INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOFICIN (MOFICIN)

Composition:

Active substance: moxifloxacin;

One vial (250 ml of solution) contains 400 mg of moxifloxacin (as moxifloxacin hydrochloride);

Excipients: sodium chloride, anhydrous sodium sulfate, hydrochloric acid 1 N, sodium hydroxide 1 N, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, free from visible particles, greenish-yellow solution.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group. ATC code J01MA14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for replication, transcription, and repair of bacterial DNA.

Pharmacokinetics/pharmacodynamics.

The ability of fluoroquinolones to kill bacteria is directly concentration-dependent. Pharmacodynamic studies of fluoroquinolones in animal models of infectious-inflammatory diseases and in humans indicate that the primary determinant of efficacy is the ratio between the area under the pharmacokinetic curve (AUC24) and the minimum inhibitory concentration (MIC).

Mechanism of resistance.

Resistance to fluoroquinolones may arise due to mutations in DNA gyrase and topoisomerase IV. Other mechanisms include overexpression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase. Cross-resistance between moxifloxacin and other fluoroquinolones can be expected.

Resistance mechanisms characteristic of antibacterial agents belonging to other classes do not affect the antibacterial efficacy of moxifloxacin.

Breakpoints.

Clinical breakpoints for minimum inhibitory concentration (MIC) and disk diffusion test breakpoints for moxifloxacin according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) (01.01.2012):

* Species-unrelated breakpoints were primarily established based on pharmacokinetic/pharmacodynamic data relationships and do not depend on MIC values for individual species. These data are used for species without individually defined breakpoints and do not apply to species for which interpretive criteria are to be determined.

Microbiological susceptibility.

The prevalence of acquired resistance among isolated species may vary geographically and over time; therefore, information on local resistance patterns is necessary, especially when treating severe infections. Consultation with specialists should be sought if local resistance prevalence has reached a level where the benefit of using the agent, at least for certain types of infections, is questionable.

Generally susceptible microorganisms.

Aerobic Gram-positive microorganisms: Staphylococcus aureus * +, Streptococcus agalactiae (Group B), Streptococcus milleri group* (S. anginosus, S. constellatus, and S. intermedius), Streptococcus pneumoniae *, Streptococcus pyogenes * (Group A), Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus).

Aerobic Gram-negative microorganisms: Acinetobacter baumannii, Haemophilus influenzae *, Legionella pneumophila, Moraxella (Branhamella) catarrhalis *.

Anaerobic microorganisms: Prevotella spp.

Other microorganisms: Chlamydophila (Chlamydia) pneumoniae *, Coxiella burnetii, Mycoplasma pneumoniae *.

Microorganisms with potential for developing resistance.

Aerobic Gram-positive microorganisms: Enterococcus faecalis*, Enterococcus faecium*.

Aerobic Gram-negative microorganisms: Enterobacter cloacae *, Escherichia coli * #, Klebsiella pneumoniae * #, Klebsiella oxytoca, Proteus mirabilis *.

Anaerobic microorganisms: Bacteroides fragilis*.

Resistant microorganisms.

Aerobic Gram-negative microorganisms: Pseudomonas aeruginosa.

* Clinical efficacy has been adequately demonstrated in clinical studies.

• Methicillin-resistant S. aureus is very frequently also resistant to fluoroquinolones. In methicillin-resistant S. aureus, resistance rates to moxifloxacin exceed 50%.

Strains producing extended-spectrum beta-lactamases (ESBL) are also resistant to fluoroquinolones.

Pharmacokinetics.

Absorption and bioavailability

After a single 1-hour intravenous infusion of 400 mg moxifloxacin, peak drug concentration is reached at the end of the infusion and is approximately 4.1 mg/L, which is about 26% higher than that observed after oral administration (3.1 mg/L). The AUC is approximately 39 mg*h/L following intravenous administration, slightly exceeding the value after oral administration (35 mg*h/L); absolute bioavailability is approximately 91%. No dose adjustment according to age or gender is required when moxifloxacin is administered intravenously. Pharmacokinetics are linear within the range of 50–200 mg for single oral doses, up to 600 mg for single intravenous doses, and up to 600 mg administered once daily for 10 days.

