INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOXIFLOXACIN-PHARMEX (MOXIFLOXACIN-PHARMEX)

Composition:

Active ingredient: moxifloxacin;

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

Excipients: sodium croscarmellose, microcrystalline cellulose, lactose monohydrate, magnesium stearate;

Coating: hypromellose, polyethylene glycol 4000, titanium dioxide (E 171), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex film-coated tablets of light red to red 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 effect of moxifloxacin is due to inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for replication, transcription, and repair of bacterial DNA.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to the C8-H moiety. The presence of a bulky diazabicyclic group at the C-7 position prevents active efflux mediated by the norA or pmrA genes identified in some Gram-positive bacteria.

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

Effect on intestinal flora in humans

In two studies involving adult 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. An increase in the number of Bacteroides fragilis was observed. The counts of the aforementioned microorganisms returned to normal within two weeks.

Resistance mechanisms

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, because moxifloxacin inhibits both topoisomerases (II and 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 ≥ 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

* Non-species-related breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the MIC distribution of specific species. These data are used only for species for which species-specific breakpoints have not been defined and are not used for species for which interpretive criteria are to be determined.

Microbiological susceptibility

The frequency of acquired resistance may vary depending on the geographical region and over time, as defined for specific microorganisms. It is desirable to have access to local information on microbial resistance, especially when treating severe infections. Consultation with an expert in antibiotic resistance should be sought if local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious agents 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

* Adequate activity against susceptible strains has been demonstrated in 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 haematopoietic system (mild reduction in red blood cells 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 (central nervous system (CNS) effects, including 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 has shown 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 cause phototoxic reactions, as well as exhibit photomutagenic and photocarcinogenic effects. However, data indicate the absence of phototoxic and photogenotoxic properties of moxifloxacin when tested within a comprehensive program in in vitro and in vivo studies. Under similar conditions, other quinolones have 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 prolongation without arrhythmias. Reversible non-lethal ventricular arrhythmias were observed only after intravenous administration of a high cumulative dose more than 50 times the human dose (> 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 of 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 (for a 50 kg body weight), calculated on the basis of dose/body weight ratio (mg/kg), with plasma concentrations 2 to 3 times higher than those expected with the maximum therapeutic dose.

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

Studies on the effects of moxifloxacin on animal reproductive function have demonstrated 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 of moxifloxacin or effects on fertility. Skeletal malformations were observed in rabbits after intravenous administration of moxifloxacin at a dose of 20 mg/kg. Increased rates of abortions 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, 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%.

Within the dose range of 50–800 mg after single administration and at a dose of 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 mg/L and 0.6 mg/L, respectively. At steady state, exposure over the dosing interval is almost 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 is independent of drug concentration.

Table 2

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

Tissue	Concentration	Local level – plasma blood level
Blood plasma	3.1 mg/L
Saliva	3.6 mg/L	0.75–1.3
Skin blister fluid	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.

1 10 hours after administration.

2 Free concentration.

3 From 3 hours to 36 hours after dose administration.

4 At the end of the 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 sulfocompounds (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. During in vitro studies and phase I clinical trials, no metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation mediated by cytochrome P450 enzymes were observed. 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 ml/min to 246 ml/min. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug by the kidneys. After administration of a 400 mg dose, cumulative excretion in urine (approximately 19% as unchanged drug, approximately 2.5% as M1, and approximately 14% as M2) and feces (approximately 25% as 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 were observed in patients with impaired renal function (including patients with creatinine clearance > 20 ml/min/1.73 m²). As renal function decreases, the concentration of 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 obtained from studies involving patients with hepatic insufficiency (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 moxifloxacin use for treating patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of the following bacterial infections caused by microorganisms sensitive to moxifloxacin (see sections “Pharmacological properties”, “Particular 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, typically recommended for the treatment of such infections, is considered inappropriate:

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

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

• Community-acquired pneumonia, excluding community-acquired pneumonia with severe course.
• 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 tablet form of moxifloxacin is not recommended for use as monotherapy in moderate to severe pelvic inflammatory diseases (add), but may be used (except for moxifloxacin-resistant strains of Neisseria gonorrhoeae) in combination with other appropriate antibacterial agents (e.g., with cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin (see sections “Pharmacological properties” and “Particular use”).

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

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

The tablet form of moxifloxacin 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 medicinal product.

Age under 18 years.

Pregnancy or breastfeeding (see section “Use during pregnancy or breastfeeding”).

Patients with a history of tendon disorders related to quinolone therapy.

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiology, manifested as prolongation of the QT interval. 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 used concomitantly with other medicinal products that prolong the QT interval (see section “Interaction with other medicinal products and other forms of interaction”).

