Moxifloxacin: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Moxifloxacin (MOXIFLOXACIN)

Composition:

Active substance: moxifloxacin;

One tablet contains 436.8 mg of moxifloxacin hydrochloride, equivalent to 400 mg of moxifloxacin;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hypromellose, iron oxide red (E 172), macrogol 4000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated, elongated-shaped tablets, pink in color, with convex upper and lower surfaces.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group.

ATC code J01M A14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms. The bactericidal activity of moxifloxacin is due to inhibition of two type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for bacterial DNA replication, transcription, and repair.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to C8-H compounds. The presence of a bulky dicyclic amine substituent at the C-7 position prevents active efflux associated with the norA or pmrA genes found in some Gram-positive bacteria.

Pharmacodynamic studies indicate that moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are usually similar to minimal inhibitory concentrations (MIC).

Effect on intestinal flora in humans

In two studies involving healthy volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. The numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes such as Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, were reduced. An increase in Bacteroides fragilis was observed. The numbers of the above-mentioned microorganisms returned to normal within two weeks.

Mechanism of resistance

Mechanisms of resistance that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not affect the antibacterial efficacy of moxifloxacin. Other resistance mechanisms, such as permeability barriers (common in Pseudomonas aeruginosa) and efflux mechanisms, may influence susceptibility to moxifloxacin.

Development of resistance to moxifloxacin in vitro has been observed as a gradual process involving point mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux mechanisms in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones occurs. However, since moxifloxacin inhibits both topoisomerase II and IV with similar potency in certain Gram-positive bacteria, these bacteria may be resistant to other quinolones but remain susceptible to moxifloxacin.

Clinical breakpoints

Table 1

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

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
Non-species related breakpoints*	≤ 0.5 mg/L	> 1 mg/L

*Species-unrelated breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the distribution of MICs for specific species. These data are used only for species for which species-specific breakpoints have not been defined and are not used for species where interpretative criteria are subject to determination.

Microbiological susceptibility

The frequency of acquired resistance may vary depending on the geographical region and over time, as determined for specific microorganisms. It is advisable to have access to local information on microbial resistance, especially when treating severe infections.

If necessary, consultation with an expert in antimicrobial resistance should be sought when local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious pathogens becomes questionable.

Susceptible species

Aerobic Gram-positive microorganisms

Gardnerella vaginalis

Staphylococcus aureus * (methicillin-susceptible)

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 *

Haemophilus parainfluenzae *

Legionella pneumophila

Moraxella (Branhamella) catarrhalis *

Anaerobic microorganisms

Fusobacterium spp.

Prevotella spp.

Other microorganisms

Chlamydophila (Chlamydia) pneumoniae *

Chlamydia trachomatis*

Coxiella burnetii

Mycoplasma genitalium

Mycoplasma hominis

Mycoplasma pneumoniae *

Species with possible acquired resistance

Aerobic Gram-positive microorganisms

Enterococcus faecalis*

Enterococcus faecium*

Staphylococcus aureus (methicillin-resistant)+

Aerobic Gram-negative microorganisms

Enterobacter cloacae*

Escherichia coli*#

Klebsiella pneumoniae*#

Klebsiella oxytoca

Neisseria gonorrhoeae*+

Proteus mirabilis*

Anaerobic microorganisms

Bacteroides fragilis*

Peptostreptococcus spp.*

Resistant species

Aerobic Gram-negative microorganisms

Pseudomonas aeruginosa

*Demonstrated adequate activity against susceptible strains during clinical studies within approved clinical indications.

#Strains producing ESBLs are usually resistant to fluoroquinolones.

+Resistance rate > 50% in one or more countries.

Preclinical safety data

Effects on the hematopoietic system (mild reduction in erythrocytes and platelets) were observed in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was noted in rats, monkeys, and dogs. Neurotoxicity (CNS effects manifested as seizures) was observed in monkeys. These effects were observed only after administration of high doses of moxifloxacin or prolonged treatment.

Moxifloxacin, like other quinolones, showed genotoxicity in in vitro tests with bacteria or mammalian cells. Since this effect is explained by interaction with bacterial gyrase and, at higher concentrations, with topoisomerase II in mammalian cells, a threshold concentration for genotoxicity can be assumed. No signs of genotoxicity were detected in in vivo tests, despite administration of high doses of moxifloxacin. Thus, the drug demonstrated sufficient safety potential for humans when used at therapeutic doses. Moxifloxacin did not show carcinogenic effects in studies conducted in rats.

