urinary tract infections, as the benefit does not outweigh the risks in such patients.

Fluoroquinolone antibiotics should not be used:

• for the treatment of infections that are not severe and may resolve without antibacterial therapy (e.g., oropharyngeal infections);
• for the treatment of non-bacterial infections, such as non-bacterial (chronic) prostatitis;
• for the prevention of traveler's diarrhea or recurrent lower urinary tract infections (infections that do not extend beyond the urinary bladder);
• for the treatment of moderate bacterial infections when other usually recommended antibacterial agents cannot be used;
• in patients with acute bacterial sinusitis, acute exacerbation of chronic bronchitis of bacterial etiology, and uncomplicated urinary tract infections if alternative medicinal products are available.

An aneurysm and dissection of the aorta and regurgitation/insufficiency of heart valves.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of 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 heart 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 other therapeutic treatment options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with an existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

• both for aneurysm and dissection of the aorta, and for regurgitation/insufficiency of heart valves (e.g., connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Takayasu arteritis, giant cell arteritis, Behçet's disease, hypertension, rheumatoid arthritis, known atherosclerosis), or additionally

− for aneurysm and dissection of the aorta (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or additionally

− for regurgitation/insufficiency of heart valves (e.g., infective endocarditis).

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

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 in case of acute shortness of breath, new onset of palpitations, or development of abdominal or lower limb edema.

Patients with renal function impairment.

The medicinal product should be used with caution in patients with impaired renal function. Dose and dosing intervals should be adjusted according to the delayed elimination of the drug.

Patients with hepatic function impairment.

The medicinal product should be used with caution in patients with impaired liver function. Cases of fulminant hepatitis, potentially leading to liver failure (including fatal cases), have been reported during treatment with fluoroquinolones.

In case of symptoms of liver disease such as anorexia, jaundice, darkening of urine, pruritus, or abdominal tenderness on palpation (see section "Adverse reactions"), patients are advised to discontinue the medicinal product and consult a physician.

Patients with disorders of the central nervous system.

The medicinal product should be used with caution in patients with disorders of the central nervous system (severe atherosclerosis of cerebral vessels, history of acute cerebral circulation insufficiency), patients with myasthenia gravis, and patients with a history of peripheral neuropathy.

Myasthenia gravis.

Fluoroquinolones, including ofloxacin, 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.

Ofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Patients with a history of psychotic disorders.

The medicinal product should be used with caution in patients with psychiatric disorders or a history of psychotic disorders. Psychotic reactions have been reported in patients taking fluoroquinolones. In some cases, these reactions progressed to suicidal thoughts or self-destructive behavior, including suicide attempts, sometimes even after a single dose of the medicinal product.

If such reactions occur, the medicinal product should be discontinued and appropriate therapeutic measures initiated.

Hypoglycemia.

Alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported with the use of all quinolones (see section "Adverse reactions").

The medicinal product should be used with caution in patients with diabetes mellitus who are receiving concomitant treatment with oral hypoglycemic agents (e.g., glibenclamide) or insulin due to the potential risk of hypoglycemia. Cases of hypoglycemic coma have been reported. Blood glucose levels should be closely monitored in diabetic patients.

Patients with glucose-6-phosphate dehydrogenase deficiency.

The medicinal product should be used with caution in patients with latent or confirmed glucose-6-phosphate dehydrogenase deficiency due to the potential risk of hemolytic reactions during treatment with fluoroquinolones.

QT interval prolongation.

In very rare cases, QT interval prolongation has been reported in patients taking fluoroquinolones.

The medicinal product should be used with caution in patients with risk factors for QT interval prolongation, including:

• advanced age;
• uncorrected electrolyte imbalance (hypokalemia, hypomagnesemia);
• congenital long QT syndrome;
• acquired QT interval prolongation;
• heart disease (heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, caution should be exercised when prescribing fluoroquinolones, including ofloxacin, to these patient groups.

In rare cases, QT interval prolongation has been reported in patients taking fluoroquinolones.

Patients taking vitamin K antagonists.

The medicinal product should be used with caution in patients who are concurrently taking vitamin K antagonists. There have been reports of increased coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding in patients taking fluoroquinolones (including ofloxacin) in combination with vitamin K antagonists (e.g., warfarin). Close monitoring of coagulation test results is required.

Methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus is likely to have cross-resistance to fluoroquinolones, including ofloxacin. Therefore, ofloxacin is not recommended for the treatment of known or suspected MRSA infections, except in cases where laboratory testing has confirmed susceptibility of the pathogen to ofloxacin.

Infections caused by Escherichia coli.

