Moxifloxacin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOXIFLOXACIN

Composition:

Active substance: moxifloxacin;

250 ml of solution contains 436 mg of moxifloxacin hydrochloride (equivalent to 400 mg of moxifloxacin);

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow to yellowish-greenish tinted liquid.

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 dependent on their concentration. 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 concentration-time 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 can be expected between moxifloxacin and other fluoroquinolones. Resistance mechanisms characteristic of antibacterial agents belonging to other classes do not affect the antibacterial efficacy of moxifloxacin.

Breakpoints

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

Table 1

Microorganism	Susceptible	Resistant
Staphylococcus spp.	≤ 0.5 mg/l ≥ 24 mm	> 1 mg/l < 21 mm
S. pneumoniae	≤ 0.5 mg/l ≥ 22 mm	> 0.5 mg/l < 22 mm
Streptococcus groups A, B, C, G	≤ 0.5 mg/l ≥ 18 mm	> 1 mg/l < 15 mm
H. influenzae	≤ 0.5 mg/l ≥ 25 mm	> 0.5 mg/l < 25 mm
M. catarrhalis	≤ 0.5 mg/l ≥ 23 mm	> 0.5 mg/l < 23 mm
Enterobacteriaceae	≤ 0.5 mg/l ≥ 20 mm	> 1 mg/l < 17 mm
Intermediate values not related to bacterial species*	≤ 0.5 mg/l	> 1 mg/l

*Non-species-related breakpoints were primarily established based on the relationship between pharmacokinetic and pharmacodynamic data and do not depend on the MIC for individual species. These data are used for species lacking individually defined breakpoints and are not applied to species for which interpretive criteria are still to be determined.

Microbiological susceptibility

The prevalence of acquired resistance among isolated species may vary depending on geographical location and time. Therefore, local information on resistance patterns is necessary, especially when treating severe infections. Consultation with specialists should be sought when local resistance prevalence has reached a level at which the benefit of using the medicinal product is questionable, at least for certain types of infections.

Usually 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 resistance development

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 sufficiently demonstrated in clinical studies. +Methicillin-resistant S. aureus is very often simultaneously 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, the maximum plasma concentration (Cmax) of the drug 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 after intravenous administration, slightly exceeding the value after oral administration (35 mg*h/l); the absolute bioavailability is approximately 91%. There is no need to adjust the dose of moxifloxacin according to age or gender when administered intravenously. The 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 binds primarily to serum albumin. Maximum 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 administration. The corresponding Cmax 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 a maximum free concentration of 1.0 mg/l (geometric mean) reached approximately 1.8 hours after intravenous administration.

Metabolism

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

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

Elimination

The elimination half-life of moxifloxacin in plasma 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, renal excretion of unchanged drug was approximately 22% and fecal excretion was 26%. Overall excretion (unchanged drug and metabolites) was 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 the renal clearance of the parent drug.

Renal Impairment

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

Hepatic Impairment

Pharmacokinetic data from studies in patients with hepatic impairment (Child-Pugh classes A and B) do not allow definitive conclusions regarding differences in pharmacokinetic parameters between patients with hepatic impairment and healthy volunteers. Hepatic impairment 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 to recommend its use in patients with hepatic impairment.

Preclinical Safety Data

In traditional repeated-dose toxicity studies in animals, moxifloxacin showed hematological and hepatotoxic effects. Toxic effects on the central nervous system (CNS) were 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.

After intravenous administration, systemic toxicity 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 extending into peri-arterial soft tissues were observed, indicating that intra-arterial administration of moxifloxacin should be avoided.

Moxifloxacin was genotoxic in in vitro tests using bacteria or mammalian cells. However, no genotoxicity was observed in in vivo studies, even with very high doses of moxifloxacin. Moxifloxacin did not show carcinogenic potential in animal carcinogenicity studies.

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

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

In studies of the effects of moxifloxacin on animal reproductive function, it was 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 malformations were observed in animals, but only at a dose (20 mg/kg intravenously) associated with severe maternal toxicity. Increased rates of pregnancy loss were observed in animals at plasma concentrations corresponding to therapeutic levels expected in humans.

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

Clinical characteristics.

Indications.

Community-acquired pneumonia.

Complicated skin and soft tissue infections.

Moxifloxacin should be used only when the use of other antibacterial agents, typically recommended for initial treatment of these infections, is inappropriate.

Attention should be paid to official guidelines on the appropriate use of antibacterial agents.

Contraindications.

• Hypersensitivity to moxifloxacin, other quinolone antibiotics, or to any of the excipients of the medicinal product;
• Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding");
• Pediatric age (under 18 years);
• History of tendon disorders related to the use of quinolones.