Many quinolones are photoreactive and may provoke phototoxic reactions, as well as exhibit photomutagenic and photocarcinogenic effects. However, data from comprehensive testing programs in vitro and in vivo indicate the absence of phototoxic and photogenotoxic properties of moxifloxacin. Under the same conditions, other quinolones demonstrated these effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the delayed rectifier potassium current in cardiomyocytes and may therefore lead to QT interval prolongation. Toxicological studies in dogs, in which the drug was administered orally at doses ≥ 90 mg/kg, resulting in plasma concentrations ≥ 16 mg/L, revealed QT interval prolongation without arrhythmias. Reversible non-lethal ventricular arrhythmias were observed only after intravenous administration of a high cumulative dose exceeding the human dose by more than 50 times (> 300 mg/kg), resulting in plasma concentrations ≥ 200 mg/L (more than 40 times the therapeutic level).

It is known that quinolones cause damage to cartilage in large diarthrodial joints in young animals. The lowest oral dose of moxifloxacin causing arthrototoxic effects in young dogs was four times higher than the maximum recommended therapeutic dose of 400 mg (calculated for a 50 kg body weight) based on dose/body weight ratio (mg/kg), resulting in plasma concentrations two to three times higher than those expected with the maximum therapeutic dose.

Toxicity studies in rats and monkeys (repeated dosing for up to six months) did not reveal any risk to the visual organs. In dogs, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L caused changes in electroretinograms and, in some cases, retinal atrophy.

Studies on the effects of moxifloxacin on animal reproductive function have shown that moxifloxacin crosses the placenta. Studies in rats (with oral and intravenous administration of moxifloxacin) and monkeys (with oral administration of moxifloxacin) did not reveal teratogenic effects or effects on fertility. Skeletal malformations were observed in rabbits after intravenous administration of moxifloxacin at 20 mg/kg. Increased rates of abortion were observed in monkeys and rabbits after administration of moxifloxacin at therapeutic doses. In rats, reduced fetal weight, increased abortion rates, slight prolongation of gestation period, and increased spontaneous activity in offspring were observed after administration of moxifloxacin at a dose 63 times higher than the recommended dose.

Pharmacokinetics.

Absorption and bioavailability

After oral administration, moxifloxacin is rapidly and almost completely absorbed. Absolute bioavailability reaches approximately 91%.

Over the dose range of 50–800 mg after single administration and at 600 mg daily for 10 days, pharmacokinetics are linear. After oral administration of a 400 mg dose, maximum plasma concentration (Cmax) is reached within 0.5–4 hours and amounts to 3.1 mg/L. Maximum and minimum plasma concentrations at steady state (400 mg once daily) are 3.2 and 0.6 mg/L, respectively. At steady state, exposure over the dosing interval is approximately 30% higher than after the first dose.

Distribution

Moxifloxacin rapidly distributes into the extravascular space. After administration of a 400 mg dose, the area under the pharmacokinetic concentration-time curve (AUC) is 35 µg·h/mL. The volume of distribution at steady state is 2 L/kg. As determined in in vitro and ex vivo experiments, plasma protein binding is approximately 40–42% and does not depend on drug concentration.

Table 2

Maximum concentration (geometric mean) after single oral dose of 400 mg moxifloxacin

Tissue	Concentration	Local level – plasma level ratio
Plasma	3.1 mg/L	-
Saliva	3.6 mg/L	0.75–1.3
Vesicle contents	1.61 mg/L	1.71
Bronchial mucosa	5.4 mg/kg	1.7–2.1
Alveolar macrophages	56.7 mg/kg	18.6–70.0
Epithelial lining fluid	20.7 mg/L	5–7
Maxillary sinus	7.5 mg/kg	2.0
Ethmoid sinuses	8.2 mg/kg	2.1
Nasal polyps	9.1 mg/kg	2.6
Interstitial fluid	1.02 mg/L	0.8–1.42
Female genital organs*	10.24 mg/kg	1.724

*Intravenous administration of a single 400 mg dose.

110 hours after administration.

2Free concentration.

3From 3 to 36 hours after dose administration.

