Moxifloxacin

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

Composition:

Active substance: moxifloxacin;

1 tablet contains 400 mg of moxifloxacin as moxifloxacin hydrochloride;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; magnesium stearate; coating: hypromellose, polyethylene glycol 6000, titanium dioxide (E 171), iron oxide red (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, biconvex, film-coated tablets of pink color.

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

ATC code J01MA14.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms. The bactericidal action 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 group 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 large dicyclic amine substituent at the C-7 position prevents active efflux mediated by norA or pmrA genes identified in some Gram-positive bacteria.

Pharmacodynamic studies indicate that moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are generally 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. Decreased numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, were noted. An increase in Bacteroides fragilis was observed. The counts of the aforementioned microorganisms returned to normal within two weeks.

Mechanism of resistance

Resistance mechanisms 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 occurs gradually through point mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux systems in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones may occur. However, because moxifloxacin inhibits both type II topoisomerases (DNA gyrase and topoisomerase IV) with similar potency in certain Gram-positive bacteria, these bacteria may be resistant to other quinolones but remain susceptible to moxifloxacin.

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 ³ 24 mm	> 1 mg/L < 21 mm
S. pneumoniae	≤ 0.5 mg/L ³ 22 mm	> 0.5 mg/L < 22 mm
Streptococcus, groups A, B, C, G	≤ 0.5 mg/L ³ 18 mm	> 1 mg/L < 15 mm
H. influenzae	≤ 0.5 mg/L ³ 25 mm	> 0.5 mg/L < 25 mm
M. catarrhalis	≤ 0.5 mg/L ³ 23 mm	> 0.5 mg/L < 23 mm
Enterobacteriaceae	≤ 0.5 mg/L ³ 20 mm	> 1 mg/L < 17 mm
Non-species related breakpoints*	≤ 0.5 mg/L	> 1 mg/L

*Breakpoints not species-related were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the spread of MICs of specific species. These data are applied only to species for which species-specific breakpoints have not been established and are not used for species in which interpretative criteria are subject to definition.

Microbiological susceptibility

The frequency of acquired resistance in certain microorganism species may vary depending on the geographical region and over time. It is desirable to have access to local information on microbial resistance, especially when treating severe infections. If necessary, consultation with an expert in antibiotic resistance should be sought when local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious agents remains 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 potential for developing 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

*Satisfactory activity against susceptible strains has been demonstrated in clinical studies within the scope of approved clinical indications.

#Strains producing ESBLs are usually resistant to fluoroquinolones.

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

Pharmacokinetics.

Absorption and bioavailability

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

Following single oral doses in the range of 50–800 mg and repeated administration of 600 mg daily for 10 days, pharmacokinetics are linear. After an oral dose of 400 mg, peak plasma concentration 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 nearly 30% higher than after the first dose.

Distribution

Moxifloxacin rapidly distributes into the extravascular space; after a 400 mg dose, 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, protein binding in blood is approximately 40–42% and is independent of drug concentration.

Table 2

Peak 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 content	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
Ethmoidal sinuses	8.2 mg/kg	2.1
Nasal polyps	9.1 mg/kg	2.6
Interstitial fluid	1.02 mg/L	0.8–1.42,3
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 hours to 36 hours after dose administration.

4At the end of the infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both unchanged and as inactive sulfated metabolites (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 showed no evidence of metabolic pharmacokinetic interactions with other drugs metabolized by cytochrome P450 enzymes involved in phase I biotransformation. There are no signs 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% as M1, and approximately 14% as M2) and feces (approximately 25% unchanged drug, approximately 36% as 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 impaired renal function (including patients with creatinine clearance > 20 mL/min/1.73 m²). As renal function declines, the concentration of the metabolite M2 (glucuronide) increases 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 dysfunction was associated with higher plasma exposure of 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.

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

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

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

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

• Community-acquired pneumonia, excluding severe community-acquired pneumonia.
• Moderate to mild inflammatory pelvic diseases (including infectious involvement of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. Moxifloxacin 400 mg film-coated tablets are not recommended for use as monotherapy in moderate to mild inflammatory pelvic diseases, but may be used (except in cases of infection with moxifloxacin-resistant Neisseria gonorrhoeae strains) in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin (see sections “Special precautions for use”, “Pharmacological properties”).

