INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Moflaxa® (Moflaxa®)

Composition:

Active substance: moxifloxacin;

One tablet contains 400 mg of moxifloxacin as moxifloxacin hydrochloride;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate;

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

Medicinal form. Film-coated tablets.

Main physicochemical properties: dark pink, film-coated, biconvex, capsule-shaped tablets.

Pharmacotherapeutic group.

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

ATC code J01M A14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Moxifloxacin is an 8-methoxyfluoroquinolone agent with a broad spectrum of bactericidal activity. In vitro, moxifloxacin is effective against many Gram-positive and Gram-negative microorganisms.

Moxifloxacin has been shown to be effective against bacteria resistant to β-lactam and macrolide agents.

The bactericidal action 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 substituent. The presence of a large dicyclic amine substituent at the C-7 position prevents active efflux mediated by norA or pmrA genes found in some Gram-positive bacteria.

Moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are generally equivalent 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 the anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, were reduced. An increase in Bacteroides fragilis was observed. The levels of the aforementioned microorganisms returned to normal within two weeks.

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 affect 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 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.

Clinical breakpoints

Table 1

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

*Species-unrelated breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the distribution of MICs 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 where interpretive criteria are subject to determination.

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.

When necessary, 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 is 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 during clinical trials within approved clinical indications.

Strains producing ESBLs are generally 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 is nearly 91%.

Within the dose range of 50–800 mg following single doses and at a dose of 600 mg daily for 10 days, pharmacokinetics are linear. Steady state is achieved within three days. After administration of a single 400 mg oral dose, 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.

Distribution

Moxifloxacin rapidly distributes into the extravascular space. After administration of 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, plasma protein binding is approximately 40–42% and is independent of moxifloxacin concentration.

Table 2

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

* 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 eliminated from the body via the kidneys as well as in feces/bile, both in unchanged form and as inactive sulfate 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 enzyme system in phase I biotransformation. There are no signs of oxidative metabolism.

Elimination

The elimination half-life of moxifloxacin 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 moxifloxacin in the kidneys. After administration of 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 moxifloxacin.

Pharmacokinetics in specific patient populations.

Elderly patients and patients with low body weight

Higher plasma concentrations of moxifloxacin have been reported in healthy volunteers with low body weight (particularly in women) and in healthy elderly volunteers.

Renal impairment.

No significant changes in the pharmacokinetics of moxifloxacin 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 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 impairment 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 moxifloxacin to recommend its use in 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 instructions", "Adverse reactions"), in patients aged 18 years and older.

Moxifloxacin should be prescribed only when the use of antibacterial agents usually recommended for the following indications is considered inappropriate:

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

Moxifloxacin should be prescribed only when the use of antibacterial agents usually recommended for initial treatment of the following indications is considered inappropriate or has been ineffective:

• Community-acquired pneumonia, excluding severe community-acquired pneumonia.
• Mild to moderate pelvic inflammatory diseases (such as infectious involvement of the upper genital tract in women, including salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses.

The tablet form of Mofoxaca® is not recommended for use as monotherapy in mild to moderate pelvic inflammatory diseases, but may be used in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of moxifloxacin to Neisseria gonorrhoeae (except for moxifloxacin-resistant strains of N. gonorrhoeae) (see sections "Pharmacological properties", "Special instructions").

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

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

The tablet form of Mofoxaca® 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 during pregnancy or breastfeeding").
• History of tendon disorders related to treatment with quinolones.
• Congenital or diagnosed acquired QT interval prolongation.
• Electrolyte imbalance, 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 drugs that prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction").

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

Interaction with other medicinal products and other forms of interaction.

Interaction with medicinal products

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may lead to an increased risk of ventricular arrhythmias, including torsade de pointes. Therefore, the use of moxifloxacin in combination with any of the following medicinal products is contraindicated (see also section "Contraindications"):

• Class IA antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Antipsychotic agents (e.g., phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• Tricyclic antidepressants;
• Certain antimicrobial agents (sildenafil, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, including halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Others (cisapride, intravenous vinca alkaloids, 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 (in 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 intake of products containing divalent or trivalent cations (such as antacids containing magnesium or aluminum, didanosine tablets, sucralfate, and iron or zinc-containing preparations) and moxifloxacin.

When activated charcoal and moxifloxacin are administered orally at a dose of 400 mg, systemic bioavailability of moxifloxacin is reduced by more than 80% due to inhibition of 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% at steady state was reported, without affecting AUC (area under the concentration-time curve) or trough levels. Therefore, no precautionary measures are required when digoxin is co-administered.

