Atovax: detailed information

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

Composition:

Active substance: moxifloxacin (moxifloxacin);

One film-coated tablet contains 400 mg of moxifloxacin hydrochloride, calculated as moxifloxacin;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone K 29/32, magnesium stearate, Opadry 03F84827 pink* coating;

*Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), iron oxide red (E 172), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, pink in color, capsule-shaped, smooth on both sides.

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 activity of moxifloxacin is due to inhibition of two type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for bacterial DNA replication, transcription, and repair.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to the C8-H substituent. The presence of a bulky dicycloamine substituent 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 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. Decreased counts of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes including Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus. An increase in Bacteroides fragilis was observed. The numbers of the above-mentioned microorganisms returned to normal levels within two weeks.

Mechanism of resistance

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

Development of resistance to moxifloxacin in vitro occurs gradually through point mutations in both type II topoisomerases—DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux systems in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones may occur. However, since 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

Clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2011) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing)

Table 1

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 group 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 distribution of MICs for specific species. These data apply only to species for which specific breakpoints have not been defined and are not used for species in which interpretive criteria need to be determined.

Microbiological susceptibility

The frequency of acquired resistance may vary according to geographical location and over time, as defined for specific microorganism species. It is advisable to have access to information on local microbial resistance, especially when treating severe infections. Consultation with an expert in antimicrobial resistance should be sought if local resistance prevalence is so high that the efficacy of the 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 potential for developing resistance

Aerobic Gram-positive microorganisms

Enterococcus faecalis*

Enterococcus faecium*

Staphylococcus aureus (methicillin-resistant)+

Aerobic Gram-negative microorganisms

Enterobacter cloacae*

Escherichia coli*#

Klebsiella pneumoniae*#

Klebsiella oxytoca

Neisseria gonorrhoeae*+

Proteus mirabilis*

Anaerobic microorganisms

Bacteroides fragilis*

Peptostreptococcus spp.*

Resistant species

Aerobic Gram-negative microorganisms

Pseudomonas aeruginosa

* Adequate activity against susceptible strains has been demonstrated in clinical trials within approved clinical indications.

#Strains producing ESBL are usually resistant to fluoroquinolones.

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

Pharmacokinetics.

Absorption and bioavailability

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

When single doses of 50–800 mg and daily doses of 600 mg are administered for 10 days, pharmacokinetics are linear. Following an oral dose of 400 mg, maximum plasma concentration (Cmax) is achieved 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 almost 30% higher than after administration of the first dose.

Distribution

Moxifloxacin rapidly distributes into the extravascular space. After a 400 mg dose, the area under the concentration–time curve (AUC) is 35 µg·h/l. The volume of distribution at steady state is 2 l/kg. In vitro and ex vivo studies have shown that plasma protein binding is approximately 40–42% and independent of drug concentration. Moxifloxacin binds primarily to plasma albumin.

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

Table 2

Tissue	Concentration	Local level – plasma level
Plasma	3.1 mg/L	-
Saliva	3.6 mg/L	0.75–1.3
Vesicle contents	1.61 mg/L	1.71
Bronchial mucosa	5.4 mg/kg	1.7–2.1
Alveolar macrophages	56.7 mg/kg	18.6–70.0
Epithelial lining fluid	20.7 mg/L	5–7
Maxillary sinus	7.5 mg/kg	2.0
Ethmoid sinuses	8.2 mg/kg	2.1
Nasal polyps	9.1 mg/kg	2.6
Interstitial fluid	1.02 mg/L	0.8–1.42,3
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 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 feces/bile, both in unchanged form and as inactive metabolites: sulfates (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 did not reveal any metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation mediated by cytochrome P450 enzymes. There is no evidence of oxidative metabolism.

Elimination

The elimination half-life of the drug is approximately 12 hours. The mean total clearance after administration of 400 mg ranges from 179 to 246 ml/min. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug by the kidneys. After administration of a 400 mg dose, total 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) amounted to approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Pharmacokinetics in different patient groups.

