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

Composition:

Active substance: moxifloxacin;

One film-coated tablet contains moxifloxacin (as moxifloxacin hydrochloride) 400 mg;

Excipients: microcrystalline cellulose (PH 102); sodium starch glycolate (type A); mannitol (E 421); magnesium stearate;

Film coating Opadry® Pink 85F240036 (polyvinyl alcohol; titanium dioxide (E 171); polyethylene glycol; talc; iron oxide red (E 172); iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

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

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

The C8-methoxy substituent is believed to enhance activity and reduce selection of resistant mutants among Gram-positive bacteria compared to C8-H substituents. The presence of a bulky dicycloamino side chain 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) generally correspond 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 numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus. An increase in Bacteroides fragilis was observed. The numbers of the above-mentioned microorganisms returned to normal within 2 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 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 systems in Gram-positive microorganisms.

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

Breakpoints

Clinical MIC values and disk diffusion breakpoints for moxifloxacin (01.01.2012) 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, groups A, B, C, G	≤ 0.5 mg/l ≥ 18 mm	> 1 mg/l < 15 mm
H. influenzae	≤ 0.5 mg/l ≥ 25 mm	> 0.5 mg/l < 25 mm
M. catarrhalis	≤ 0.5 mg/l ≥ 23 mm	> 0.5 mg/l < 23 mm
Enterobacteriaceae	≤ 0.5 mg/l ≥ 20 mm	> 1 mg/l < 17 mm
Non-species related breakpoints*	≤ 0.5 mg/l	> 1 mg/l

• Species-unrelated 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 species-specific breakpoints have not been defined and are not used for species where interpretive criteria are yet to be determined.

Microbial 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 in clinical studies within approved clinical indications.

Strains producing ESBLs are usually resistant to fluoroquinolones.

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

Preclinical safety data.

Effects on the hematopoietic system (mild reduction in red blood cells and platelets) were observed in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was noted in rats, monkeys, and dogs. Cases of neurotoxicity (CNS effects – seizures) were recorded in monkeys. These effects were observed only after administration of high doses of moxifloxacin or following prolonged treatment.

Moxifloxacin, like other quinolones, showed genotoxicity in in vitro tests with bacteria or mammalian cells. Since this effect is explained by interaction with bacterial gyrase and, at higher concentrations, with topoisomerase II in mammalian cells, a threshold concentration for genotoxicity can be assumed. No signs of genotoxicity were detected in in vivo tests, despite administration of high doses of moxifloxacin. Thus, moxifloxacin demonstrated an adequate safety potential when used at therapeutic doses for humans. Moxifloxacin did not show carcinogenic effects in studies conducted in rats.

Many quinolones are photoreactive and may provoke phototoxic reactions, as well as exhibit photomutagenic and photocarcinogenic effects. However, data indicate the absence of phototoxic and photogenotoxic properties of moxifloxacin when tested within a comprehensive program in both in vitro and in vivo studies. Under similar conditions, other quinolones have demonstrated such effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the cardiac delayed rectifier potassium current and may therefore lead to QT interval prolongation. Toxicological studies in dogs, in which moxifloxacin 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 exceeding the human dose by more than 50 times (> 300 mg/kg), resulting in plasma concentrations ≥ 200 mg/L (more than 40 times higher than 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 (for a 50 kg body weight), calculated based on dose/body weight ratio (mg/kg), with plasma concentrations two to three times higher than those expected with the maximum therapeutic dose.

Toxicity studies conducted in rats and monkeys (repeated dosing over periods up to 6 months) did not reveal any signs of risk to ocular organs. In dog studies, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L led to changes in electroretinograms and, in individual cases, to retinal atrophy.

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

Pharmacokinetics.

Absorption and bioavailability

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

Pharmacokinetics is linear within the dose range of 50–800 mg after single doses and at 600 mg daily for 10 days. 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.

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

Table 2

Tissue	Concentration	Local level – plasma blood level
Blood 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 hours to 36 hours after dose administration.