Due to limited clinical data on drug use, it 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 (ULN)).

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. This interaction may lead to an increased risk of ventricular arrhythmias, including torsades de pointes (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 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, including halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Others (cisapride, vincamine IV, bepridil, difemanil).

Moxifloxacin should be prescribed with caution to patients taking 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 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 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 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% at steady state was observed, without affecting AUC or trough levels. Therefore, no precautionary measures are required when digoxin is co-administered.

In studies involving adult volunteers and patients with diabetes mellitus, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of glyburide peak 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), age, and the patient's general condition. Due to these circumstances, it is difficult to determine whether the infection or the treatment causes deviations in INR values. As a precaution, 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 have confirmed the above. Based on these results, 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.

The use of moxifloxacin should be avoided in patients with a history of serious adverse reactions to drugs containing quinolone or fluoroquinolone (see section "Adverse reactions"). Treatment with moxifloxacin in these patients should be initiated only when no alternative treatment options are 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 QT 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 medications that may lead to hypokalemia (see sections "Contraindications" and "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 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 higher drug concentrations; therefore, the recommended dose should not be exceeded.

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

Hypersensitivity/allergic reactions

Hypersensitivity and allergic reactions to fluoroquinolones, including moxifloxacin, have been reported after the first dose. Anaphylactic reactions may progress to life-threatening anaphylactic shock even after the first administration. In such cases, the drug should be discontinued immediately and appropriate therapy (e.g., anti-shock treatment) initiated.

Severe hepatic impairment

Cases of potentially fatal fulminant hepatitis leading to hepatic failure (including fatal outcomes) have been reported during moxifloxacin therapy (see section "Adverse reactions"). If symptoms of fulminant hepatitis such as rapidly developing fatigue accompanied by jaundice, dark urine, tendency to bleeding, 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

Cases of severe skin reactions, including toxic epidermal necrolysis (also known as Lyell’s syndrome), Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during moxifloxacin use (see section "Adverse reactions"), which may be life-threatening or fatal. Patients should be warned about signs and symptoms of severe skin reactions, and closely monitored. If signs or symptoms suggestive of these reactions occur, moxifloxacin should be discontinued immediately and alternative treatment considered. Re-administration of moxifloxacin should be strictly avoided in patients who have experienced severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or DRESS during prior therapy.

Patients predisposed to seizures

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

Prolonged, disabling, and potentially irreversible serious adverse reactions

Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems (musculoskeletal, nervous, psychiatric, and sensory organs), sometimes involving multiple systems, 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 symptoms of neuropathy 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 develop even after the first dose of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions may progress to suicidal ideation 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

Antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported 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 AAD or AAC is suspected or confirmed, treatment with antibacterial agents, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, 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 occasionally occurring 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, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of this medicinal product with corticosteroids should be avoided.

If early symptoms of tendinitis (e.g., painful swelling, inflammation) occur, moxifloxacin therapy should be discontinued and alternative treatment considered. Appropriate treatment (e.g., immobilization) should be initiated for the affected limb(s). Corticosteroids should not be used if signs of tendinopathy occur.

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 cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions"). Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative 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 conditions associated with aortic aneurysm and dissection (e.g., vasculitis such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and 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 they experience acute shortness of breath, rapid heartbeat, or develop abdominal or lower limb swelling.

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 deterioration or any effect on the eyes, patients should seek immediate consultation with an ophthalmologist (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse reactions").

Dysglycemia

As with other fluoroquinolones, deviations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported during moxifloxacin therapy (see section "Adverse reactions"). Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin. 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 photosensitivity. 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 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 therapy is 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 resistance of Neisseria gonorrhoeae 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 diabetic foot complicated by osteomyelitis has not been established.

Impact on biological tests

Moxifloxacin therapy may interfere with culture-based detection of Mycobacterium spp. due to inhibition of microbial growth, potentially leading to false-negative results in samples from patients currently receiving moxifloxacin.

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

Moxifloxacin is not recommended for the treatment of infections caused by MRSA. In suspected or confirmed MRSA infections, appropriate antibacterial therapy should be initiated (see section "Pharmacological properties").

Children

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

Information on excipients

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

This medicinal product contains less than 1 mmol sodium (23 mg) per film-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 in humans is not known.

Due to the risk of fluoroquinolone-induced joint damage 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").

Period of breastfeeding

Like other quinolones, moxifloxacin 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 effects on fertility (see section "Pharmacological properties").

Ability to influence reaction rate 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 impair the ability to drive or operate machinery due to central nervous system reactions (e.g., dizziness, acute transient visual loss, see section "Adverse reactions") or acute transient 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

Adults

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

Renal or hepatic impairment

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

There is insufficient 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

The 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 treatment with moxifloxacin tablets 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;
• Moderate to severe pelvic inflammatory disease – 14 days.