Elderly patients and patients with low body weight

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

Renal impairment

No significant changes in moxifloxacin pharmacokinetics have been observed in patients with impaired renal function (including patients with creatinine clearance > 20 ml/min/1.73 m²). As renal function declines, the concentration of metabolite M2 (glucuronide) increases up to 2.5-fold (in patients with creatinine clearance < 30 ml/min/1.73 m²).

Hepatic impairment

Pharmacokinetic studies conducted in patients with hepatic insufficiency (Child-Pugh classes A–C) do not allow definitive conclusions regarding differences 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 moxifloxacin use for the treatment of patients with hepatic impairment.

Clinical characteristics.

Indications.

Due to the risk of prolonged, disabling, and potentially irreversible serious adverse reactions (see sections "Special warnings and precautions for use" and "Adverse reactions"), moxifloxacin should be used only when the use of other antibacterial agents is considered inappropriate. This applies to all the indications listed below.

Situations in which prescribing other antibacterial agents may be inappropriate:

resistance to other first-line antibacterial agents recommended for treatment of the infection;
other first-line antibacterial agents are contraindicated for a particular patient;
other first-line antibacterial agents have caused adverse reactions requiring discontinuation of treatment;
treatment with other first-line antibacterial agents has proven ineffective.

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

Acute bacterial sinusitis.
Exacerbations of chronic obstructive pulmonary disease, including bronchitis.
Community-acquired pneumonia, except severe community-acquired pneumonia.
Mild to moderate pelvic inflammatory disease (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 mild to moderate pelvic inflammatory disease but may be used in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin, except in cases where resistance of Neisseria gonorrhoeae to moxifloxacin can be excluded (see sections "Pharmacological properties" and "Special warnings and precautions for use").

The tablet form of moxifloxacin may be used to complete a treatment course in which initial therapy with intravenous 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.

Hypersensitivity to moxifloxacin or to other quinolones or to any of the excipients of the drug.
Pregnancy or breastfeeding (see section "Use during pregnancy or lactation").
Age under 18 years.
Patients with a history of tendon disorders related to quinolone therapy.

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

congenital or diagnosed acquired QT interval prolongation;
electrolyte imbalances, particularly uncorrected hypokalemia;
clinically significant bradycardia;
clinically significant heart failure with reduced left ventricular ejection fraction;
symptomatic arrhythmias in medical history.

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 the use of the drug, it is also contraindicated in patients with hepatic impairment (Child-Pugh class C) and in patients with elevated transaminase levels (more than 5 times above the upper limit of normal).

Interaction with other medicinal products and other forms of interaction.

Interactions with medicinal products

Medicinal products that may prolong the QT interval

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction increases the risk of ventricular arrhythmias, including torsades 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, vinca alkaloids IV, bepridil, difeminal).

Medicinal products that reduce potassium levels

Moxifloxacin should be administered 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.

Medicinal products containing bivalent or trivalent cations

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

Activated charcoal

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

Digoxin

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

Glibenclamide

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glibenclamide resulted in a reduction of glibenclamide peak concentration by approximately 21%. The combination of glibenclamide with moxifloxacin may theoretically lead to mild transient 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 glibenclamide has been identified.

Change in international normalized ratio (INR)

Numerous cases of increased anticoagulant activity have been reported in patients receiving oral anticoagulants in combination with antibacterial agents, including fluoroquinolones, macrolides, tetracyclines, cotrimoxazole, and certain cephalosporins. Risk factors include infectious diseases (and associated inflammatory processes), advanced age, and the patient's general condition. Due to these circumstances, it is difficult to determine whether the deviation in INR is caused by infection or treatment. More frequent monitoring of INR may be advisable. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

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

Interactions with food

No clinically significant interactions with food, including dairy products, have been observed for moxifloxacin.

Special precautions for use.

The use of moxifloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Side effects"). Treatment with moxifloxacin in such patients should only be initiated if no alternative treatment options are 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

In some patients, moxifloxacin may cause prolongation of the QT interval on electrocardiogram (ECG). Analysis of ECG results showed that QTc interval prolongation with moxifloxacin was 6 ms ± 26 ms (1.4% compared to baseline). Since women generally have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients may also be more susceptible to drug-related effects on the QT interval.