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiological parameters manifested by 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 five times or more above the upper limit of normal.

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 torsades de pointes type. Therefore, 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 (sildenafil, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Other medicinal products (cisapride, intravenous vinpocetine, bepridil, difemanyl).

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

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

In studies involving volunteers and diabetic patients, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of glyburide plasma Cmax 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 result in changes in pharmacodynamic parameters (blood glucose, insulin levels). Therefore, there is no clinically significant interaction between moxifloxacin and glyburide.

Changes 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 infection and inflammatory conditions, age, and general patient condition. Therefore, it is difficult to determine whether the changes in INR are due to the infection or the treatment. As a precautionary measure, INR should be monitored more frequently. Dose adjustment of the oral anticoagulant should be performed as needed.

In clinical studies, the following substances have been shown not to have a clinically significant interaction with moxifloxacin: ranitidine, probenecid, oral contraceptives, calcium supplements, parenterally administered 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 safety precautions.

One vial of the medicinal product 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 injection; 0.9% sodium chloride solution; 1-molar sodium chloride solution; 5%, 10%, 40% glucose solutions; 20% xylitol solution; Ringer's solution; complex lactated sodium solutions (Ringer's lactate solution).

Moxifloxacin infusion solution must not be administered simultaneously with other medicinal products.

The medicinal product must not be used if visible particulate matter or cloudiness is present in the solution.

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

Special precautions for use.

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

The benefit of moxifloxacin treatment, especially in cases of mild infections, must be evaluated considering the information contained in this section.

Prolongation of the QTc interval and clinical conditions in which QTc interval prolongation may occur

Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram (ECG) in some patients. The degree of QT interval prolongation may increase with rising plasma concentrations of the drug during rapid intravenous infusion. Therefore, the recommended duration of infusion, which should be at least 60 minutes, must be observed, and the intravenous dose should not exceed 400 mg once daily. For further details, see sections "Contraindications" and "Interaction with other medicinal products and other forms of interactions".

Treatment with moxifloxacin should be discontinued if symptoms that may be related to cardiac arrhythmia occur, 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 are at increased risk of developing ventricular arrhythmias (including polymorphic ventricular tachycardia such as torsades de pointes) 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 taking medicinal products associated with clinically significant bradycardia (see also section "Contraindications").

Women and elderly patients may exhibit increased sensitivity to the effects of medicinal products that prolong the QTc interval, such as moxifloxacin; therefore, these patients require special attention.

Increased sensitivity/allergic reactions

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

Severe hepatic impairment

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

Liver function tests should be performed if signs of impaired liver function occur.

Severe skin adverse reactions

Cases of severe skin adverse 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 syndrome), some of which were life-threatening or resulted in fatal outcomes, have been reported during moxifloxacin use (see section "Adverse reactions"). Patients should be warned about the signs and symptoms of severe skin reactions and closely monitored during treatment. Moxifloxacin should be immediately discontinued and alternative therapy considered upon the appearance of signs or symptoms suggestive of such reactions. If a patient develops severe skin reactions such as SJS, TEN, AGEP, or DRESS syndrome during moxifloxacin therapy, re-administration of moxifloxacin to this patient is absolutely contraindicated.

Patients predisposed to seizures

Quinolones are known to induce seizures. They should be prescribed with caution in patients with CNS 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 months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients treated with quinolones and fluoroquinolones, regardless of patient age or existing 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 polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients treated with quinolones and fluoroquinolones. Patients receiving moxifloxacin should be advised to inform their physician about the development of neuropathic symptoms such as pain, burning, tingling, numbness, or weakness before continuing treatment to prevent 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 have progressed to suicidal thoughts and self-harming behaviors such as suicide attempts (see section "Adverse reactions"). If such reactions occur, moxifloxacin treatment should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with psychiatric disorders, including those in their medical history.

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 events may range from mild diarrhea to fatal colitis. Therefore, it is important to consider the possibility of this diagnosis in patients who develop severe diarrhea during or after moxifloxacin treatment. If suspected or confirmed AAD or AAC occurs, antimicrobial therapy, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. Additionally, appropriate infection control measures should be implemented to reduce the risk of transmission. 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 (myasthenia gravis), as symptoms may be exacerbated.

Tendon inflammation and tendon rupture

Tendon inflammation and ruptures (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur during treatment with quinolones and fluoroquinolones, developing as early as within 48 hours of treatment initiation and persisting for several months after discontinuation of therapy (see sections "Contraindications" and "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplants, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of moxifloxacin and corticosteroids should be avoided.

