Ozerlik

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OZERLYK® (OZERLYK®)

Composition:

Active substance: gatifloxacin;

One tablet contains 400 mg of gatifloxacin, calculated as gatifloxacin sesquihydrate;

Excipients: maize starch, povidone K-30, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide, sodium croscarmellose, Opadry 03B52014 yellow: hypromellose, titanium dioxide (E 171), polyethylene glycol, quinoline yellow (E 104), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Antibacterials for systemic use. Fluoroquinolones. ATC code J01MA16.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of the drug is associated with inhibition of DNA gyrase and topoisomerase IV. Gatifloxacin, belonging to the 8-methoxyfluoroquinolones, is active against a broad range of Gram-negative and Gram-positive microorganisms, thus it is indicated for the treatment of infections caused by the following pathogens:

Gram-positive microorganisms: susceptible – Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes; and relatively susceptible – Streptococcus milleri, Streptococcus mitior, Streptococcus agalactiae, Streptococcus dysgalactiae, Staphylococcus cohnii, Staphylococcus epidermidis (including methicillin-resistant strains), Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Corynebacterium diphtheriae;

Gram-negative microorganisms: susceptible – Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis (including β-lactamase-producing strains), Escherichia coli, Enterobacter cloacae, Neisseria gonorrhoeae (including β-lactamase-producing strains); and relatively susceptible – Bordetella pertussis, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter intermedius, Enterobacter sakazakii, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia stuartii;

Relatively susceptible anaerobes: Bacteroides distasonis, Bacteroides eggerthii, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Fusobacterium spp., Porphyromonas spp., Porphyromonas anaerobius, Porphyromonas asaccharolyticus, Porphyromonas magnus, Prevotella spp., Propionibacterium spp., Clostridium perfringens, Clostridium ramosum;

Susceptible atypical pathogens: C. pneumoniae, C. trachomatis, M. pneumoniae, L. pneumophila, Ureaplasma;

Relatively susceptible atypical forms: Legionella pneumophila, Coxiella burnetii.

Gatifloxacin is active against Mycobacterium tuberculosis and H. pylori.

The antibacterial action of gatifloxacin is due to inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is a key enzyme involved in DNA replication of pathogens. Topoisomerase IV is an enzyme playing a major role in chromosome segregation during bacterial cell division.

Gatifloxacin is effective against bacteria resistant to β-lactam and macrolide antibiotics.

Pharmacokinetics.

Gatifloxacin is well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of gatifloxacin is 96%. Peak plasma concentration is reached within 1–2 hours after oral administration. Plasma protein binding is approximately 20%.

Gatifloxacin penetrates well into most body tissues and rapidly distributes into biological fluids. High concentrations are achieved in lung tissue, bronchial mucosa, nasal sinuses, alveolar macrophages, middle ear tissues, skin tissues, prostate tissue and secretion, saliva, bile, seminal fluid, vagina, uterus, endometrium and myometrium, fallopian tubes, and ovaries.

Gatifloxacin undergoes biotransformation in the body, with less than 1% of the dose excreted unchanged in urine.

It is eliminated via the kidneys. The mean elimination half-life of gatifloxacin ranges from 7 to 14 hours and does not depend on dose or dosing regimen.

In animal experiments, gatifloxacin freely crossed the placenta and was excreted into breast milk.

Differences in gatifloxacin pharmacokinetics have been observed in women. Elderly women showed a 21% increase in maximum plasma concentration, a 32% increase in area under the concentration-time curve (AUC_0–∞), and slower elimination compared to younger women.

Pediatrics. The pharmacokinetics of gatifloxacin in children have not been established.

Renal impairment. In individuals with renal impairment, gatifloxacin clearance is reduced and systemic exposure is increased.

Clinical characteristics.

Indications.

Treatment of infectious-inflammatory processes caused by microorganisms sensitive to the drug:

• respiratory tract infections (including exacerbations of chronic bronchitis, acute sinusitis, community-acquired pneumonia);
• kidney and urinary tract infections (including complicated urinary tract infections, acute pyelonephritis, uncomplicated urinary tract infections (cystitis));
• uncomplicated urethral gonorrhea in men;
• endocervical gonorrhea in women.

For exacerbations of chronic bronchitis, acute sinusitis, and cystitis, the medicinal product Ozelix® should be used only when it is considered inappropriate to use antibacterial agents usually recommended for the treatment of these infections.

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

Contraindications.

Hypersensitivity to gatifloxacin and other fluoroquinolones in medical history or to any other components of the drug. Diabetes mellitus, central nervous system disorders (epilepsy, lowered seizure threshold).

Interaction with other medicinal products and other forms of interactions.