Resistance of E. coli – the most common pathogen in urinary tract infections – to fluoroquinolones varies across different countries of the European Union. Prescribers are advised to consider the local prevalence of E. coli resistance to fluoroquinolones.

Infections caused by Neisseria gonorrhoeae.

Due to increasing resistance of N. gonorrhoeae, ofloxacin should not be used as an empirical approach to antibacterial therapy in suspected gonococcal infection (gonococcal urethritis, pelvic inflammatory disease, epididymo-orchitis), except in cases where the pathogen has been identified and its susceptibility to ofloxacin confirmed. If no clinical improvement is observed after 3 days of treatment, therapy should be re-evaluated.

Pelvic inflammatory disease.

For the treatment of pelvic inflammatory disease, ofloxacin should only be used in combination with agents active against anaerobic microorganisms.

Clostridium difficile-associated disease.

Diarrhea occurring during or after treatment with ofloxacin (including several weeks after treatment), especially if severe, prolonged, and/or associated with bleeding, may be a symptom of pseudomembranous colitis (caused by Clostridium difficile). The severity of Clostridium difficile-associated diseases ranges from mild conditions to life-threatening states, with pseudomembranous colitis being the most severe form (see section "Adverse reactions"). Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with ofloxacin.

In case of suspected pseudomembranous colitis, the medicinal product should be immediately discontinued and appropriate specific antibiotic therapy initiated (e.g., oral vancomycin, oral teicoplanin, or metronidazole). In this clinical situation, medicinal products that inhibit intestinal peristalsis are contraindicated.

Patients with a predisposition to seizures.

Quinolones may lower the seizure threshold and provoke seizures. Ofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). Like other quinolones, it should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant treatment with substances that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction").

If seizures occur, the medicinal product should be discontinued.

Prevention of photosensitization.

Cases of photosensitization have been reported during ofloxacin use (see section "Adverse reactions"). Patients taking ofloxacin should avoid exposure to intense sunlight and ultraviolet radiation (mercury-quartz lamps, solariums) unless absolutely necessary during treatment and for 48 hours after discontinuation of the drug.

Tendinitis and tendon rupture.

During treatment with ofloxacin, tendinitis may rarely occur, which may lead to tendon rupture, particularly of the Achilles tendon. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and, as reported, may even occur several months after discontinuation of treatment. The risk of developing this pathology is increased in elderly patients, organ transplant recipients, patients with renal impairment, and those receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

The daily dose should be calculated based on creatinine clearance (see section "Dosage and administration"). If tendinitis is suspected (e.g., swelling or inflammation of joints), the medicinal product should be immediately discontinued, the patient should consult their physician, and appropriate therapeutic measures for the affected tendon should be taken (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Hypersensitivity reactions.

Allergic and hypersensitivity reactions have been reported during treatment with ofloxacin after administration of the initial dose of fluoroquinolones. Anaphylactic and anaphylactoid reactions may progress to life-threatening shock, even after the initial dose. In such cases, the medicinal product should be immediately discontinued and appropriate therapeutic measures initiated. The use of the medicinal product should be avoided in patients with a history of severe adverse reactions (tendinitis, severe neurological reactions) to other quinolones due to the increased risk of similar reactions to ofloxacin. Treatment of these patients should only be initiated if no alternative treatment options are available and after careful benefit/risk assessment.

Severe bullous reactions.

Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported during ofloxacin use (see section "Adverse reactions"). In case of skin and/or mucosal reactions, patients should be advised to immediately contact their physician before continuing treatment.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

With the use of quinolones and fluoroquinolones, regardless of patient age or pre-existing risk factors, very rare prolonged (months or years) and potentially irreversible, sometimes combined, adverse reactions may occur affecting tendons, muscles, joints, sensory organs, peripheral nerves, the central nervous system, and mental health, which may lead to disability. If such disorders or their initial symptoms (tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, muscle weakness, neuropathy, paresthesia (tingling, numbness in hands or feet), depression, fatigue, confusion, hallucinations, memory impairment, sleep disturbances, hearing impairment, visual disturbances, taste and smell disturbances) occur, the medicinal product should be immediately discontinued, and the patient should consult a physician regarding the possibility of switching to other antibacterial agents to complete the treatment course.

Peripheral neuropathy.

Peripheral sensory or sensorimotor polyneuropathy leading to paresthesia or hypesthesia, dysesthesia, or weakness has been reported during treatment with ofloxacin in patients receiving quinolones and fluoroquinolones (including ofloxacin). Patients undergoing treatment with Ofloxacin-Darnytsia should be informed about the necessity to discontinue treatment upon the onset of neuropathy symptoms (pain, burning, tingling, numbness, and/or weakness in hands or feet) to prevent the development of irreversible conditions.