Distribution

Moxifloxacin rapidly distributes into the extravascular space. The volume of distribution at steady state (Vss) is approximately 2 L/kg. In vitro and ex vivo studies indicate that protein binding is approximately 40–42%, independent of drug concentration. Moxifloxacin is primarily bound to serum albumin.

Peak concentrations of 5.4 mg/kg and 20.7 mg/L (geometric mean values) were observed in bronchial mucosa and epithelial lining fluid, respectively, 2.2 hours after oral dosing. The corresponding peak concentration in alveolar macrophages was 56.7 mg/kg. A concentration of 1.75 mg/L was observed in blister fluid 10 hours after intravenous administration. The "free concentration-time" profile in interstitial fluid is similar to that in plasma, with peak free concentration reaching approximately 1.0 mg/L (geometric mean) about 1.8 hours after intravenous administration.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys (approximately 40%) and feces/bile (approximately 60%), both unchanged and as sulfate conjugate (M1) and glucuronide (M2) metabolites. M1 and M2 are metabolites relevant only to humans and are microbiologically inactive.

In vitro and Phase I clinical studies showed no metabolic pharmacokinetic interactions with other drugs involved in Phase I biotransformation, including cytochrome P450 enzyme system. There is no evidence of oxidative metabolism.

Elimination

The plasma elimination half-life of moxifloxacin is approximately 12 hours. The mean steady-state total clearance after administration of 400 mg ranges from 179 to 246 mL/min. After intravenous administration of 400 mg, unchanged drug excretion in urine is approximately 22% and in feces approximately 26%. Overall excretion (unchanged drug and metabolites) is approximately 98% after intravenous administration. Renal clearance is approximately 24–53 mL/min, indicating partial tubular reabsorption of the drug in the kidneys. Concomitant administration of ranitidine and probenecid with moxifloxacin does not alter renal clearance of the parent drug.

Renal impairment

No significant changes in moxifloxacin pharmacokinetics have been observed in patients with renal impairment (including patients with creatinine clearance > 20 mL/min/1.73 m²). With decreasing renal function, the concentration of metabolite M2 (glucuronide) increases nearly 2.5-fold (with creatinine clearance < 30 mL/min/1.73 m²).

Hepatic impairment

Pharmacokinetic data from studies involving patients with hepatic insufficiency (Child-Pugh classes A and B) do not allow definitive conclusions regarding differences in parameters between patients with impaired liver function and healthy volunteers. Impaired liver function was associated with higher plasma exposure to metabolite M1, while exposure to the parent drug was similar to that in healthy volunteers. There is insufficient clinical experience with moxifloxacin use for treating patients with hepatic impairment.

Preclinical safety data

In traditional repeated-dose toxicity studies in animals, moxifloxacin caused hematological and hepatotoxic effects. Toxic effects on the central nervous system (CNS) were also observed. These effects occurred after administration of high doses of moxifloxacin or prolonged treatment.

High oral doses in animals (≥ 60 mg/kg), resulting in plasma concentrations ≥ 20 mg/L, caused changes in electroretinogram parameters and, in some cases, retinal atrophy.

Systemic toxicity after intravenous administration was most pronounced when moxifloxacin was given as bolus injections (45 mg/kg) and was not observed when administered as slow infusions (40 mg/kg over 50 minutes).

After intra-arterial administration, inflammatory changes spreading to perivascular soft tissues were observed, indicating that intra-arterial administration of moxifloxacin should be avoided.

Moxifloxacin was genotoxic in vitro in bacterial and mammalian cell assays. In vivo genotoxicity was not observed, despite administration of very high doses of moxifloxacin. Moxifloxacin showed no carcinogenic effects in animal carcinogenicity studies.

In vitro, moxifloxacin at high concentrations affected cardiac electrophysiological parameters, potentially causing QT interval prolongation.

After intravenous administration of moxifloxacin to animals at 30 mg/kg via infusions lasting 15, 30, or 60 minutes, a relationship between the degree of QT prolongation and infusion rate was observed: the shorter the infusion duration, the more pronounced the QT prolongation. No QT prolongation was observed when the 30 mg/kg dose was administered via a 60-minute infusion.