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

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

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

Increased sensitivity/allergic reactions

Cases of hypersensitivity and allergic reactions after first administration of fluoroquinolones, including moxifloxacin, have been reported. Anaphylactic reactions may manifest as life-threatening shock even after the first dose of the drug. In cases of clinically evident severe hypersensitivity reactions, moxifloxacin should be discontinued and appropriate therapy (e.g., anti-shock treatment) initiated.

Severe hepatic impairment

Cases of fulminant hepatitis potentially leading to liver failure, including fatal outcomes, have been reported during moxifloxacin treatment (see section "Side effects"). If symptoms of fulminant hepatitis occur, such as rapidly developing fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy, patients are advised to consult a physician before continuing treatment.

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

Severe skin reactions

Severe adverse 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 with moxifloxacin use, which may be life-threatening or fatal (see section "Side effects"). Patients should be informed about signs and symptoms of severe skin reactions and the need for close monitoring. If signs or symptoms suggestive of these reactions appear, moxifloxacin should be immediately discontinued and alternative treatment considered. If a patient develops a serious reaction such as SJS, TEN, AGEP, or DRESS during moxifloxacin treatment, re-administration of moxifloxacin is contraindicated.

Patients predisposed to seizures

Quinolones are known to provoke seizures. Moxifloxacin should be used with caution in patients with central nervous system (CNS) disorders or other risk factors that may cause 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 or sometimes multiple organ systems (musculoskeletal, nervous, and sensory systems, and organs of sense) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors. There are no effective pharmacological treatments for symptoms related to prolonged or disabling adverse reactions associated with fluoroquinolone use. At the first sign or symptom of any serious adverse reaction, moxifloxacin should be immediately discontinued and medical advice sought for proper evaluation and to avoid further exposure to the drug, which could worsen the reaction.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones or fluoroquinolones. Patients taking moxifloxacin should be advised to inform their physician of any developing neuropathic symptoms such as pain, burning, tingling, numbness, or weakness before continuing treatment to prevent potentially irreversible damage (see section "Side effects").

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 thoughts and self-harm, including suicide attempts (see section "Side effects"). If such reactions occur, moxifloxacin 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, with severity ranging from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin treatment. If AAD or AAC is suspected or confirmed, antimicrobial therapy, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. In addition, appropriate hygiene and infection control measures should be implemented to reduce the risk of transmission. Antiperistaltic agents are contraindicated in patients with severe diarrhea.

Patients with severe myasthenia gravis

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

Tendinitis and tendon rupture

Tendinitis and tendon ruptures (particularly of the Achilles tendon, but not exclusively) may occur within 48 hours of starting quinolone or fluoroquinolone therapy or even several months after discontinuation (see sections "Contraindications" and "Side effects"). Elderly patients, patients with renal impairment or organ transplants, and those receiving corticosteroids are at higher risk of developing tendinitis and tendon ruptures. Therefore, concomitant use of corticosteroids with moxifloxacin should be avoided.

If early signs of tendinitis (e.g., inflammation, swelling, and pain) occur, moxifloxacin should be discontinued and alternative treatment considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Aortic aneurysm/dissection, valvular regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves following fluoroquinolone use.

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Side effects").

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative treatment options in patients with a history of aortic aneurysm or congenital heart valve defect, or in patients with existing aortic aneurysm and/or dissection, heart valve disease, or other risk factors or conditions predisposing to their development:

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

The risk of aortic aneurysm/dissection and rupture may be increased in patients concurrently receiving corticosteroids.

If sudden abdominal, chest, or back pain occurs, patients should seek immediate emergency medical attention.

Patients should be advised to seek immediate medical help if acute dyspnea, new-onset palpitations, abdominal swelling, or lower limb edema occur.

Patients with renal impairment

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

Visual disturbances

If visual impairment or other effects on the visual organs occur, patients should immediately consult an ophthalmologist (see sections "Ability to affect reaction rate when driving or operating machinery" and "Side effects").

Dysglycemia

As with other fluoroquinolones, abnormalities in blood glucose levels, including hypoglycemia and hyperglycemia, have been observed with moxifloxacin use (see section "Side effects"). Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin.

Cases of hypoglycemic coma have been reported. Diabetic patients should be closely monitored for blood glucose levels (see section "Side effects").