Visual disturbances.

If any visual disturbances or adverse reactions affecting the eyes occur during ofloxacin intake, patients should immediately consult an ophthalmologist (see sections "Effect on ability to drive and use machines" and "Adverse reactions").

Other important information.

Antibacterial treatment (including ofloxacin), especially prolonged treatment, may lead to overgrowth of resistant microflora. Patients should be monitored, and appropriate therapeutic measures should be taken in case of secondary infection.

The consumption of alcoholic beverages is not recommended during treatment with ofloxacin.

Important information on excipients.

The medicinal product contains sodium; therefore, patients on a sodium-restricted diet should exercise caution when using this product.

Use during pregnancy or breastfeeding.

Animal studies have shown damage to articular cartilage in immature animals, but teratogenic effects were absent. Therefore, ofloxacin is contraindicated during pregnancy and breastfeeding.

Ofloxacin is excreted in breast milk in small amounts. Due to the potential risk of arthropathy and other serious toxicities in the breastfed infant, breastfeeding should be discontinued during treatment with ofloxacin.

Effect on ability to drive and use machines.

Patients should refrain from driving or operating machinery due to the possible occurrence of dizziness, coordination disturbances, somnolence, visual disturbances, and other nervous system reactions. These effects may be potentiated by alcohol consumption.

Dosage and Administration.

The medicinal product should be taken orally. Tablets should be swallowed with liquid. The interval between taking ofloxacin and sucralfate, zinc or iron preparations, or aluminum/magnesium-containing antacids should be at least 2 hours, since the absorption of ofloxacin may be reduced when administered concomitantly with these medicinal products.

Dosage.

The dose of the medicinal product depends on the type and severity of the infectious disease. The dosage range for adults is from 200 mg to 800 mg per day. Doses up to 400 mg may be taken as a single dose, preferably in the morning; higher doses should be divided into two equal doses administered at regular intervals.

Exacerbation of chronic obstructive pulmonary diseases (including chronic bronchitis), community-acquired pneumonia: the medicinal product should be administered at a dose of 400 mg once daily; if necessary, up to 400 mg twice daily.

Complicated skin and soft tissue infections: the medicinal product should be administered at a dose of 400 mg twice daily.

Urinary tract infections: doses and administration regimens depending on indications are presented in Table 1.

Table 1

*In prostatitis, the need for prolongation of treatment duration may be considered after careful re-evaluation of the patient.

Ofloxacin may also be used to complete the treatment course in patients who show improvement following initial therapy with intravenous ofloxacin.

Patients with renal impairment.

The drug should be administered at the usual initial dose; however, subsequent doses should be reduced according to creatinine clearance (CrCl):

Table 2

Serum ofloxacin concentrations should be monitored in patients with severe renal impairment and in patients undergoing dialysis.

In cases where creatinine clearance cannot be measured, it can be calculated from serum creatinine levels using the Cockcroft formula provided below for adults:

or

For women: ClCr (mL/min) = 0.85 × (value in men)

In patients with impaired liver function.

Excretion of the drug in patients with severe liver dysfunction may be reduced. Therefore, the daily dose should not exceed 400 mg.

In elderly patients.

Dose adjustment is not required (see section "Special precautions"), except in cases related to the patient's liver or kidney function.

Duration of treatment.

The duration of treatment depends on the severity of infection and the patient's response to therapy.

The usual course of treatment lasts 5–10 days, except for uncomplicated gonorrhea, for which a single 400 mg dose of the drug is recommended.

The duration of treatment should not exceed 2 months.

Children.

The drug is contraindicated in children.

Overdose.

Symptoms: the most significant expected signs of acute overdose are symptoms related to the central nervous system, particularly confusion, dizziness, impaired consciousness and seizures, hallucinations, tremor, as well as gastrointestinal reactions such as nausea and erosive mucosal damage.

Treatment: measures to remove unabsorbed ofloxacin (e.g., gastric lavage, administration of adsorbents and magnesium sulfate, if possible within the first 30 minutes after overdose), monitoring of electrocardiogram parameters due to possible QT interval prolongation. Ofloxacin fractions may be removed from the body by hemodialysis. Peritoneal dialysis and chronic ambulatory peritoneal dialysis are not effective for elimination of ofloxacin from the body. There is no specific antidote for this drug. Elimination of ofloxacin from the body may be enhanced by forced diuresis.

To protect gastric mucosa, antacids are recommended.

Side effects.