Studies on the effects of moxifloxacin on animal reproductive function have demonstrated that moxifloxacin crosses the placenta. Animal studies did not reveal teratogenic effects or impaired fertility after moxifloxacin administration. Slight increases in the incidence of spinal and rib developmental abnormalities were observed in animals, but only after administration of a dose (20 mg/kg intravenously) associated with marked maternal systemic toxicity. Increased rates of pregnancy loss were observed in animals at plasma concentrations predicted for therapeutic use in humans.

It is known that quinolones, including moxifloxacin, cause damage to cartilage in large diarthrodial joints in immature animals.

Clinical characteristics.

Indications.

Community-acquired pneumonia.

Complicated skin and soft tissue infections.

Moxifloxacin should be used only when other antibacterial agents normally recommended for initial treatment of these infections are inappropriate.

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

Contraindications.

Hypersensitivity to moxifloxacin, other quinolone antibiotics, or any of the excipients.

Pregnancy or breastfeeding (see section "Use in pregnancy or breastfeeding").

Pediatric age (under 18 years).

History of tendon disorders associated with quinolone use.

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiological parameters, manifested as QT interval prolongation. For this reason, moxifloxacin is contraindicated in patients with:

• congenital or acquired QT prolongation;
• electrolyte imbalance, particularly uncorrected hypokalemia;
• clinically significant bradycardia;
• clinically significant heart failure with reduced left ventricular ejection fraction;
• history of symptomatic arrhythmias.

Moxifloxacin must not be used concomitantly with drugs that prolong the QT interval (see also section "Interaction with other medicinal products and other forms of interaction").

Due to insufficient clinical experience, moxifloxacin is contraindicated in patients with hepatic impairment (Child-Pugh class C) and in those with transaminase levels elevated fivefold or more.

Special precautions.

The vial is intended for single use only. Any unused solution must be discarded.

The following diluents have been shown to be compatible with the 400 mg moxifloxacin infusion solution: water for injections; 0.9% sodium chloride solution; 1-molar sodium chloride solution; 5%, 10%, and 40% glucose solutions; 20% xylitol solution; Ringer's solution; compound sodium lactate solutions (Hartmann's solution, lactated Ringer's solution).

Moxifloxacin infusion solution must not be administered simultaneously with other drugs.

Do not use the medicinal product if visible particulate matter or cloudiness is present.

Precipitation may occur upon storage in cool conditions, but the precipitate dissolves at room temperature. Therefore, storage of the infusion solution below 15°C is not recommended.

Interaction with other medicinal products and other forms of interaction.

Interaction with medicinal products

An additive effect of moxifloxacin and other medicinal products capable of inducing QTc interval prolongation cannot be excluded. This effect may lead to the development of ventricular arrhythmias, including polymorphic ventricular tachycardia of the torsade de pointes type. For this reason, the use of moxifloxacin in combination with any of the following medicinal products is contraindicated (see also section "Contraindications"):

• class IA antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• antipsychotic agents (e.g., phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• tricyclic antidepressants;
• certain antimicrobial agents (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, particularly halofantrine);
• certain antihistamines (terfenadine, astemizole, mizolastine);
• other medicinal products (cisapride, intravenous vincamine, bepridil, difemalil).

Moxifloxacin should be used with caution in patients receiving medicinal products that may reduce potassium levels (e.g., loop and thiazide diuretics, laxatives and enemas (at high doses), corticosteroids, amphotericin B), or medicinal products associated with clinically significant bradycardia.

Following repeated administration of moxifloxacin in healthy volunteers, an increase in digoxin Cmax of approximately 30% was observed, without affecting AUC or trough levels.

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of glyburide plasma maximum concentration by approximately 21%. The combination of glyburide with moxifloxacin may theoretically provoke mild, short-term hyperglycemia. However, the observed pharmacokinetic changes of glyburide did not lead to changes in pharmacodynamic parameters (blood glucose levels, insulin levels). Therefore, there is no clinically significant interaction between moxifloxacin and glyburide.

Change in international normalized ratio (INR).

Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antimicrobial agents, particularly fluoroquinolones, macrolides, tetracyclines, cotrimoxazole, and certain cephalosporins. Risk factors include infectious diseases and inflammatory processes, age, and the patient's general condition. Therefore, it is difficult to determine whether changes in INR are caused by the infection or by treatment. As a precautionary measure, INR may be monitored more frequently. Dose adjustment of the oral anticoagulant should be performed as needed.

