AVELOX

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

Composition:

Active substance: moxifloxacin;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: red, matte, elongated film-coated tablets, 17 × 7 mm in size, marked with "BAYER" on one side and "M400" on the other.

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

ATC code J01M A14.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms. The bactericidal activity of moxifloxacin is due to inhibition of two type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for 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 C8-H substituents. 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. Minimum bactericidal concentrations (MBC) are generally equivalent to minimum 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 numbers of the above-mentioned microorganisms returned to normal levels within two weeks.

Mechanism of resistance

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

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

Cross-resistance with other fluoroquinolones 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)

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

Microbiological susceptibility

The frequency of acquired resistance may vary according to geographical region and over time, as defined for specific microorganisms. Local information on microbial resistance should be available, especially when treating severe infections. Expert advice on antimicrobial resistance should be sought if local resistance prevalence is so high that the efficacy of a particular medicinal product against certain 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 potential 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 trials 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 decrease in red blood cells and platelets) were observed in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was observed in rats, monkeys, and dogs. Neurotoxicity (CNS effects manifesting as seizures) was observed in monkeys. These effects were observed only after administration of high doses of moxifloxacin or prolonged treatment.

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

Many quinolones are photoreactive and may cause phototoxic reactions, as well as photomutagenic and photocarcinogenic effects. However, data from comprehensive testing programs, both in vitro and in vivo, indicate that moxifloxacin lacks phototoxic and photogenotoxic properties under conditions where other quinolones demonstrated such effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the delayed rectifier potassium current in cardiomyocytes and thus may lead to QT interval prolongation. Toxicological studies in dogs, in which the drug was administered orally at doses ≥ 90 mg/kg, resulting in plasma concentrations ≥ 16 mg/L, revealed QT interval prolongation without arrhythmias. Reversible non-lethal ventricular arrhythmias were observed only after intravenous administration of a high cumulative dose 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 in large diarthrodial joints in young animals. The lowest oral dose of moxifloxacin causing arthrototoxic effects in young dogs was four times higher than the maximum recommended therapeutic dose of 400 mg (based on a 50 kg body weight), calculated on the basis of dose/body weight ratio (mg/kg), with plasma concentrations two to three times higher than those expected with the maximum therapeutic dose.

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

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

Pharmacokinetics.

Absorption and bioavailability

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

Within the dose range of 50–800 mg after single doses and at a dose of 600 mg daily for 10 days, pharmacokinetics are linear. After a single 400 mg oral dose, peak blood 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, plasma protein binding is approximately 40–42% and is independent of drug concentration.

Table 2

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

*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 feces/bile, both in unchanged form and as inactive sulfate conjugates (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro studies and clinical phase I trials showed no evidence of metabolic pharmacokinetic interactions with other medicinal products involved in phase I biotransformation mediated by cytochrome P450 enzymes. There is no indication 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 in the kidneys. After administration of a 400 mg dose, overall elimination was approximately 96%, with urinary excretion (about 19% – unchanged drug, about 2.5% – M1, and about 14% – M2) and fecal excretion (about 25% – unchanged drug, about 36% – M1, and no excretion as M2). 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 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 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 metabolite M1, while exposure to the parent drug was comparable to that in healthy volunteers. There is insufficient clinical experience with the use of moxifloxacin in patients with hepatic impairment.

Clinical characteristics.

Indications.

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

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

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

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

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

Avelox® 400 mg film-coated tablets may be used to complete a course of treatment where initial therapy with intravenous Avelox® has been effective and was indicated for the following:

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

Avelox® 400 mg film-coated tablets are not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia.

Consideration should be given 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 in pregnancy or lactation").
• History of tendon disorders related to fluoroquinolone therapy.

In preclinical and clinical studies, administration of moxifloxacin has been associated with changes in cardiac electrophysiology manifesting as prolongation of the QT interval. Therefore, for safety reasons, the medicinal product is contraindicated in patients with:

• Congenital or diagnosed acquired prolonged QT interval;
• Electrolyte imbalances, particularly uncorrected hypokalaemia;
• 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 medicinal products that prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction").

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

Interaction with other medicinal products and other forms of interaction.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore, the use of moxifloxacin in combination 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);
• Antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• Tricyclic antidepressants;
• Certain antimicrobials (sacquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials such as halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Others (cisapride, vinca alkaloids IV, bepridil, difemanil).

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

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

Concomitant administration of activated charcoal and moxifloxacin 400 mg orally reduces systemic bioavailability of moxifloxacin 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 C_max of digoxin by approximately 30% was observed, without affecting AUC (area under the concentration-time curve) or trough concentrations. Therefore, no precautionary measures are required when digoxin is co-administered.

In studies involving volunteers with diabetes mellitus, concomitant oral administration of moxifloxacin and glyburide (glibenclamide) resulted in a reduction of peak glyburide concentration by approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to mild, transient hyperglycaemia. 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 effect have been reported in patients receiving oral anticoagulants in combination with antibacterial agents, including fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins. Risk factors include infection (and associated inflammatory response), age, and general condition of the patient. Due to these factors, it is difficult to determine whether infection or treatment causes deviations in INR. As a precaution, more frequent monitoring of INR may be considered. Dose adjustment of the oral anticoagulant should be performed as necessary.

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

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

Special precautions for use.

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

The benefits of moxifloxacin treatment, particularly in cases of mild infections, should be evaluated considering the information provided in this section.