Moxifloxacin in tablet form may be used to complete a course of treatment initiated with intravenous moxifloxacin, when such initial therapy has been effective, for the following indications:

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

Moxifloxacin in tablet form is not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia.

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

Contraindications.

• Hypersensitivity to moxifloxacin or to other quinolones, or to any of the excipients of the medicinal product.
• Age under 18 years.
• Pregnancy or breastfeeding (see section “Use during pregnancy or lactation”).
• History of tendon disorders related to quinolone therapy.

In preclinical and clinical studies, changes in cardiac electrophysiology, such as QT interval prolongation, have been observed after administration of moxifloxacin. 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 medicinal product should not be used concomitantly with other drugs that prolong the QT interval (see section “Interaction with other medicinal products and other forms of interaction”).

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 above the upper limit of normal).

Interaction with other medicinal products and other forms of interaction.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. Such interaction increases the risk of ventricular arrhythmias, including torsade de pointes. For this reason, the concomitant use of moxifloxacin with any of the following medicinal products is contraindicated (see also section “Contraindications”):

• Class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (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 taking drugs that may reduce potassium levels (e.g., loop and thiazide diuretics, enemas and laxatives (at high doses), corticosteroids, amphotericin B), or drugs whose action is associated with clinically significant bradycardia.

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

Concomitant administration of activated charcoal and oral moxifloxacin at a dose of 400 mg reduces systemic bioavailability of the drug by more than 80% due to inhibition of its absorption. Therefore, concomitant use of these two agents 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 by approximately 30% was observed, without affecting AUC (area under the concentration-time curve) or trough concentrations. Therefore, no preventive measures are required when digoxin is co-administered.

In studies involving volunteers and patients with diabetes mellitus, 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 levels, insulin levels). 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 reported 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), advanced age, and poor general condition of the patient. Due to these circumstances, it is difficult to determine whether the infection or the treatment causes deviations in INR values. More frequent monitoring of INR may be advisable. 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 on human cytochrome P450 enzymes have confirmed the above. Thus, metabolic interaction via cytochrome P450 enzymes is unlikely.

The absorption of moxifloxacin is not affected by food intake (including dairy products).

Special precautions for use.

Avoid using moxifloxacin in patients with a history of severe adverse reactions after taking medicinal products containing quinolones or fluoroquinolones (see section "Side effects"). 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 benefits of moxifloxacin treatment, especially in mild infections, should be evaluated considering the information contained in this section.

QTc interval prolongation and clinical conditions associated with QTc interval prolongation

In some patients, moxifloxacin may cause QT interval prolongation on electrocardiogram. Analysis of ECG data from clinical trial programs showed that QTc interval prolongation with moxifloxacin was 6 ms ± 26 ms (1.4%) compared to baseline. Since women generally 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-related 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 women and elderly patients), such as acute myocardial ischemia or QT interval prolongation, as this increases the risk of ventricular arrhythmias, including torsade de pointes and cardiac arrest (see section "Contraindications"). The degree of QT interval prolongation may increase with higher drug concentrations. Therefore, the recommended dose should not be exceeded.

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

Increased sensitivity/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 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 therapy).

Severe hepatic impairment

Cases of fulminant hepatitis, which may lead to liver failure (including fatal cases), have been reported with moxifloxacin use (see section "Side effects"). 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 use (see section "Side effects"), which may be life-threatening or fatal. Patients should be warned about signs and symptoms of severe skin reactions, and closely monitored. If symptoms suggestive of such reactions occur, moxifloxacin should be discontinued immediately and alternative therapy considered. If severe skin reactions such as SJS, TEN, AGEP, or DRESS develop during moxifloxacin therapy, re-administration of moxifloxacin in these patients 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 (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 several months or years), disabling, and potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous, psychiatric, and sensory organs), sometimes simultaneously, have been reported in patients treated with quinolones and fluoroquinolones, regardless of patient age or presence of 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 symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness before continuing treatment to prevent potentially irreversible conditions (see section "Side effects").

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 "Side effects"). 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.