In clinical studies, the absence of clinically significant interaction with moxifloxacin has been demonstrated for the following agents: ranitidine, probenecid, oral contraceptives, calcium supplements, parenteral morphine, theophylline, cyclosporine, or itraconazole.

In vitro studies using human cytochrome P450 enzymes have confirmed these results. Thus, metabolic interaction via cytochrome P450 enzymes is unlikely.

Interaction with food

Moxifloxacin does not exhibit clinically significant interaction with food, including dairy products.

Special precautions for use.

Avoid using moxifloxacin in patients with a history of serious adverse reactions after taking drugs containing quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with moxifloxacin should be initiated in such patients only when no alternative therapy is available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

The benefits of moxifloxacin therapy, especially in cases of mild infections, should be evaluated considering the information provided in this section.

QTc interval prolongation and clinical conditions associated with QTc interval prolongation

Moxifloxacin has been shown to prolong the QTc interval on electrocardiogram in some patients. The degree of QT interval prolongation may increase with higher plasma concentrations of the drug during rapid intravenous infusion. Therefore, it is essential to follow the recommended infusion duration of at least 60 minutes and not exceed the intravenous dose of 400 mg once daily. For further details, see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Moxifloxacin therapy should be discontinued immediately upon the appearance of symptoms that may be related to cardiac arrhythmia, regardless of whether this is confirmed by ECG findings.

Moxifloxacin should be used with caution in patients with conditions predisposing to arrhythmia (e.g., acute myocardial ischemia), as such patients have an increased risk of ventricular arrhythmias (including polymorphic ventricular tachycardia of the torsades de pointes type) and cardiac arrest (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Moxifloxacin should be used cautiously in patients taking medicinal products that may reduce potassium levels (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be prescribed with caution to patients receiving medicinal products associated with clinically significant bradycardia (see also section "Contraindications").

Women and elderly patients may exhibit increased sensitivity to the effects of drugs that cause QT interval prolongation, such as moxifloxacin, and therefore require special attention.

Hypersensitivity / allergic reactions

Cases of hypersensitivity and allergic reactions have been reported after the first dose of fluoroquinolones, including moxifloxacin. Anaphylactic reactions may manifest as life-threatening shock even after the first administration of the drug. In case of clinical manifestations of severe hypersensitivity reactions, moxifloxacin should be discontinued immediately and appropriate treatment initiated (e.g., shock therapy).

Severe hepatic impairment

Cases of fulminant hepatitis, which may lead to hepatic failure (including fatal cases), have been reported during moxifloxacin therapy (see section "Adverse Reactions"). If symptoms of fulminant hepatitis such as rapidly developing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy occur, patients are advised to consult a physician before continuing treatment.

Liver function tests should be performed if signs of hepatic dysfunction appear.

Severe skin reactions

Severe skin reactions, including toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during moxifloxacin therapy (see section "Adverse Reactions"). These reactions may be life-threatening or fatal. Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. Moxifloxacin should be immediately discontinued and alternative therapy considered if symptoms suggestive of such reactions occur. If a patient develops severe skin reactions such as SJS, TEN, AGEP, or DRESS during moxifloxacin therapy, re-administration of moxifloxacin in this patient is absolutely contraindicated.

Patients predisposed to seizures

Quinolones are known to induce seizures. They should be used with caution in patients with central nervous system disorders or other risk factors that may provoke seizures or lower the seizure threshold. If seizures occur, moxifloxacin should be discontinued and appropriate measures taken.

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 various body systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients treated with quinolones and fluoroquinolones, regardless of patient age or presence of risk factors. Moxifloxacin should be immediately discontinued at the first signs of any serious adverse reaction, and patients should be advised to consult a physician.

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral neuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients taking fluoroquinolones, including moxifloxacin. Moxifloxacin should be discontinued if symptoms of neuropathy such as pain, burning sensation, tingling, numbness, or weakness occur, to prevent the development of potentially irreversible conditions (see section "Adverse Reactions").