Moxifloxacin should be discontinued upon the first symptoms of tendinitis (e.g., painful swelling or inflammation), and alternative therapy should be considered. Appropriate treatment (e.g., immobilization) should be initiated for the affected limb(s). Corticosteroids should not be used in cases of tendonopathy.

Aortic aneurysm and aortic dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, as well as the development of aortic and mitral valve regurgitation following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal outcomes), and regurgitation/insufficiency of any cardiac valve have been reported in patients treated with fluoroquinolones (see section "Adverse reactions"). Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a history of aortic aneurysm or congenital heart valve defect, or in patients diagnosed with aortic aneurysm and/or aortic dissection or heart valve disease, as well as in the presence of other risk factors or conditions predisposing to aortic aneurysm and aortic dissection, and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or also aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or also valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of developing aortic aneurysm and dissection, as well as their rupture, may be increased in patients receiving concomitant systemic corticosteroid therapy.

Patients should seek immediate medical attention if sudden abdominal pain, chest pain, or back pain occurs.

Patients should also be advised to seek immediate medical help if acute dyspnea, tachycardia, or development of abdominal or lower limb edema occurs.

Patients with renal impairment

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

Visual disturbances

Immediate consultation with an ophthalmologist is required in case of visual deterioration or any effect on the eyes (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose abnormalities, both hypoglycemia and hyperglycemia, have been reported during moxifloxacin treatment (see section "Adverse reactions"). Dysglycemia occurred predominantly in elderly patients with diabetes mellitus who were receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin with moxifloxacin. Cases of hypoglycemic coma have been reported. Patients with diabetes mellitus are advised to closely monitor their blood glucose levels.

Prevention of photosensitization reactions

Quinolones have been shown to cause photosensitization reactions in patients. Although studies have shown that the risk of photosensitization reactions with moxifloxacin is lower, patients should still avoid exposure to ultraviolet radiation and prolonged and/or intense sunlight during moxifloxacin treatment (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase deficiency, as well as those with a family history of this condition, are predisposed to hemolytic reactions during treatment with quinolones. Therefore, moxifloxacin should be used with caution in this patient population.

Periarterial tissue inflammation

Moxifloxacin infusion solution is intended for intravenous use only. Intraarterial 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 related to burns, fasciitis, and infected diabetic foot associated with osteomyelitis has not been established.

Effect on biological tests

Moxifloxacin may affect the results of Mycobacterium spp. detection tests by suppressing mycobacterial growth, which in turn 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").

Information about excipients

This medicinal product contains 787 mg (approximately 34 µmol) of sodium in one vial containing 250 mL of infusion solution, equivalent to 39.35% of the maximum daily sodium intake (2 g) recommended by WHO for adults.

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 in humans is unknown. Due to 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").

Period of breastfeeding

There are no data on the use of moxifloxacin 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 in breastfed infants and considering the experimental risk of harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals, breastfeeding is contraindicated during moxifloxacin treatment (see section "Contraindications").

Fertility

Animal studies have not shown effects on fertility (see section "Pharmacological properties").

Ability to influence reaction rate 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 response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosage

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

Initial intravenous therapy may be continued with oral administration of 400 mg moxifloxacin tablets, provided there are clinical indications.

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 drug should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special Instructions").

If indicated, the infusion solution may be administered via a 3-way stopcock together with compatible infusion solutions (see section "Special Precautions").

Physical and chemical stability of the prepared solutions, under aseptic conditions, has been demonstrated for 24 hours at 25 °C after dilution in 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 solution (Ringer's lactate solution). From a microbiological standpoint, if the method of dilution does not exclude the possibility of microbial contamination, the medicinal product should be used immediately. If the medicinal product is not used immediately, the storage time and conditions prior to use are the responsibility of the user.

Renal/Liver Impairment

Patients with mild to severe renal impairment, as well as patients on chronic dialysis (e.g., undergoing hemodialysis or long-term ambulatory peritoneal dialysis), 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 negative effects 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.

Specific measures are not recommended following accidental overdose. In case of overdose, symptomatic treatment should be administered. Since QT interval prolongation is possible, ECG monitoring is required. Administration of activated charcoal together with a 400 mg dose of moxifloxacin given orally or intravenously reduces systemic bioavailability by more than 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], and oral). Adverse reactions are classified according to their frequency.