4At the end of infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both in unchanged form and as inactive sulfate conjugates (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro studies and Phase I clinical trials have shown no metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation mediated by cytochrome P450 enzymes. There is no evidence of oxidative metabolism.

Elimination

The elimination half-life of the drug is approximately 12 hours. The mean total clearance after administration of 400 mg ranges from 179 to 246 mL/min. Renal clearance is approximately 24–53 mL/min, indicating partial tubular reabsorption of the drug by the kidneys. After a 400 mg dose, cumulative excretion in urine (approximately 19% – unchanged drug, approximately 2.5% – M1, and approximately 14% – M2) and feces (approximately 25% – unchanged drug, approximately 36% – M1, and no excretion as M2) totaled approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Elderly patients and patients with low body weight

Higher plasma concentrations of the drug were observed in healthy volunteers with low body weight (particularly in women) and in healthy elderly volunteers.

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). As renal function decreases, the concentration of metabolite M2 (glucuronide) increases by up to 2.5-fold (in patients with creatinine clearance < 30 mL/min/1.73 m²).

Hepatic impairment

Based on pharmacokinetic data from studies involving patients with hepatic impairment (Child–Pugh classes A–C), it is not possible to determine whether there is a difference compared to healthy volunteers. Hepatic impairment was associated with higher plasma levels of metabolite M1, while exposure to the parent drug was comparable to that in healthy volunteers. There is insufficient clinical experience with the use of moxifloxacin for the treatment of patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of the bacterial infections listed below, caused by microorganisms sensitive to moxifloxacin (see sections “Pharmacological properties”, “Special warnings and precautions for use”, and “Adverse reactions”), in patients aged 18 years and older.

Moxifloxacin should be used for the following indications only when the use of other antibacterial agents, usually recommended for the treatment of such infections, is considered inappropriate:

Acute bacterial sinusitis.
Exacerbation of chronic obstructive pulmonary disease, including bronchitis.

Moxifloxacin should be prescribed for the following indications only when the use of other antibacterial agents, usually recommended for initial treatment of the infections listed below, is inappropriate or when such treatment has been ineffective:

Community-acquired pneumonia, excluding severe community-acquired pneumonia.
Moderate to severe pelvic inflammatory diseases (including infection of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. The medicinal product is not recommended for use as monotherapy in moderate to severe pelvic inflammatory diseases, but may be used (except for moxifloxacin-resistant strains of Neisseria gonorrhoeae) in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin (see sections “Pharmacological properties” and “Special warnings and precautions for use”).

The medicinal product may be used to complete a course of treatment in which initial parenteral therapy with the drug was effective and indicated for the following conditions:

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

The medicinal product is not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia.

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

Contraindications.

Known hypersensitivity to moxifloxacin or to other quinolones or to any of the excipients of the drug.
Age under 18 years.
Pregnancy or breastfeeding (see section “Use in pregnancy or lactation”).
History of tendon disorders related to treatment with quinolones.

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiology, manifested as QT interval prolongation. Therefore, for safety reasons, the drug is contraindicated in patients with:

Congenital or diagnosed acquired QT interval prolongation;
Electrolyte imbalances, particularly uncorrected hypokalemia;
Clinically significant bradycardia;
Clinically significant heart failure with reduced left ventricular ejection fraction;
History of symptomatic arrhythmias.

The drug should not be administered concomitantly with other medicinal products that prolong the QT interval (see section “Interaction with other medicinal products and other types of interactions”).

Due to limited clinical data, the drug is also contraindicated in patients with hepatic impairment (Child–Pugh class C) and in patients with elevated transaminase levels (more than 5 times the upper limit of normal).

Interaction with other medicinal products and other types of interactions.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may increase the risk of ventricular arrhythmias, including torsade de pointes. For this reason, concomitant use of moxifloxacin 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, antimalarials such as halofantrine);
Certain antihistamines (terfenadine, astemizole, mizolastine);
Others (cisapride, vinca alkaloids IV, bepridil, difemanil).

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

An interval of approximately 6 hours should be maintained between the administration of medicinal products containing bivalent or trivalent cations (such as antacids containing magnesium or aluminum, didanosine tablets, sucralfate, and medicinal products containing iron or zinc) and moxifloxacin.

Concomitant oral administration of activated charcoal and moxifloxacin 400 mg reduces systemic bioavailability of the drug by more than 80% due to inhibition of its absorption. Therefore, concomitant use of these two medicinal products is not recommended (except in cases of overdose; see also section “Overdose”).