Administration of gatifloxacin one hour after cimetidine (200 mg once daily orally) does not affect the pharmacokinetics of gatifloxacin. These results indicate that absorption of gatifloxacin is not influenced by histamine H2-receptor antagonists such as cimetidine and famotidine.

Concomitant administration of gatifloxacin with antacid medicinal products reduces its bioavailability.

Gatifloxacin should be administered 4 hours before taking ferrous sulfate, dietary supplements containing zinc, magnesium, or iron (such as multivitamins), or antacids containing magnesium and aluminum, to exclude any significant pharmacokinetic interactions.

Administration of gatifloxacin does not affect systemic clearance of intravenous midazolam. A daily intravenous dose of midazolam 0.0145 mg/kg does not affect the pharmacokinetics of gatifloxacin. These results may be considered in case of insufficient efficacy of gatifloxacin during studies involving the CYP3A4 isoenzyme in humans.

Concomitant administration of gatifloxacin and theophylline did not affect the pharmacokinetics of either of these drugs.

Combined use of gatifloxacin and warfarin did not affect the pharmacokinetics of either drug, and prothrombin time remained unchanged. However, since enhanced effects of warfarin or its derivatives have been reported with some quinolone derivatives, appropriate coagulation tests should be performed during treatment.

Concomitant use of gatifloxacin with oral hypoglycemic agents may lead to fluctuations in blood glucose levels (hypoglycemia or hyperglycemia may occur), requiring careful monitoring of blood glucose levels throughout treatment with gatifloxacin. If dangerous deviations in blood glucose levels occur, gatifloxacin should be discontinued.

The risk of developing ventricular rhythm disturbances with gatifloxacin increases and becomes a real danger in elderly patients, especially in women, in the presence of heart disease, concomitant use of medicinal products that prolong the QT interval (cisapride, erythromycin, antipsychotic drugs, tricyclic antidepressants) or that suppress heart rate (class IA antiarrhythmics (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol)), those causing hypokalemia, and when concomitantly used with drugs having competing metabolic pathways and altering each other's concentrations.

Concomitant administration of gatifloxacin and digoxin did not produce a significant effect on the pharmacokinetics of gatifloxacin. Patients taking digoxin should be monitored for signs and symptoms of toxicity. In patients who develop signs or symptoms of digoxin intoxication, serum digoxin concentration should be checked and digoxin dosage adjusted accordingly.

Systemic elimination of gatifloxacin is significantly increased with concomitant administration of gatifloxacin and probenecid.

During preclinical and clinical studies, it has been shown that concomitant use of fluoroquinolones with nonsteroidal anti-inflammatory drugs may increase the risk of central nervous system disorders and seizures.

Special precautions for use.

Gatifloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with gatifloxacin in such patients should only be initiated if no alternative treatment options are available and after careful evaluation of the benefit-risk ratio (see also section "Contraindications").

Prolonged, disabling, and potentially irreversible serious adverse reactions.

Rare cases of prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting multiple organ systems (musculoskeletal, nervous system, psychiatric, and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. If any signs or symptoms of a serious adverse reaction occur, gatifloxacin should be discontinued immediately and medical advice should be sought.

QT interval prolongation on electrocardiogram. Gatifloxacin may prolong the QT interval in some patients, increasing the risk of ventricular arrhythmias, including torsades de pointes. Rare cases of torsades de pointes have occurred spontaneously during post-marketing use of quinoline derivatives, including gatifloxacin. Almost all of these cases were associated with one or more of the following risk factors: age ≥60 years, female sex, underlying heart disease, and/or concomitant use of multiple medications. The extent of QT interval prolongation increases with higher drug concentrations; therefore, recommended doses should not be exceeded. Gatifloxacin should not be administered to patients with a history of QT interval prolongation, uncorrected hypercalcemia, decompensated hypokalemia, or those receiving Class IA (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmic agents. Caution should be exercised when prescribing gatifloxacin to patients receiving cisapride, erythromycin, antipsychotics, or tricyclic antidepressants. The drug should be used with caution in patients with cardiac conditions such as bradycardia or acute myocardial ischemia.

Glucose level disturbances. Disturbances in blood glucose levels, including symptomatic hyperglycemia and hypoglycemia, have been reported with gatifloxacin use, particularly in diabetic patients receiving concomitant hypoglycemic agents or insulin. Patients receiving this drug should be monitored for blood glucose levels, with particular attention to signs of hyper- or hypoglycemia during the first 3 days of treatment. If blood glucose levels decrease or increase significantly, the drug should be discontinued and medical advice should be sought.

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 or fluoroquinolones, or even several months after discontinuation of therapy. Elderly patients, patients with impaired renal function or organ transplants, and those receiving corticosteroids are at higher risk of developing tendinitis and tendon rupture. Therefore, concomitant use of corticosteroids with gatifloxacin should be avoided.