Diarrhea associated with antibiotic use, including colitis

Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-induced diarrhea, have been observed with 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, antimicrobial therapy, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, appropriate infection control measures should be implemented to reduce transmission risk. Patients who develop severe diarrhea should not receive peristalsis-inhibiting agents.

Patients with severe myasthenia

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

Tendon inflammation and tendon rupture

Tendon inflammation and ruptures (especially of the Achilles tendon), sometimes bilateral, may occur during therapy with quinolones and fluoroquinolones, developing within 48 hours of treatment initiation and possibly occurring several months after treatment discontinuation (see sections "Contraindications" and "Side effects"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use with corticosteroids should be avoided.

If early symptoms of tendinitis (e.g., painful swelling, inflammation) occur, moxifloxacin should be discontinued and alternative therapy considered. The affected limb requires appropriate management (e.g., immobilization). Corticosteroids should not be used if symptoms of tendinopathy develop.

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 aortic and mitral valve regurgitation following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), as well as cases of regurgitation/insufficiency of any cardiac valve have been reported in patients treated with fluoroquinolones (see section "Side effects"). 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 with diagnosed aortic aneurysm and/or aortic dissection, or with heart valve disease, and in the presence of other risk factors:

• conditions predisposing to aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis;
• conditions predisposing to aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;
• conditions predisposing to cardiac valve regurgitation/insufficiency: infective endocarditis.

The risk of aortic aneurysm, dissection, and rupture is increased in patients receiving concomitant systemic corticosteroid therapy.

In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention.

Patients should 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 intake, as dehydration increases the risk of renal failure.

Visual disturbances

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", "Side effects").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose abnormalities, including both hypoglycemia and hyperglycemia, have been reported during moxifloxacin therapy (see section "Side effects"). 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 observed in patients receiving quinolones. However, studies have shown that moxifloxacin has a lower risk of photosensitization. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense sunlight exposure during moxifloxacin therapy (see section "Side effects").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase deficiency or 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

Oral moxifloxacin 400 mg tablets are not recommended for patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess) who require intravenous therapy.

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 the presence of moxifloxacin-resistant Neisseria gonorrhoeae 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 treating severe infections associated with burns, fasciitis, and infected diabetic foot with 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, potentially leading to false-negative results in samples from patients currently taking moxifloxacin.

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

Moxifloxacin is not recommended for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In suspected or confirmed MRSA infection, 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 is contraindicated in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per coated tablet, i.e., essentially "sodium-free".

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 for humans has not been established.

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 should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

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, moxifloxacin is contraindicated during breastfeeding (see section "Contraindications").

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of moxifloxacin on the ability to drive or operate machinery have been conducted. However, fluoroquinolones, including moxifloxacin, may cause central nervous system reactions such as dizziness, acute transient visual loss, or acute brief loss of consciousness (see section "Side effects"), thereby impairing the ability to drive or operate machinery. 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 no reliable information regarding patients with hepatic impairment (see section "Contraindications").

Elderly Patients / Patients with Low Body Weight

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

Method of Administration

Tablets should be taken whole, without chewing, and swallowed with sufficient amount of water. The drug can be administered regardless of food intake.

Duration of Therapy

The duration of treatment with moxifloxacin tablets depends on the type of infection and is as follows:

• Acute exacerbation of chronic obstructive pulmonary disease, including bronchitis — 5–10 days;
• Community-acquired pneumonia — 10 days;
• Acute bacterial sinusitis — 7 days;
• Moderate to severe pelvic inflammatory disease — 14 days.

According to clinical study data, the duration of moxifloxacin tablet therapy was up to 14 days.

Step-down (Intravenous/Oral) Therapy

During clinical studies of step-down therapy, most patients switched from intravenous to oral administration of moxifloxacin within 4 days (for community-acquired pneumonia) or 6 days (for complicated skin and soft tissue infections). The recommended total duration of treatment with moxifloxacin in both solution and tablet 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 duration of treatment 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 measures are recommended. In the event of overdose, treatment should be based on clinical presentation, including symptomatic and supportive therapy, and 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 by more than 80%. In cases of oral overdose, early administration of activated charcoal during the initial absorption phase may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions.