According to clinical studies, the duration of treatment with moxifloxacin tablets was up to 14 days.

Step-down (intravenous to oral) therapy

In 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 tablets and infusion solution 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 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 antidote is recommended. In the event of overdose, management should be based on clinical symptoms and include symptomatic and supportive therapy, as well as ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a single 400 mg oral dose of moxifloxacin reduces systemic bioavailability by more than 80%. In cases of oral overdose, early administration of activated charcoal during the initial phase of absorption 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) 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 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); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Table 3

System organ classes (MedDRA)	Common	Uncommon	Occasional	Rare	Frequency not known
Infections and infestations	Superinfection due to bacterial or fungal resistance, e.g. oral or vaginal candidiasis
Blood and lymphatic system disorders		Anemia, leukopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		Elevated prothrombin level/decreased INR, agranulocytosis, pancytopenia
Immune system disorders		Allergic reactions (see section "Special precautions")	Anaphylaxis, including rare cases of shock (life-threatening), allergic edema/angioedema, including laryngeal edema (potentially life-threatening) (see section "Special precautions")
Metabolism and nutrition disorders		Hyperlipidemia	Hypoglycemia, hypoglycemic coma	Hyperglycemia, hyperuricemia
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 precautions")), hallucinations, delirium	Depersonalization, psychotic reactions (with possible self-harm such as suicidal ideation/thoughts or suicide attempts)
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 disorders (including gait disturbance due to dizziness or vertigo), seizures with various clinical manifestations (including grand mal seizures (see section "Special precautions")), attention disorders, speech disorders, amnesia, peripheral neuropathy and polyneuropathy	Hyperesthesia
Eye disorders*		Visual disturbances, including diplopia and blurred vision (especially during CNS reactions (see section "Special precautions"))	Photophobia	Transient vision loss (especially during CNS reactions (see sections "Special precautions" and "Effect on ability to drive or use machinery")), uveitis and bilateral acute iris transillumination (see section "Special precautions")
Ear and labyrinth disorders*			Tinnitus, hearing disturbances including deafness (usually reversible)
Cardiac disorders**	QT interval prolongation in patients with hypokalemia (see sections "Contraindications" and "Special precautions")	QT interval prolongation (see section "Special precautions"), palpitations, tachycardia, atrial fibrillation, angina pectoris	Ventricular tachyarrhythmias, syncope (i.e. acute and transient loss of consciousness)	Non-specific arrhythmias, "torsade de pointes" ventricular tachycardia (see section "Special precautions"), cardiac arrest (see section "Special precautions")
Vascular disorders**		Vasodilation	Arterial hypertension, arterial hypotension	Vasculitis
Respiratory, thoracic and mediastinal disorders		Dyspnea (including asthmatic attack)
Gastrointestinal disorders	Nausea, vomiting, abdominal pain, diarrhea	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 precautions"))
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 precautions"))
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 precautions"))	Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions"), fixed drug eruption, photosensitivity reactions (see section "Special precautions")
Musculoskeletal and connective tissue disorders*		Arthralgia, myalgia	Tendinitis (see section "Special precautions"), muscle twitching, muscle cramps, muscle weakness	Tendon rupture, arthritis, muscle rigidity, exacerbation of symptoms in myasthenia gravis	Rhabdomyolysis
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Renal and urinary disorders		Dehydration	Renal function impairment (including increased blood urea nitrogen and plasma creatinine), renal failure (see section "Special precautions")
General disorders*		General weakness (mainly asthenia or fatigue), pain sensation (including back pain, chest pain, limb pain, pelvic pain), hyperhidrosis	Edema

* 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, difficulty walking, neuropathy associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration disturbances, 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 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 reported after treatment with other fluoroquinolones, which may possibly also occur during moxifloxacin use, include: hypernatremia, hypercalcemia, hemolytic anemia, and rhabdomyolysis.

Reporting suspected adverse reactions

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

All cases of adverse reactions must be reported to the manufacturer:

PHARMEKS GROUP LLC, Ukraine, 08301, Boryspil, Kyiv region, Shevchenka St., 100, tel.: +38(044)391-19-19, fax: +38(044)391-19-18, or via the form on the website: http://www.pharmex.com.ua/farmakonadzor.

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 tablets in a blister; 1 or 2 blisters per cardboard box.

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

Prescription status.

Prescription only.

Manufacturer.

PHARMEKS GROUP LLC.

Manufacturer's address and location of operations.

100, Shevchenka St., Boryspil, Kyiv region, 08301, Ukraine.