If early signs of tendinitis (e.g., inflammation, swelling, and pain) occur, gatifloxacin should be discontinued and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy develop.

Peripheral neuropathy. Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones or fluoroquinolones. Patients taking gatifloxacin should be advised to inform their physician of any neuropathic symptoms (pain, burning, tingling, numbness, or weakness) before continuing treatment to prevent potentially irreversible damage (see section "Adverse Reactions").

Hypersensitivity. Severe, and sometimes fatal, hypersensitivity and/or anaphylactic reactions have been reported with quinoline derivatives. These reactions may occur after the first dose. If skin rash or any other signs of hypersensitivity occur, treatment with gatifloxacin should be discontinued.

Pseudomembranous colitis. Antibiotic use alters intestinal flora and may promote the overgrowth of Clostridium difficile, leading to antibiotic-associated colitis. Cases of potentially life-threatening pseudomembranous colitis have been reported with gatifloxacin use. This diagnosis should be considered in patients who develop diarrhea following antibacterial therapy.

Aortic aneurysm/dissection, valvular regurgitation/insufficiency.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use.

Cases of aortic aneurysm and 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 only be used after careful assessment of the benefit-risk ratio and consideration of alternative treatment options in patients with a history of aortic aneurysm or congenital heart valve defects, or in patients with existing aortic aneurysm, dissection, or valvular disease, as well as other predisposing factors:

• factors predisposing to aortic aneurysm/dissection and/or valvular regurgitation/insufficiency, such as connective tissue disorders (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome), Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis;
• factors predisposing to aortic aneurysm/dissection, such as vascular diseases (e.g., Takayasu arteritis, giant cell arteritis), atherosclerosis, Sjögren’s syndrome;
• factors predisposing to valvular regurgitation/insufficiency, such as infective endocarditis.

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

If sudden abdominal, chest, or back pain occurs, patients should seek immediate emergency medical attention.

Patients should be advised to seek immediate medical help if acute dyspnea, new-onset palpitations, abdominal distension, or lower limb edema occur.

Other. Cases of increased intracranial pressure and psychosis have been reported in patients receiving quinoline derivatives. Drugs in this class may also cause central nervous system stimulation, manifesting as tremor, restlessness, dizziness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. In such cases, gatifloxacin should be discontinued and appropriate measures taken. Gatifloxacin should be used with caution in patients with known or suspected central nervous system disorders, such as severe atherosclerosis.

To avoid photosensitization and phototoxicity during treatment with this drug, exposure to ultraviolet radiation should be avoided. Gatifloxacin should be used with caution in elderly patients.

Severe and sometimes fatal reactions, some due to hypersensitivity and others of unclear etiology, have been reported with antibacterial agents. Clinical manifestations may include one or more of the following: fever, allergic pneumonia, urticaria, rash, or severe dermatological reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome), anaphylactic reactions (some accompanied by cardiovascular collapse, hypotension/shock, seizures, loss of consciousness, tinnitus, angioedema involving tongue, throat, larynx, or face), acute respiratory distress, dyspnea, vasculitis, arthralgia, myalgia, serum sickness, interstitial nephritis, acute renal failure, hepatitis, jaundice, acute hepatocellular necrosis, or liver dysfunction; anemia (including hemolytic or aplastic), thrombocytopenia (including thrombocytopenic purpura), leukopenia, agranulocytosis, pancytopenia, and/or other blood disorders. If any of these symptoms occur, the drug should be discontinued and appropriate measures initiated (e.g., oxygen, antihistamines, corticosteroids, pressor amines).

Caution should be exercised when prescribing gatifloxacin to patients with impaired renal function. Since gatifloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with creatinine clearance <40 mL/min. For patients undergoing hemodialysis, gatifloxacin should be administered after the dialysis session. The treatment regimens for uncomplicated gonorrhea (400 mg as a single dose) and uncomplicated urinary tract infections (200 mg daily for 3 days) do not require dose adjustment in patients with renal impairment.

Mild hepatic impairment does not require dose adjustment. Data on severe hepatic impairment are lacking.

Alcohol should not be consumed during treatment with gatifloxacin.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy.

Breastfeeding should be discontinued for the duration of treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

If adverse reactions affecting the nervous system occur during treatment, patients should refrain from driving or operating machinery.

Method of administration and dosage.

The medication should be taken regardless of food intake, usually once daily.

Dosage for adult patients with normal renal function

Since gatifloxacin is primarily eliminated via renal excretion, dosage adjustment is required for patients with a creatinine clearance of < 40 mL/min, including patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis.

The following dosage modifications are recommended for patients with renal impairment:

* Use at the appropriate dosage.

The single-dose regimen of 400 mg (for the treatment of uncomplicated urinary tract infections and gonorrhea) does not require dose adjustment in patients with impaired renal function.