There have been reports from studies involving diabetic volunteers that concomitant oral administration of moxifloxacin and glyburide resulted in a decrease in peak glyburide concentration of approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to mild, short-term hyperglycemia. However, the pharmacokinetic changes observed 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 general patient condition. Due to these circumstances, it is difficult to determine whether infection or treatment causes deviations in INR (international normalized ratio). 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 confirmed the above. Based on these results, metabolic interaction via cytochrome P450 enzymes is unlikely.

Interaction with food and dairy products

Absorption of moxifloxacin is not affected by food intake (including dairy products). Therefore, moxifloxacin may be administered independently of meals.

Special precautions for use.

Avoid using moxifloxacin in patients who have previously experienced serious adverse reactions to drugs containing quinolone or fluoroquinolone (see section "Adverse reactions"). Treatment with moxifloxacin should be initiated in such patients only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

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 dose. In cases of clinical manifestations of severe hypersensitivity reactions, the drug should be discontinued immediately and appropriate therapy (e.g., anti-shock treatment) initiated.

QTc interval prolongation and clinical conditions associated with QTc prolongation

Prolongation of the QT interval on electrocardiogram has been observed in some patients receiving moxifloxacin. Analysis of ECG data from clinical trials 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 drugs that may lead to hypokalemia (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be used cautiously in patients with ongoing proarrhythmic conditions (especially 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.

The benefit of moxifloxacin treatment, especially in mild infections, should be carefully weighed according to the information provided in this section "Special precautions for use".

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

Aortic aneurysm and dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart 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 aneurysm or congenital heart valve defects, or diagnosed aortic aneurysm and/or dissection, or valvular heart disease, or in the presence of other risk factors or predisposing conditions:

• for both aortic aneurysm and dissection and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or additionally
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or additionally
• for valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and rupture may be increased in patients receiving concomitant systemic corticosteroids.

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, new-onset palpitations, or development of abdominal or lower limb edema occurs.

Severe hepatic impairment

Cases of fulminant hepatitis, potentially leading to hepatic failure (including fatal outcomes), have been reported with moxifloxacin use (see section "Adverse reactions"). Patients should be advised to consult a physician before continuing treatment if symptoms of fulminant hepatitis develop, such as jaundice-associated asthenia, rapidly progressing fatigue, dark urine, tendency to bleeding, or hepatic encephalopathy.

If symptoms of liver dysfunction occur, liver function tests and examinations should be performed.

Severe skin adverse reactions

Severe skin adverse reactions (SSARs), 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), which may be life-threatening or fatal, have been reported with moxifloxacin use (see section "Adverse reactions"). Patients should be informed about signs and symptoms of SSARs and closely monitored. If signs or symptoms suggestive of these reactions occur, moxifloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN, AGEP, or DRESS during moxifloxacin treatment, moxifloxacin therapy must never be restarted.

Patients predisposed to seizures

Quinolones are known to provoke seizures. Moxifloxacin 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

Very rare cases of prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting multiple systems (musculoskeletal, nervous, psychiatric, and sensory systems), sometimes involving several systems simultaneously, have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors. Moxifloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should consult a physician.

Peripheral polyneuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. To prevent potentially irreversible conditions, patients receiving moxifloxacin should be advised to consult a physician immediately if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop (see section "Adverse reactions").

Psychiatric reactions

Psychiatric reactions may occur even after the first dose of quinolones, including moxifloxacin. In rare cases, depression or psychotic reactions have led to suicidal ideation and self-harm, including suicide attempts (see section "Adverse reactions"). If such reactions occur, moxifloxacin should be discontinued and appropriate measures taken.

Moxifloxacin should be prescribed with caution in patients with psychosis or a history of psychiatric disorders.

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 broad-spectrum antibiotics, including moxifloxacin. The severity ranges from mild diarrhea to fatal colitis. This diagnosis should be considered in patients who develop severe diarrhea during or after moxifloxacin treatment. If AAD or AAC is suspected or confirmed, antibacterial therapy, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. In addition, appropriate sanitary and epidemiological measures should be taken to reduce the risk of transmission. Antiperistaltic agents are contraindicated in patients with severe diarrhea.

Patients with myasthenia gravis

Moxifloxacin should be used with caution in patients with myasthenia gravis due to the potential for symptom exacerbation.

Tendon inflammation and rupture

Tendon inflammation and rupture (especially Achilles tendon), sometimes bilateral, may occur during treatment with quinolones and fluoroquinolones, even within the first 48 hours of therapy initiation. Cases have also been reported several months after treatment discontinuation. There is an increased risk of tendon inflammation and rupture during therapy with quinolones, including moxifloxacin, particularly 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 symptoms of tendinitis such as pain, swelling, or inflammation occur, moxifloxacin treatment should be discontinued and alternative therapy considered. The affected limb(s) should receive appropriate treatment (e.g., immobilization). Corticosteroids should not be used in cases of tendinopathy.