Psychiatric reactions

Psychiatric reactions may occur even after the first dose of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions may progress to suicidal thoughts and self-harming behaviors such as suicide attempts (see section "Adverse Reactions"). If such reactions occur, moxifloxacin therapy should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with current or past psychiatric disorders.

Antibiotic-associated diarrhea, including colitis

Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been observed with the use of broad-spectrum antibiotics, including moxifloxacin. The severity of these conditions may range from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin therapy. If suspected or confirmed AAD or AAC occurs, antimicrobial therapy, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, measures to control infection and reduce transmission risk should be implemented. Medicinal products that inhibit peristalsis are contraindicated in patients who develop severe diarrhea.

Patients with severe myasthenia

Moxifloxacin should be used with caution in patients with severe myasthenia gravis, as symptoms may be exacerbated.

Tendinitis and tendon rupture

Tendinitis may occur in individual patients. Development of tendinitis and tendon rupture (particularly of the Achilles tendon), sometimes bilateral, may occur within the first 48 hours of starting quinolone or fluoroquinolone therapy, and such cases have even been reported several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients who have undergone solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

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

Aortic aneurysm and aortic dissection, valvular regurgitation/insufficiency

Epidemiological studies 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 valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse Reactions").

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

• risk factors for both aortic aneurysm/dissection and valvular 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 valvular regurgitation/insufficiency: infective endocarditis.

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

Patients should be advised to seek immediate medical attention in case of sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help in case of acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema.

Patients with renal impairment

Moxifloxacin should be used with caution in elderly patients with renal disorders who are unable to maintain adequate fluid intake, as dehydration increases the risk of renal failure.

Eye disorders

In case of visual impairment or any effect on the eyes, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction speed when driving or operating machinery", "Adverse Reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose deviations, both hypoglycemia and hyperglycemia, have been reported during moxifloxacin therapy (see section "Adverse Reactions"). Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin with moxifloxacin. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels.

Prevention of photosensitization reactions

Photosensitization reactions have been reported in patients during quinolone therapy. However, study data indicate that the risk of photosensitization reactions with moxifloxacin is low. Nevertheless, patients should avoid prolonged and/or intense exposure to sunlight or ultraviolet radiation during moxifloxacin therapy (see section "Adverse Reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

In patients with latent or known glucose-6-phosphate dehydrogenase deficiency, quinolone therapy may lead to hemolytic reactions. Therefore, moxifloxacin should be used with caution in such patients, with monitoring for possible hemolysis.

Periarterial tissue inflammation

Moxifloxacin infusion solution is intended for intravenous use only. Intra-arterial administration should be avoided, as periarterial tissue inflammation has been observed in preclinical studies with this route of administration.

Patients with specific complicated skin and soft tissue infections

The clinical efficacy of moxifloxacin in the treatment of severe infections associated with burns, fasciitis, and infected diabetic foot accompanied by osteomyelitis has not been established.

Effect on biological tests

Moxifloxacin may affect the results of tests for Mycobacterium spp. by inhibiting mycobacterial growth, which may lead to false-negative results in patients taking moxifloxacin.

Patients with infections caused by methicillin-resistant Staphylococcus aureus (MRSA)

Moxifloxacin is not recommended for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). If MRSA infection is suspected or confirmed, appropriate antibacterial therapy should be initiated (see section "Pharmacodynamics").

Important information about excipients.

This medicinal product contains 1072 mg (approximately 46.6 mmol) of sodium per dose (1 vial). Caution should be exercised when administering this medicinal product to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of moxifloxacin use during pregnancy in humans has not been established. Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk to humans has not been established. Given the experimentally demonstrated risk of harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals and considering the development of reversible joint lesions in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

There are no data on the use of this medicinal product during breastfeeding in women. Preclinical studies indicate that a small amount of moxifloxacin passes into breast milk. Due to the lack of data on effects on breastfed infants and considering the experimental risk of harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals, breastfeeding is contraindicated during moxifloxacin therapy (see section "Contraindications").

Fertility

Animal studies did not reveal any effect on fertility (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of moxifloxacin on the ability to drive or operate machinery have not been conducted. However, fluoroquinolones, including moxifloxacin, may affect reaction speed when driving or operating machinery by causing central nervous system reactions (e.g., dizziness, acute transient loss of vision) or acute and short-term loss of consciousness (syncope) (see section "Adverse Reactions"). Patients are advised to assess their individual response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosage

The recommended dosage regimen is 400 mg of moxifloxacin as an infusion once daily.