Children.

The drug is contraindicated in children.

Overdose.

Symptoms: lethargy, confusion, decreased respiratory rate, dizziness, nausea, vomiting, diarrhea, abdominal pain, seizures, tremor, psychosis, visual and hearing disturbances, QT interval prolongation on electrocardiogram, and intensification of adverse reactions.

Treatment: gastric lavage. The patient should be under medical supervision and receive symptomatic therapy. Appropriate hydration therapy should be administered according to the patient's condition. Gatifloxacin is inadequately removed from the body by hemodialysis (approximately 14% over 4 hours) or by forced hemodialysis (approximately 11% over 8 days).

Adverse Reactions

Immune system disorders: hypersensitivity reactions, serum sickness, anaphylactoid reactions, anaphylactic shock, vasculitis, eczema, angioneurotic edema.

Skin and subcutaneous tissue disorders: skin rashes, urticaria, erythema, pruritus, photosensitization, phototoxicity, eczema, allergic dermatitis, increased sweating, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Nervous system disorders*: agitation, nervousness, altered consciousness, loss of consciousness, depression, restlessness, anxiety, nightmares or paranoia, sleep disturbances, insomnia, somnolence, restless sleep, paresthesia, taste disturbances, dizziness, headache, tremor, convulsions, neuropathy.

Eye disorders*: visual disturbances.

Ear and labyrinth disorders*: tinnitus, ototoxicity.

Cardiovascular system disorders**: tachycardia, bradycardia, palpitations, hypertension, hypotension, peripheral edema, vasodilation, QT interval prolongation on ECG, syncope, torsades de pointes.

Gastrointestinal disorders: abdominal pain, anorexia, constipation, dyspepsia, bloating, glossitis, gastritis, oral candidiasis, stomatitis, oral ulceration, heartburn, diarrhea, appetite disturbances, vomiting, nausea, thirst, dry mouth, pancreatitis, gastrointestinal hemorrhage.

Musculoskeletal and connective tissue disorders*: arthropathies, arthralgia, myalgia, muscle cramps, joint cartilage disorders, tendinitis, tenosynovitis, tendon rupture.

Hepatobiliary disorders: elevated liver enzymes, cholestatic jaundice, hepatitis, right upper quadrant pain, acute hepatocellular necrosis, hepatic failure.

Endocrine disorders: blood glucose fluctuations – hypoglycemia (including hypoglycemic coma), hyperglycemia (including hyperosmolar non-ketotic hyperglycemia).

Renal and urinary system disorders: renal function impairment, including acute renal failure, crystalluria, transient nephritis, dysuria, hematuria, vaginitis.

Respiratory system disorders: dyspnea, shortness of breath, pharyngitis.

Blood and lymphatic system disorders: neutropenia, anemia (including hemolytic and aplastic anemia), thrombocytopenia, agranulocytosis, pancytopenia, thrombocytopenic purpura, leukopenia, or other blood disorders.

Laboratory abnormalities: increased levels of ALT, AST, alkaline phosphatase, bilirubin, amylase, electrolyte imbalances, prolonged INR (International Normalized Ratio)/prothrombin time.

General disorders*: fever, hot flushes, chills, asthenia (weakness), back pain, chest pain.

Additional adverse reactions may occur during administration of gatifloxacin as monotherapy or in combination therapy: impaired thinking, alcohol intolerance, arthritis, bronchial asthma (bronchospasm), ataxia, bone pain, bradycardia, back pain, cheilitis, colitis, cyanosis, depersonalization, dysphagia, ear pain, ecchymoses, epistaxis, euphoria, eye pain, ocular photosensitivity, gastrointestinal hemorrhages, generalized edema, gingivitis, hostility, hallucinations, uterine bleeding, hematuria, hyperesthesia, hyperventilation, hypoglycemia, lymphadenopathy, maculopapular rash, metrorrhagia, migraine, lip swelling, myalgia, myasthenia, neck pain, panic attacks, paranoia, parosmia, photophobia, pseudomembranous colitis, psychosis, ptosis, rectal hemorrhages, stress, substernal pain, vesiculobullous eruptions.

* In patients receiving quinolones and fluoroquinolones, very rare, prolonged (lasting for several months or years), disabling and potentially irreversible serious adverse reactions affecting multiple systems, sometimes several simultaneously, including sensory organs, have been observed. These include tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy associated with paresthesia, neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), impaired memory and concentration, confusion, hearing, vision, taste, and smell disturbances. In some cases, these reactions occurred in patients without risk factors (see section "Special Warnings and Precautions for Use").

** Cases of aneurysms 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 "Special Warnings and Precautions for Use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 1 blister in a cardboard box.

10 tablets in a blister pack, 1 blister in a cardboard box, 10 cardboard boxes in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.