After repeated administration of moxifloxacin in healthy volunteers, an increase in digoxin Cmax of approximately 30% was observed, without affecting AUC or minimum concentrations. Therefore, no precautionary measures are required when digoxin is co-administered.

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of peak glyburide concentration by approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to mild, short-term hyperglycemia. However, the observed pharmacokinetic changes did not result in changes in pharmacodynamic parameters (blood glucose level, insulin level). Thus, no clinically relevant interaction between moxifloxacin and glyburide has been identified.

Change in international normalized ratio (INR)

Numerous cases of increased anticoagulant activity have been observed in patients receiving oral anticoagulants in combination with antibacterial agents, including fluoroquinolones, macrolides, tetracyclines, cotrimoxazole, and certain cephalosporins. Risk factors include infectious diseases (and associated inflammatory processes), age, and the patient’s general condition. Due to these factors, it is difficult to determine whether the infection or its treatment causes deviations in INR values. As a precautionary measure, more frequent monitoring of INR may be considered. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

Substances for which absence of clinically significant interaction with moxifloxacin has been demonstrated: ranitidine, calcium supplements, theophylline, oral contraceptives, cyclosporine, itraconazole, morphine administered parenterally, probenecid. In vitro studies of human cytochrome P450 enzymes confirmed the above. Based on these results, metabolic interaction via cytochrome P450 enzymes is unlikely.

Moxifloxacin absorption is not affected by food intake (including dairy products).

Special precautions for use.

The use of moxifloxacin should be avoided in patients with a history of serious adverse reactions following administration of drugs containing quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment with moxifloxacin in such patients should be initiated only if 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 contained in this section.

QTc interval prolongation and clinical conditions associated with QT interval prolongation

Prolongation of the QT interval on electrocardiogram (ECG) may occur in some patients receiving moxifloxacin. Analysis of ECG results obtained during clinical trial programs showed that QTc prolongation with moxifloxacin was 6 ms ± 26 ms (1.4%) compared to baseline. Since women have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.

Patients receiving moxifloxacin should use with caution medicinal products that may lead to decreased potassium levels (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions (particularly elderly patients and younger women), such as acute myocardial ischemia or QT interval prolongation, as this may increase the risk of ventricular arrhythmias, including torsade de pointes, and cardiac arrest (see section "Contraindications"). The degree of QT interval prolongation may increase with increasing drug concentration. Therefore, the recommended dose should not be exceeded.

If symptoms of arrhythmia occur during treatment, therapy should be discontinued and an ECG performed.

Hypersensitivity/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 drug. In case of clinical manifestations of severe hypersensitivity reactions, moxifloxacin should be discontinued and appropriate therapy initiated (e.g., anti-shock measures).

Severe hepatic impairment

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

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

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (also known as Lyell's syndrome), acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms (DRESS), some of which were life-threatening or fatal, have been reported during moxifloxacin use (see section "Adverse reactions"). Patients should be warned about signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of such reactions occur, moxifloxacin should be immediately discontinued and alternative therapy considered.

If a patient develops severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or DRESS during moxifloxacin therapy, moxifloxacin treatment must never be resumed in this patient.

Patients predisposed to seizures

Quinolones are known to induce seizures. Quinolones should be used 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 receiving quinolones and fluoroquinolones, regardless of age or existing risk factors. Moxifloxacin should be discontinued immediately upon the first symptoms 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, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients receiving moxifloxacin should be advised to inform their physician if they develop neuropathic symptoms such as pain, burning, tingling, numbness, or weakness before continuing treatment, 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 progressed 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 psychiatric disorders or a history thereof.

Antibiotic-associated diarrhea, including colitis

Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and diarrhea associated with Clostridium difficile, 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 therapy. If suspected or confirmed AAD or AAC occurs, antimicrobial therapy, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. In addition, appropriate infection control measures should be implemented to reduce the risk of transmission. Antiperistaltic agents 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 rupture (especially of the Achilles tendon), sometimes bilateral, may occur during therapy with quinolones and fluoroquinolones, developing within 48 hours of starting treatment and possibly occurring even several months after discontinuation (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.