The adverse reactions listed below were observed during clinical trials following administration of moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral], and oral therapy) 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 events are listed in order of decreasing severity. Frequency is defined as follows: common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated based on available data).

Table 3

Organ systems (MedDRA — Medical Dictionary for Regulatory Activities)	Adverse reactions	Frequency
Infections	Superinfection due to bacterial or fungal resistance, e.g. oral or vaginal candidiasis	Common
Blood and lymphatic system disorders	Anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time / increased INR (International Normalized Ratio) Increased prothrombin levels / decreased INR, agranulocytosis, pancytopenia	Uncommon Very rare
Immune system disorders	Allergic reactions (see section "Special warnings and precautions for use") Anaphylaxis, including rare cases of shock (life-threatening), angioedema / allergic oedema, including laryngeal oedema (potentially life-threatening) (see section "Special warnings and precautions for use")	Uncommon Rare
Endocrine disorders	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Rare
Metabolism and nutrition disorders	Hyperlipidaemia Hypoglycaemia, hyperglycaemia, hyperuricaemia Hypoglycaemia, hypoglycaemic coma	Uncommon Rare Very rare
Psychiatric disorders*	Anxiety reactions, increased psychomotor activity/agitation Mood lability, depression (in rare cases with self-harm such as suicidal ideation/thoughts or suicide attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium Depersonalisation, psychotic reactions (possibly with self-harm such as suicidal ideation/thoughts or suicide attempts) (see section "Special warnings and precautions for use")	Uncommon Rare Very rare
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 disorders (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	Common Uncommon Rare Very rare
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" and "Effect on ability to drive and use machines"), uveitis and bilateral acute iris transillumination	Uncommon Rare Very rare
Ear and labyrinth disorders*	Tinnitus, hearing disturbances including deafness (usually reversible)	Rare
Cardiac disorders**	QT interval prolongation in patients with hypokalaemia (see sections "Special warnings and precautions for use" and "Contraindications") 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, cardiac arrest (see section "Special warnings and precautions for use")	Common Uncommon Rare Very rare
Vascular disorders**	Vasodilation Arterial hypertension, arterial hypotension Vasculitis	Uncommon Rare Very rare
Respiratory, thoracic and mediastinal disorders	Dyspnoea (including asthmatic attack)	Uncommon
Gastrointestinal disorders	Nausea, vomiting, abdominal pain, diarrhoea Decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels Dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, rarely with life-threatening complications) (see section "Special warnings and precautions for use")	Common Uncommon Rare
Hepatobiliary disorders	Elevated transaminase levels Liver function abnormalities (including elevated LDH [lactate dehydrogenase] levels), elevated bilirubin levels, elevated GGT (gamma-glutamyl transferase) levels, elevated alkaline phosphatase levels in blood Jaundice, hepatitis (predominantly cholestatic) Fulminant hepatitis, which may lead to life-threatening liver failure (including fatal outcomes) (see section "Special warnings and precautions for use")	Common Uncommon Rare Very rare
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") 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")	Uncommon Very rare Frequency not known
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	Uncommon Rare Very rare Frequency not known
Renal and urinary disorders	Dehydration Renal function impairment (including increased blood urea nitrogen and plasma creatinine levels), renal failure	Uncommon Rare
General disorders*	General weakness (mainly asthenia or fatigue), pain (including back pain, chest pain, limb pain, pelvic pain), hyperhidrosis Oedema	Uncommon Rare

* Rare cases of prolonged (for several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems and sensory organs (including such reactions as tendon inflammation, tendon rupture, arthralgia, pain in extremities, difficulty in walking, neuropathy associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration disturbances, as well as disturbances in hearing, vision, taste and smell) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age and presence of risk factors (see section "Special warnings and 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 cardiac valve have been reported in patients treated with fluoroquinolones (see section "Special warnings and precautions for use").

Rare adverse reactions have been reported after treatment with other fluoroquinolones, which may also occur during moxifloxacin use: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatraemia, hypercalcaemia, haemolytic anaemia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical 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.

2 years.

Storage conditions.

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

Packaging.

5 or 10 tablets in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address and place of business.

6, Kyivska Street, city of Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.