QTc interval prolongation and clinical conditions associated with QTc prolongation

Prolongation of the QT interval on electrocardiogram may occur in some patients receiving moxifloxacin. Analysis of ECG data from clinical trial programs showed that QTc 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 taking moxifloxacin should use with caution medications that may lead to decreased potassium levels (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be administered with caution to 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 symptoms of arrhythmia occur during treatment, therapy should be discontinued and an ECG performed.

Hypersensitivity/allergic reactions

Cases of hypersensitivity and allergic reactions have been reported following the first 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 treatment).

Severe hepatic impairment

Cases of fulminant hepatitis, which may lead to liver failure (including fatal cases), have been reported during moxifloxacin treatment (see section "Adverse reactions"). If symptoms of fulminant hepatitis such as rapidly developing fatigue accompanied by jaundice, dark urine, 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 treatment (see section "Adverse reactions"), which may be life-threatening or fatal. Patients should be warned about the signs and symptoms of severe skin reactions, and closely monitored. If signs or symptoms suggestive of such reactions occur, moxifloxacin should be immediately discontinued and alternative therapy considered. If severe skin reactions such as SJS, TEN, AGEP, or DRESS develop during moxifloxacin therapy, re-administration of moxifloxacin to that patient 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 disorders or other risk factors that may provoke seizures or lower the seizure threshold. If seizures occur, moxifloxacin should be discontinued and appropriate measures taken.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of patient 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, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients receiving moxifloxacin should be advised to inform their physician if they experience 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 occur even after the first dose of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions progressed to suicidal thoughts and self-harming behaviors such as suicide attempts (see section "Adverse reactions"). If such reactions occur, moxifloxacin treatment 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-associated 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 treatment. If suspected or confirmed AAD or AAC occurs, antimicrobial treatment including moxifloxacin should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, appropriate infection control measures should be implemented to reduce the risk of transmission. Antiperistaltic agents are contraindicated in patients who develop severe diarrhea.

Patients with severe myasthenia

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

Tendon inflammation and tendon rupture

Tendon inflammation and ruptures (especially of the Achilles tendon), sometimes bilateral, may occur during therapy with quinolones and fluoroquinolones, developing within 48 hours of starting treatment and sometimes 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 with corticosteroids should be avoided.

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

Aortic aneurysm and aortic dissection, valve 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), as well as 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 aortic aneurysm or congenital heart valve defect, or in patients diagnosed with aortic aneurysm and/or aortic dissection, or with heart valve disease, as well as in the presence of other risk factors or conditions predisposing to aortic aneurysm and dissection, and valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos vascular type, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or also aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or also valve regurgitation/insufficiency (e.g., infective endocarditis).

The risk of developing aortic aneurysm and dissection, and their rupture, may be 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 shortness of breath, rapid heartbeat, or development of abdominal or lower limb swelling occurs.

Patients with renal impairment

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

Visual disturbances

In case of visual impairment or any effect on the eyes, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction rate when driving or operating machinery", "Adverse reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose deviations, both hypoglycemia and hyperglycemia, have been reported during moxifloxacin treatment (see section "Adverse reactions"). Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin with moxifloxacin therapy. 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 exposure to sunlight during moxifloxacin treatment (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as those with a family history of this condition, are prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in this patient group.

Patients with pelvic inflammatory disease

For patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess), for whom intravenous therapy is considered necessary, treatment with Avelox® 400 mg film-coated tablets is not recommended.

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 the treatment of severe infections associated with burns, fasciitis, and infected diabetic foot with osteomyelitis has not been established.

Effect on biological tests

Moxifloxacin treatment 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 receiving moxifloxacin.

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

Moxifloxacin is not recommended for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In case of 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

Patients with rare hereditary problems of galactose intolerance, total 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., is 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 has not been established.

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 must not be given to pregnant women (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, has been shown to cause joint 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 rate when driving or operating machinery.

Studies on the effect of moxifloxacin on the ability to drive and operate machinery have not been conducted. However, fluoroquinolones, including moxifloxacin, may impair the ability to drive and operate machinery due to central nervous system reactions (such as dizziness, acute transient visual loss, see section "Adverse reactions") or acute brief loss of consciousness (syncope, see section "Adverse reactions"). Patients should be advised to monitor their response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosage (Adults)

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

Renal 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 no reliable information regarding patients with hepatic impairment (see section "Contraindications").

Elderly Patients / Patients with Low Body Weight

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

Method of Administration

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

Duration of Therapy

The duration of treatment with the tablet form of the drug Avelox® 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 the tablet form of Avelox® was up to 14 days.

Sequential (Intravenous/Oral) Therapy

In clinical studies of sequential therapy, most patients switched from intravenous to oral administration of moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (complicated skin and soft tissue infections). The recommended total duration of treatment with Avelox® 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.

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 the clinical picture and include symptomatic 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 case of overdose following oral intake, administration of activated charcoal at the early stage 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 only, sequential [intravenous/oral], and oral regimens) 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 diarrhoea. 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 (≥ 1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

Table 3

* 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 tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration impairment, and disturbances of hearing, vision, taste and smell) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age and existing risk factors (see section "Special 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 cases of adverse reactions following treatment with other fluoroquinolones, which might possibly also occur during moxifloxacin use, include increased intracranial pressure (including idiopathic intracranial hypertension), hypernatraemia, hypercalcaemia, and haemolytic anaemia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

5 years.

Storage conditions.

Store in the original packaging to protect from moisture at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Bayer AG, Germany.

Bayer HealthCare Manufacturing S.r.l., Italy.

Manufacturer's address and place of business.

Kaiser-Wilhelm-Allee, 51368, Leverkusen, Germany.

Via delle Groane, 126-20024, Garbagnate Milanese, Italy.