If first symptoms of tendinitis (e.g., painful swelling, inflammation) occur, moxifloxacin should be discontinued and alternative therapy 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, and development of regurgitation on aortic and mitral valves following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal), as well as regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions"). Therefore, fluoroquinolones should be used only after careful 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 with valvular heart disease, or in the presence of other risk factors or conditions predisposing to aortic aneurysm and 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 aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or valvular regurgitation/insufficiency (e.g., infective endocarditis).

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

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

Patients should be advised to seek immediate medical help if acute shortness of breath, rapid heartbeat, or swelling of the abdomen or lower limbs develops.

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

In case of visual impairment or any effect on the eyes, patients should immediately consult an ophthalmologist (see sections "Ability to influence driving and use of machines" and "Adverse reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose abnormalities, including both hypoglycemia and hyperglycemia, have been reported during moxifloxacin therapy (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. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor their blood glucose levels.

Prevention of phototoxicity reactions

Phototoxicity reactions have been observed in patients receiving quinolones. However, studies have shown that moxifloxacin has a lower risk of phototoxicity. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense exposure to sunlight during moxifloxacin therapy (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 prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in these patients.

Patients with pelvic inflammatory disease

Patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess), for whom intravenous therapy is considered necessary, should not be treated with the 400 mg tablet formulation.

Pelvic inflammatory disease may be caused by Neisseria gonorrhoeae resistant to fluoroquinolones. Therefore, empirical use of moxifloxacin in such cases should be combined with another appropriate antibiotic (e.g., a cephalosporin) if resistance to moxifloxacin cannot be fully excluded. If there is no clinical improvement after 3 days of treatment, therapy should be re-evaluated.

Patients with specific complicated skin and soft tissue infections

The clinical efficacy of intravenous 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 therapy may interfere with microbiological testing for Mycobacterium spp. due to inhibition of mycobacterial growth, which may lead to false-negative results in samples from patients currently receiving moxifloxacin.

Patients with infections caused by methicillin-resistant Staphylococcus aureus

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

Children

Moxifloxacin causes cartilage damage in young animals (see section "Pharmacological properties"); therefore, its use in children (under 18 years of age) is contraindicated (see section "Contraindications").

Information on excipients

This medicinal product contains 32 mg of sodium per coated tablet. Caution should be exercised when using moxifloxacin in patients on a sodium-restricted diet.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of moxifloxacin use during pregnancy has not been established.

Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk to humans is unknown.

Due to the risk of fluoroquinolone-induced damage to weight-bearing joints in young animals (based on experimental data) and reversible joint lesions described in children treated with certain fluoroquinolones, moxifloxacin must not be given to pregnant women (see section "Contraindications").

Breastfeeding period

Moxifloxacin, like other quinolones, causes cartilage damage in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on the use of the drug in breastfeeding women. Therefore, during breastfeeding, the use of moxifloxacin is contraindicated (see section "Contraindications").

Fertility

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

Ability to influence the ability to drive and use machines.

No studies on the effect of moxifloxacin on the ability to drive and use machines have been conducted. However, fluoroquinolones, including moxifloxacin, may impair the ability to drive or operate machinery due to central nervous system reactions (such as dizziness, acute transient visual loss, see section "Adverse reactions") or acute short-term loss of consciousness (syncope, see section "Adverse reactions"). Patients should be advised to monitor their response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosage (adults)

It is recommended to take 1 tablet (400 mg) of moxifloxacin once daily.

Renal/hepatic impairment

Dose adjustment is not required in patients with moderate to severe renal impairment, as well as in patients undergoing continuous hemodialysis or long-term ambulatory peritoneal dialysis (see section "Pharmacological Properties").

There is insufficient data on the use of the drug in patients with hepatic impairment (see section "Contraindications").

Elderly patients/low body weight patients

Dose adjustment is not required in elderly patients or patients with low body weight.

Method of Administration

Tablets should be swallowed whole with sufficient amount of water. The drug can be taken independently of food intake.

Duration of Therapy

The duration of moxifloxacin tablet therapy depends on the type of infection and is as follows:

Exacerbation of chronic obstructive pulmonary disease, including bronchitis –
5–10 days;
Community-acquired pneumonia – 10 days;
Acute bacterial sinusitis – 7 days;
Mild to moderate pelvic inflammatory disease – 14 days.

According to clinical trial data, the treatment duration with moxifloxacin tablets was up to 14 days.

Step-down (intravenous to oral) therapy

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

The specified dose (400 mg once daily) and the treatment duration for each indication should not be exceeded.