Initial intravenous therapy may be continued with oral administration of 400 mg moxifloxacin tablets when clinically indicated.

In clinical trials, most patients switched to oral moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (complicated skin and soft tissue infections). The recommended total duration of intravenous and oral treatment is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

Method of Administration

The medicinal product should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special Warnings and Precautions for Use").

If indicated, the infusion solution may be administered via a Y-site catheter together with compatible infusion solutions (see section "Special Precautions for Safety").

Renal or Hepatic Impairment

Patients with mild to severe renal impairment and patients undergoing continuous ambulatory peritoneal dialysis (CAPD), including those on hemodialysis and CAPD, do not require dose adjustment (see section "Pharmacological Properties" for further details).

There is insufficient information regarding patients with hepatic impairment (see section "Contraindications").

Other Special Patient Groups

Elderly patients and patients with low body weight do not require dose adjustment.

Children

Due to the observed adverse effects of moxifloxacin on cartilage in young animals (see section "Pharmacological Properties"), the use of moxifloxacin in children (under 18 years of age) is contraindicated (see section "Contraindications").

The efficacy and safety of moxifloxacin in children and adolescents have not been established (see section "Contraindications").

Overdose

There are no specific recommendations for management following accidental overdose. In case of overdose, symptomatic treatment should be administered. Since QT interval prolongation may occur, ECG monitoring is required. Concomitant administration of activated charcoal with an oral or intravenous 400 mg dose of moxifloxacin reduces systemic bioavailability by over 80% or 20%, respectively. Administration of activated charcoal at the early stage of absorption may effectively prevent excessive systemic exposure to moxifloxacin in cases of oral overdose.

Adverse Reactions

The adverse reactions listed below were observed during clinical trials and the post-marketing period of moxifloxacin use at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral] therapy, and oral therapy). Adverse reactions are classified according to their frequency.

All adverse reactions, except nausea and diarrhea, occurred at a frequency of less than 3%.

Within each category, adverse events are listed in decreasing order of severity. Frequency is defined as follows: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Eye disorders*: uncommon — visual disturbances, including diplopia and blurred vision (especially during CNS-related reactions) (see section "Special warnings and precautions for use"); rare — photophobia; very rare — transient loss of vision (especially during CNS-related reactions) (see sections "Special warnings and precautions for use", "Effect on ability to drive and use machines"), uveitis, and bilateral acute iris transillumination (see section "Special warnings and precautions for use").

Ear and labyrinth disorders*: rare — tinnitus, hearing disturbances including deafness (usually reversible).

Respiratory, thoracic and mediastinal disorders: uncommon — dyspnea (including asthmatic conditions).

Gastrointestinal disorders: common — nausea, vomiting, abdominal pain and discomfort, diarrhea; uncommon — decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels; rare — dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, which in rare cases may lead to life-threatening complications) (see section "Special warnings and precautions for use").

Hepatobiliary disorders: common — increased transaminase levels; uncommon — liver function abnormalities (including increased LDH [lactate dehydrogenase] levels), increased bilirubin, GGT (gamma-glutamyl transferase), and alkaline phosphatase levels; rare — jaundice, hepatitis (predominantly cholestatic); very rare — fulminant hepatitis, which may lead to life-threatening hepatic failure (see section "Special warnings and precautions for use").

Renal and urinary disorders: uncommon — dehydration; rare — renal dysfunction (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use").

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

Metabolism and nutrition disorders: uncommon — hyperlipidemia; rare — hyperglycemia, hyperuricemia; very rare — hypoglycemia, hypoglycemic coma.

Nervous system disorders*: common — headache, dizziness; uncommon — paresthesia/dysesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (predominantly insomnia), tremor, vertigo, somnolence; rare — hypoesthesia, olfactory disturbances (including loss of smell), pathological dreams, coordination disturbances (including gait disturbances due to dizziness or vertigo), seizures (including grand mal seizures) (see section "Special warnings and precautions for use"), attention disturbances, speech disorders, amnesia, peripheral neuropathy and polyneuropathy; very rare — hyperesthesia.