Prevention of photosensitization reactions

Photosensitization reactions have been observed in patients receiving quinolones. However, studies have shown that moxifloxacin has a lower risk of photosensitization. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense sunlight exposure during moxifloxacin treatment (see section "Side effects").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase deficiency (known or familial history) are prone to hemolytic reactions when treated with quinolones. Therefore, moxifloxacin should be used with caution in such 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 Neisseria gonorrhoeae resistant to moxifloxacin cannot be fully excluded. If there is no clinical improvement after 3 days of treatment, therapy should be reassessed.

Patients with specific complicated skin and soft tissue infections

The clinical efficacy of intravenous moxifloxacin in the treatment of severe infections such as burn-related infections, fasciitis, and infected diabetic foot associated 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 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 MRSA. In cases of suspected or confirmed MRSA infection, 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

This medicinal product contains less than 1 mmol of 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. The potential risk to humans is unknown.

Due to the demonstrated risk of fluoroquinolone-induced joint damage in young animals (based on experimental data) and reported cases of reversible joint lesions in children treated with certain fluoroquinolones, moxifloxacin is contraindicated in pregnant women (see section "Contraindications").

Breastfeeding

There are no data on the use of moxifloxacin in breastfeeding women. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk.

Considering the lack of human data and the experimental evidence of risk to weight-bearing cartilage in immature animals, breastfeeding is contraindicated during moxifloxacin therapy (see section "Contraindications").

Fertility

Animal studies did not reveal any effect on fertility.

Ability to affect 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 CNS-related reactions such as dizziness, acute transient visual loss, or acute brief loss of consciousness (syncope) (see section "Side effects"). 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 medicinal product can be taken regardless of food intake.

Duration of Therapy

The duration of therapy 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 treatment duration with moxifloxacin tablets was up to 14 days.

Sequential (intravenous/oral) Therapy

During studies on 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 moxifloxacin in solution and tablet forms is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

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

Renal / Hepatic Impairment

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

There is insufficient data regarding patients with hepatic impairment (see also section "Contraindications").

Elderly Patients / Patients with Low Body Weight

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

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 required. Management should be based on clinical symptoms, including symptomatic and supportive therapy and ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with an oral 400 mg dose of moxifloxacin results in more than 80% reduction in systemic bioavailability of the drug. In cases of oral overdose, early administration of activated charcoal 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] therapy, and oral therapy) and in the post-marketing period. Adverse reactions are classified according to their frequency.

All adverse reactions occurred at a frequency of less than 3%, except for nausea and diarrhea. Within each group, adverse events are listed in decreasing order of severity. Frequency is defined as follows: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), occasional (≥1/10,000, <1/1000), rare (<1/10,000, including isolated cases), unknown (frequency cannot be estimated based on available data).