Children

Moxifloxacin is contraindicated in children (under 18 years of age). The efficacy and safety of moxifloxacin in children have not been established (see also section "Contraindications").

Overdose.

In case of accidental overdose, no specific antidotes are recommended. In the event of overdose, treatment should be based on the clinical picture and include symptomatic and supportive therapy, along with ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin reduces systemic availability of the drug by more than 80%. In cases of oral overdose, early administration of activated charcoal during the absorption phase may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions

The adverse reactions listed below were observed during clinical studies following administration of moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral], and oral) and in the post-marketing period. Adverse reactions are classified according to their frequency. All adverse reactions occurred at a frequency of less than 3%, except for nausea and diarrhea.

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

Table 3

System organ classes (MedDRA)	Common	Uncommon	Occasional	Rare	Unknown
Infections and infestations	Superinfection due to bacterial or fungal resistance, e.g. oral or vaginal candidiasis
Blood and lymphatic system disorders		Anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		Elevated prothrombin levels/decreased INR, agranulocytosis, pancytopenia
Immune system disorders		Allergic reactions (see section "Special warnings and precautions for use")	Anaphylaxis, including rare cases of life-threatening shock, allergic oedema/angioneurotic oedema, including laryngeal oedema (potentially life-threatening) (see section "Special warnings and precautions for use")
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders		Hyperlipidaemia	Hypoglycaemia, hyperuricaemia	Hypoglycaemia, hypoglycaemic coma
Psychiatric disorders*		Anxiety reactions, increased psychomotor activity/agitation	Mood lability, depression (in rare cases with possible self-harm, such as suicidal ideation/thoughts or suicide attempts (see section "Special warnings and precautions for use")), hallucinations, delirium	Depersonalisation, psychotic reactions (with possible self-harm, such as suicidal ideation/thoughts 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, olfactory disturbances (including loss of smell), pathological dreams, coordination disturbances (including gait disturbance due to dizziness or vertigo), seizures with various clinical manifestations (including grand mal seizures (see section "Special warnings and precautions for use")), attention disturbances, speech disorders, amnesia, peripheral neuropathy and polyneuropathy	Hyperesthesia
Eye disorders*		Visual disturbances, including diplopia and blurred vision (particularly during CNS reactions (see section "Special warnings and precautions for use"))	Photophobia	Transient visual loss (particularly during CNS reactions (see sections "Special warnings and precautions for use" and "Effect on ability to drive and use machines")), uveitis and bilateral acute transillumination of the iris (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 (i.e. acute and transient 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, arterial hypotension	Vasculitis
Respiratory, thoracic and mediastinal disorders		Dyspnoea (including asthmatic attack)
Gastrointestinal disorders	Nausea, vomiting, abdominal pain, diarrhoea	Decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, elevated amylase levels	Dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, rarely 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)), elevated bilirubin levels, elevated GGT (gamma-glutamyl transpeptidase), elevated alkaline phosphatase in blood	Jaundice, hepatitis (mainly cholestatic)	Fulminant hepatitis, potentially leading to life-threatening liver failure (including fatal outcomes (see section "Special warnings and precautions for use"))
Skin and subcutaneous tissue disorders		Pruritus, rash, urticaria, dry skin		Blistering skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening (see section "Special warnings and precautions for use"))	Acute generalised exanthematous pustulosis, 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*		Arthralgia, myalgia	Tendinitis (see section "Special warnings and precautions for use"), muscle twitching, muscle cramps, muscle weakness	Tendon rupture (see section "Special warnings and precautions for use"), arthritis, muscle rigidity, exacerbation of symptoms 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 plasma creatinine), renal failure (see section "Special warnings and precautions for use")
General disorders*		General weakness (mainly asthenia or fatigue), pain sensation (including back pain, chest pain, limb pain, pelvic pain), hyperhidrosis	Swelling

*Rare cases of prolonged (lasting 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, neuralgia, anxiety, suicidal thoughts, panic attacks, depression, fatigue, memory and attention disturbances, 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 for use").

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

Rare adverse reactions reported after treatment with other fluoroquinolones, which may possibly also occur during moxifloxacin use, include: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, and hemolytic anemia.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

1 tablet in a blister; 70 blisters in a cardboard box;

5, 7, or 10 tablets in a blister; 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and place of business.

8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.