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

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

System organ classes	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations	superinfections associated with resistant bacteria or fungi, e.g. oral and vaginal candidiasis
Blood and lymphatic system disorders		anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		increased prothrombin level/decreased INR, agranulocytosis, pancytopenia
Immune system disorders		allergic reactions (see section "Special warnings and precautions for use")	anaphylaxis, including life-threatening shock in rare cases (see section "Special warnings and precautions for use"), angioedema/ angioneurotic oedema (including potentially life-threatening laryngeal oedema (see section "Special warnings and precautions for use"))
Endocrine disorders				syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		hyperlipidaemia	hyperglycaemia, hyperuricaemia	hypoglycaemia, hypoglycaemic coma
Psychiatric disorders*		anxiety reactions, increased psychomotor activity/agitation	mood lability, depression (in rare cases with possible self-harm manifested as suicidal thoughts/ideation or suicide attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium	depersonalisation, psychotic reactions (with possible self-harm manifested as suicidal thoughts/ideation or suicide attempts) (see section "Special warnings and precautions for use")
Nervous system disorders*	headache, dizziness	paraesthesia/dysesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence	hypoesthesia, smell 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 disorder, amnesia, peripheral neuropathy and polyneuropathy	hyperesthesia
Eye disorders*		visual disturbances, including diplopia and blurred vision (especially during CNS reactions) (see section "Special warnings and precautions for use")	photophobia	transient visual loss (especially during CNS reactions) (see sections "Special warnings and precautions for use", "Effect on ability to drive and use machines"), uveitis and bilateral acute transient myopia (see section "Special warnings and precautions for use")
Ear and labyrinth disorders*			tinnitus; hearing disturbances, including deafness (usually reversible)
Cardiac disorders**	QT interval prolongation in patients with hypokalaemia (see sections "Contraindications" and "Special warnings and precautions for use")	QT interval prolongation (see section "Special warnings and precautions for use"), palpitations, tachycardia, atrial fibrillation, angina pectoris	ventricular tachyarrhythmias, syncope (e.g. acute and short-lasting loss of consciousness)	non-specific arrhythmias, torsade de pointes (see section "Special warnings and precautions for use"), cardiac arrest (see section "Special warnings and precautions for use")
Vascular disorders**		vasodilation	arterial hypertension, hypotension	vasculitis
Respiratory, thoracic and mediastinal disorders		dyspnoea (including asthmatic attack)
Gastrointestinal disorders	nausea, vomiting, abdominal and gastrointestinal pain, diarrhoea	decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels	dysphagia, stomatitis, 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")
Hepatobiliary disorders	elevated transaminase levels	liver function abnormalities (including elevated LDH (lactate dehydrogenase) levels), elevated bilirubin, GGT (gamma-glutamyl transferase), alkaline phosphatase	jaundice, hepatitis (mainly cholestatic)	Fulminant hepatitis, which may lead to life-threatening liver failure (see section "Special warnings and precautions for use")
Skin and subcutaneous tissue disorders		pruritus, rash, urticaria, dry skin		bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening) (see section "Special warnings and precautions for use")	AGEP, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (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*		arthralgia, myalgia	tendinitis (see section "Special warnings and precautions for use"), increased muscle tone, muscle cramps, muscle weakness	tendon rupture (see section "Special warnings and precautions for use"), arthritis, increased muscle rigidity as a symptom of myasthenia gravis (see section "Special warnings and precautions for use")	rhabdomyolysis
Renal and urinary disorders		dehydration	renal function impairment (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use")
General disorders and administration site conditions*	injection site and infusion site reactions	malaise (mainly asthenia or fatigue), pain (including back, chest, pelvic and limb pain), increased sweating, (thrombophlebitis at infusion site)	oedema

* Rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems and sensory organs (including such reactions as tendon inflammation, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell) have been reported in patients treated with quinolones and fluoroquinolones regardless of age and existing risk factors (see section "Special precautions").

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

The frequency of the following adverse reactions is higher with intravenous administration of the drug followed by oral therapy or without it.

Frequent: increased levels of gamma-glutamyl transferase.

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

Rarely, following treatment with other fluoroquinolones, adverse reactions have been reported that are also likely to occur during moxifloxacin therapy: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, hemolytic anemia.

Reporting suspected adverse reactions

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

Incompatibility.

The moxifloxacin infusion solution must not be administered simultaneously with incompatible solutions: 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".

Shelf life.

2 years.

Storage conditions.

Store in the original packaging, in a dry, light-protected place at a temperature not below 15 °C.

Do not freeze.

Keep out of reach of children.

Packaging.

250 ml in a glass bottle (flask), 1 glass bottle (flask) with instructions for medical use in a carton.

Prescription category.

Prescription only.

Manufacturer.

JSC "Halychpharm".

Manufacturer's address and location of its business activities.

6/8 Opryshkovska Street, Lviv, 79024, Ukraine.