Psychiatric disorders*: uncommon — anxiety reactions, increased psychomotor activity/agitation; rare — mood lability, depression (in rare cases with self-harm, manifesting as suicidal ideation/thoughts or suicide attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium; very rare — depersonalization, psychotic reactions (possibly with self-harm, manifesting as suicidal ideation/thoughts or suicide attempts) (see section "Special warnings and precautions for use").

Cardiac disorders**: common — QT interval prolongation in patients with hypokalemia (see sections "Contraindications", "Special warnings and precautions for use"); uncommon — QT interval prolongation (see section "Special warnings and precautions for use"), palpitations, tachycardia, atrial fibrillation, angina pectoris; rare — ventricular tachyarrhythmias, syncope (e.g., acute and brief loss of consciousness); very rare — non-specific arrhythmias, torsades de pointes (see section "Special warnings and precautions for use"), cardiac arrest (see section "Special warnings and precautions for use").

Vascular disorders**: uncommon — vasodilation; rare — arterial hypertension, hypotension; very rare — vasculitis.

Blood and lymphatic system disorders: uncommon — anemia, leukopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time / increased INR; very rare — elevated prothrombin levels / decreased INR, agranulocytosis, pancytopenia.

Immune system disorders: uncommon — allergic reactions (see section "Special warnings and precautions for use"); rare — anaphylaxis, including life-threatening shock in rare cases (see section "Special warnings and precautions for use"), allergic edema / angioedema (including laryngeal edema, potentially life-threatening) (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders: uncommon — pruritus, rash, urticaria, dry skin; very rare — bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening) (see section "Special warnings and precautions for use"); frequency not known — acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), fixed drug eruption, photosensitivity reactions (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders*: uncommon — arthralgia, myalgia; rare — tendinitis (see section "Special warnings and precautions for use"), increased muscle tone, muscle cramps, muscle weakness; very rare — tendon rupture (see section "Special warnings and precautions for use"), arthritis, muscle rigidity, exacerbation of symptoms in myasthenia gravis (see section "Special warnings and precautions for use"); frequency not known — rhabdomyolysis.

General disorders and administration site conditions*: common — injection and infusion site reactions; uncommon — malaise (predominantly asthenia or fatigue), pain (including back, chest, pelvic, and limb pain), increased sweating, (thrombo-)phlebitis at the infusion site.

Infections and infestations: common — superinfections with resistant bacteria or fungi, e.g., oral and vaginal candidiasis.

* In rare cases, patients treated with 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 multiple organ systems and sensory organs (such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, anxiety, suicidal thoughts, panic attacks, neuralgia, concentration difficulties, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances).

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

The frequency of the following effects is higher with intravenous administration of the drug, with or without subsequent oral therapy.

Common: increased gamma-glutamyl transferase levels.

Uncommon: ventricular tachyarrhythmia, hypotension, edema, antibiotic-associated colitis (including pseudomembranous colitis, which in rare cases may be associated with life-threatening complications, see section "Special warnings and precautions for use"), seizures (including grand mal seizures) (see section "Special warnings and precautions for use"), hallucinations, renal dysfunction (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use").

Rare adverse effects reported after treatment with other fluoroquinolones, which are also likely to occur during moxifloxacin therapy, include: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, hemolytic anemia.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not below 15 °C.

Do not cool. Do not freeze. Keep out of reach of children.

Incompatibility.

The moxifloxacin infusion solution must not be administered simultaneously with other incompatible solutions, including: 10% sodium chloride solution; 20% sodium chloride solution; 4.2% sodium bicarbonate solution; 8.4% sodium bicarbonate solution.

This medicinal product should not be mixed with other medicinal products except those specified in the section "Special precautions for handling and disposal".

Packaging. 250 ml of solution in a vial. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. ANFARM HELLAS S.A.

Manufacturer's address.

61st km National Road Athens-Lamia, Schimatari Viotia, 32009, Greece.

Marketing Authorization Holder. TECHNOPAC MANUFACTURE LIMITED.

Address of Marketing Authorization Holder.

Unit 4, Block 1, North Park, Finglas, Dublin, D11 E6C3, Ireland.