Table 3

System Organ Classes (MedDRA)	Common	Uncommon	Single	Rare	Unknown
Infections and infestations	Superinfection due to bacterial or fungal resistance, e.g. oral or vaginal candidiasis
Blood and lymphatic system disorders		Anaemia, leucopenia(e), neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		Elevated prothrombin level/decreased INR, agranulocytosis, pancytopenia
Immune system disorders		Allergic reactions (see section "Special warnings and precautions for use")	Anaphylaxis, including rare cases of shock (life-threatening), angioedema / angioneurotic oedema, including laryngeal oedema (potentially life-threatening) (see section "Special warnings and precautions for use")
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Hyperlipidaemia	Hypoglycaemia, hypoglycaemic coma	Hypoglycaemia, hypoglycaemic coma
Psychiatric disorders*		Anxiety reactions, increased psychomotor activity / restlessness	Mood lability, depression (in rare cases with possible self-harm such as suicidal ideation/thoughts or suicide attempts (see section "Special warnings and precautions for use")), hallucinations, delirium	Depersonalization, psychotic reactions (with possible self-harm such as suicidal ideation/thoughts or suicide attempts (see section "Special warnings and precautions for use"))
Nervous system disorders*	Headache, dizziness	Paraesthesia / dysaesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence	Hypoaesthesia, smell disturbances (including loss of smell), pathological dreams, coordination disorders (including gait disorder due to dizziness or vertigo), seizures with various clinical manifestations (including grand mal seizures (see section "Special warnings and precautions for use")), attention disturbances, speech disorders, amnesia, peripheral neuropathy and polyneuropathy	Hyperaesthesia
Eye disorders*		Visual disturbances, including diplopia and blurred vision (especially during CNS reactions (see section "Special warnings and precautions for use"))	Photophobia	Transient loss of vision (especially during CNS reactions (see section "Special warnings and precautions for use" and "Effect on ability to drive and use machines")), uveitis, acute bilateral iris transillumination (see section "Special warnings and precautions for use")
Ear and labyrinth disorders*			Tinnitus, hearing disturbances, including deafness (usually reversible)
Cardiac disorders**	QT interval prolongation in patients with hypokalaemia (see section "Special warnings and precautions for use" and "Contraindications")	QT interval prolongation (see section "Special warnings and precautions for use"), palpitations, tachycardia, atrial fibrillation, angina pectoris, vasodilation	Ventricular tachyarrhythmias, syncope (i.e. acute and transient loss of consciousness), arterial hypertension, arterial hypotension	Non-specific arrhythmias, torsade de pointes (see section "Special warnings and precautions for use"), cardiac arrest (see section "Special warnings and precautions for use"), vasculitis
Respiratory, thoracic and mediastinal disorders		Dyspnoea (including asthmatic attack)
Gastrointestinal disorders	Nausea, vomiting, abdominal pain, diarrhoea	Decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels	Dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, rarely associated with life-threatening complications (see section "Special warnings and precautions for use"))
Hepatobiliary disorders	Elevated transaminase levels	Liver function abnormalities (including elevated LDH (lactate dehydrogenase)), elevated bilirubin levels, elevated GGT (gamma-glutamyl transpeptidase), elevated alkaline phosphatase levels in blood	Jaundice, hepatitis (mainly cholestatic)	Fulminant hepatitis, potentially leading to life-threatening liver failure (including fatal outcomes (see section "Special warnings and precautions for use"))
Skin and subcutaneous tissue disorders		Itching, rash, urticaria, dry skin		Bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening (see section "Special warnings and precautions for use"))	Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), fixed drug eruption, photosensitivity reactions (see section "Special warnings and precautions for use")
Musculoskeletal and connective tissue disorders*		Arthralgia, myalgia	Tendinitis (see section "Special warnings and precautions for use"), tendon rupture (see section "Special warnings and precautions for use"), muscle twitching, muscle cramps, muscle weakness	Arthritis, muscle rigidity, exacerbation of symptoms of myasthenia gravis (see section "Special warnings and precautions for use")	Rhabdomyolysis
Renal and urinary disorders		Dehydration	Renal function impairment (including increased blood urea nitrogen and plasma creatinine), renal failure (see section "Special warnings and precautions for use")
General disorders*		General weakness (mainly asthenia or fatigue), pain sensation (including back pain, chest pain, limb pain, pelvic pain), hyperhidrosis	Swelling

In rare cases following treatment with other fluoroquinolones, the following adverse reactions have been reported, which might possibly also occur with moxifloxacin: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, and hemolytic anemia.

*Very rare, prolonged (for months or years), disabling and potentially irreversible serious adverse reactions affecting various systems or sensory organs, sometimes multiple, have been reported in patients receiving quinolones and fluoroquinolones, in some cases without identifiable risk factors (see section "Special warnings and precautions for use"). These adverse reactions may present as a range of psychiatric symptoms, which may include, but are not limited to, sleep disorders, anxiety, panic attacks, confusion, or depression. There are no pharmacological treatments known to be effective in alleviating symptoms of prolonged or disabling adverse reactions associated with fluoroquinolone use. The frequency of these prolonged, disabling, and potentially irreversible serious adverse reactions cannot be precisely estimated from available data, but the frequency derived from spontaneous adverse reaction reports suggests it is at least between 1/1000 and 1/10000 (corresponding to the category "rare").

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

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

7 tablets in a blister. 1 blister in a cardboard box.

10 tablets in a blister. 1 or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of its business activity.

40020, Ukraine, Sumy region, city of Sumy, Skryabina Street, 54.