Patients with renal impairment

Moxifloxacin should be used with caution in elderly patients with renal dysfunction who cannot ensure adequate fluid intake, as dehydration may increase the risk of renal failure.

Visual disturbances

If visual disturbances or other effects on the eyes occur, patients should seek immediate ophthalmological consultation (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").

Prevention of photosensitization reactions

Photosensitivity 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 sunlight exposure during moxifloxacin treatment (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with familial or personal history of glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in such patients.

Information on excipients

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

Patients with pelvic inflammatory disease

Oral treatment with Moflaxa® 400 mg tablets 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 Neisseria gonorrhoeae resistant to moxifloxacin cannot be fully excluded.

If there is no clinical improvement after 3 days of treatment, therapy should be re-evaluated.

Children

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

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

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

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 with osteomyelitis has not been established.

Impact on biological tests

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

Dysglycemia

As with other fluoroquinolones, alterations in blood glucose levels, including hypoglycemia and hyperglycemia, have been observed with moxifloxacin, usually in diabetic patients concomitantly receiving oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels (see section "Adverse reactions").

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 not 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, has been shown to cause cartilage damage in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on moxifloxacin use in breastfeeding women. Therefore, moxifloxacin is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Animal studies did not reveal any adverse effect 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 effects (such as dizziness, acute transient vision 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.

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

Duration of Therapy

The duration of treatment with the tablet form of Moxyflox® depends on the type of infection and is as follows:

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

Sequential (intravenous and oral) therapy

During clinical studies of sequential 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 duration of treatment for each indication should not be exceeded.

Elderly patients / patients with low body weight

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

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment (see also section "Special Warnings and Precautions for Use").

Renal impairment

Dose adjustment is not required in patients with mild to severe renal impairment (including creatinine clearance < 30 mL/min/1.73 m²), as well as in patients undergoing continuous hemodialysis or long-term ambulatory peritoneal dialysis (see section "Pharmacological Properties").

Children

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

Overdose

In case of accidental overdose, no specific antidotes are recommended. Management should be based on clinical symptoms and include symptomatic and supportive therapy 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 bioavailability by more than 80%. In cases of oral overdose, early administration of activated charcoal may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions

Below is a list of adverse effects reported from all clinical studies using moxifloxacin 400 mg (intravenous therapy only, sequential therapy [intravenous and oral], and oral therapy) as well as post-marketing reports. Adverse reactions are classified according to their frequency of occurrence. All adverse reactions were observed at a frequency of less than 3%, except for nausea and diarrhea. Within each category, adverse events are listed in order of decreasing severity. Frequency is defined as follows: common > 1% < 10%, uncommon > 0.1% < 1%, rare > 0.01% < 0.1%, very rare < 0.01%.

Table 3

1See section "Special precautions".

2Very rare cases of long-lasting (months or years), disabling and potentially irreversible serious adverse reactions affecting multiple, sometimes numerous, organ systems and sensory organs have been reported following the use of quinolones and fluoroquinolones, including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy (associated with paresthesia and neuralgia), fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, and worsening of hearing, vision, taste, and smell. These have occurred in some cases regardless of the presence of risk factors (see section "Special precautions").

3See sections "Special precautions", "Effect on ability to drive and use machines".

4Aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Special precautions").

Rare cases of adverse reactions following treatment with other fluoroquinolones, which may also possibly occur with moxifloxacin, include increased intracranial pressure (including idiopathic intracranial hypertension), hypernatraemia, hypercalcaemia, and haemolytic anaemia.

5See sections "Contraindications", "Special precautions".

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives are requested to report all suspected adverse reactions and lack of efficacy of the medicine via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from moisture. No special temperature storage conditions are required for this medicinal product. Keep out of the reach of children.

Packaging.

5 tablets in a blister; 1 blister in a cardboard box;

7 tablets in a blister; 1 or 2 blisters in a cardboard box;

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

Prescription status.

Prescription only.

Manufacturers.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

KRKA-Farma d.o.o., Croatia / KRKA-Farma d.o.o., Croatia.

TAD Pharma GmbH, Germany / TAD Pharma GmbH, Germany.

Manufacturers' locations and addresses of business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

V. Holjevca 20/E, 10450 Jastrebarsko, Croatia / V. Holjevca 20/E, 10450 Jastrebarsko, Croatia.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany / Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.