Eye disorders: irritation of the eye mucous membrane, conjunctivitis, nystagmus, decreased visual acuity, visual disturbances (including diplopia, photophobia), color blindness, uveitis.

Ear and labyrinth disorders: dizziness, tinnitus, decreased hearing acuity, hearing loss, impaired motor coordination.

Respiratory, thoracic and mediastinal disorders: cough, nasopharyngitis, dyspnea, bronchospasm, allergic pneumonitis, rhinorrhea, wheezing, allergic pulmonitis, sensation of lack of air, respiratory arrest, dyspnea, severe asthma.

Gastrointestinal disorders: anorexia, abdominal pain, nausea, vomiting, diarrhea, enterocolitis (sometimes hemorrhagic), pseudomembranous colitis, dryness or burning sensation in the mouth, dyspepsia, pyrosis, flatulence, constipation, intestinal colic, intestinal perforation, gastrointestinal bleeding, pancreatitis.

Hepatobiliary disorders: increased levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, and/or alkaline phosphatase) and bilirubin in blood plasma, jaundice (including cholestatic and parenchymatous), hepatitis, necrosis. Severe liver damage has been reported, including cases of fatal acute liver failure, primarily in patients with severe underlying liver diseases.

Renal and urinary disorders: increased plasma creatinine levels, acute renal failure, acute interstitial nephritis, polyuria, dysuria, anuria, frequent urination, urinary retention, hematuria, albuminuria, candiduria, kidney stone formation.

Metabolism and nutrition disorders: hyperglycemia, hypoglycemia in patients with diabetes mellitus taking hypoglycemic agents, increased plasma levels of triglycerides, cholesterol, and potassium, acidosis, hypoglycemic coma (see section "Special precautions").

Nervous system disorders: headache, somnolence, paresthesia, dysgeusia, parosmia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, seizures, exacerbation of myasthenia gravis, extrapyramidal disorders or other muscle coordination disturbances, memory impairment, development of epileptic seizures, ataxia, tremor, reduced reaction speed, increased intracranial pressure, vertigo.

Psychiatric disorders: agitation, sleep disorders, insomnia, psychotic disorders (including hallucinations, paranoia, manic thoughts), restlessness, confusion, nightmares, depression, psychotic disorders and depression with self-destructive behavior, including suicidal thoughts or suicide attempts; euphoria, phobias, irritability, anxiety, disorientation, delirium.

Cardiac disorders:* tachycardia, arterial hypotension, ventricular arrhythmias, polymorphic ventricular tachycardia of the "torsades de pointes" type (these reactions were observed mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on ECG, arterial hypertension, cerebral thrombosis, cardiac arrest, shock.

Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, neutropenia, eosinophilia, thrombocytopenia, agranulocytosis, bone marrow suppression (which resolves after discontinuation of the drug), pancytopenia. Development of petechiae, hematomas, and epistaxis.

Immune system disorders: hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioneurotic edema, anaphylactic/anaphylactoid shock.

Skin and subcutaneous tissue disorders: rashes (including pustular, hemorrhagic), pruritus, urticaria, flushing, hyperhidrosis, erythema, Stevens-Johnson syndrome, photosensitization reactions, drug dermatitis, vasculitic purpura, vasculitis which may exceptionally lead to skin necrosis; Lyell's syndrome (toxic epidermal necrolysis), generalized exanthematous pustulosis, drug eruptions, exfoliative dermatitis, skin hyperpigmentation, nail discoloration or nail separation.

Musculoskeletal and connective tissue disorders: tendonitis, arthralgia, myalgia, tendon ruptures (including Achilles tendon), which may be bilateral and occur within 48 hours after initiation of treatment, rhabdomyolysis and/or myopathy, muscle weakness, muscle spasms, muscle tears, muscle ruptures, tendon pain, arthritis.

Reproductive system and breast disorders: irritation, burning, and painful rashes on female external genital organs, vaginitis, dysmenorrhea, hypermenorrhea, metrorrhagia.

Congenital, familial and genetic disorders: acute attacks of porphyria in patients with porphyria.

Infections and infestations: superinfection, development of secondary infections (including fungal infections), development of resistance in pathogenic microorganisms.

General disorders: general weakness, increased fatigue, decreased appetite, malaise, asthenia, edema (including pulmonary edema), back pain, fever, chills, increased pain sensitivity, weight loss, taste and smell disturbances.

*There have been reports of some very rare, prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple (sometimes combined) organ systems and senses (including tendonitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing disturbances, 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").

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important procedure. It enables ongoing monitoring of the benefit-risk ratio for the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister pack; 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.