4 At the end of infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both in unchanged form and as inactive sulfate metabolite (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 metabolic pharmacokinetic interactions with other medicinal products involved in phase I biotransformation mediated by cytochrome P450 enzymes. There is no evidence of oxidative metabolism.

Elimination

The elimination half-life of moxifloxacin is approximately 12 hours. The mean total clearance after a 400 mg dose ranges from 179 to 246 mL/min. Renal clearance is approximately 24–53 mL/min, indicating partial tubular reabsorption in the kidneys. Following a 400 mg dose, excretion in urine (approximately 19% unchanged, approximately 2.5% as M1, and approximately 14% as M2) and in feces (approximately 25% unchanged, approximately 36% as M1, and no excretion as M2) totaled approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of moxifloxacin.

Elderly patients and patients with low body weight

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

Patients with renal impairment

No significant changes in the pharmacokinetics of moxifloxacin were observed in patients with renal impairment (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).

Patients with hepatic impairment

Based on pharmacokinetic data from studies involving patients with hepatic insufficiency (Child-Pugh classes A-C), it is not possible to determine whether there is a difference compared to healthy volunteers. Hepatic impairment was associated with higher plasma exposure of metabolite M1, whereas exposure to the parent drug was comparable to that in healthy volunteers. There is insufficient clinical experience with the use of moxifloxacin for the treatment of patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of the bacterial infections listed below, caused by microorganisms sensitive to moxifloxacin (see sections “Special precautions for use”, “Adverse reactions”, “Pharmacological properties”), in patients aged 18 years and older. Moxifloxacin should be used for the following indications only when it is considered inappropriate to use other antibacterial agents usually recommended for treatment of these infections:

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

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

• community-acquired pneumonia (excluding severe community-acquired pneumonia);
• moderate to severe 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 the treatment of moderate to severe pelvic inflammatory disease, 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 Neisseria gonorrhoeae) (see sections “Special precautions for use”, “Pharmacological properties”).

The tablet form of moxiflox游戏副本ин may be used to complete a course of treatment in which initial therapy with intravenous moxifloxacin was effective and indicated for:

• community-acquired pneumonia;
• complicated skin and skin structure infections.

The tablet form of moxifloxacin is not recommended for initial treatment of any skin and skin structure 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, other quinolones, or to any of the excipients of the medicinal product.
• History of tendon disorders related to treatment with quinolones.
• Concomitant use with medicinal products that prolong the QT interval (see section “Interaction with other medicinal products and other forms of interaction”).
• Hepatic impairment (Child-Pugh class C), elevated transaminase levels (more than 5 times the upper limit of normal).
• Pediatric age under 18 years.
• Pregnancy (see section “Use during pregnancy or breastfeeding”).
• Breastfeeding period (see section “Use during pregnancy or breastfeeding”).

During preclinical and clinical studies, changes in cardiac electrophysiology, such as QT interval prolongation, were observed after administration of moxifloxacin. Therefore, for safety reasons, the medicinal product is contraindicated in patients:

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

Interaction with other medicinal products and other forms of interaction.

Medicinal products that may cause QT interval prolongation

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. For this reason, concomitant use of moxifloxacin with any of the following medicinal products is contraindicated (see 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 antimicrobial agents (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials such as halofantrine);
• certain antihistamines (terfenadine, astemizole, mizolastine);
• others (cisapride, intravenous vinca alkaloids, bepridil, difemamil).

Medicinal products that may reduce potassium levels (e.g., loop and thiazide diuretics, enemas and laxatives in high doses, corticosteroids, amphotericin B), and medicinal products whose action is associated with clinically significant bradycardia.

Caution should be exercised when moxifloxacin is used concomitantly with such medicinal products.

Medicinal products containing bivalent or trivalent cations (such as antacids containing magnesium or aluminium, didanosine tablets, sucralfate, and medicinal products containing iron or zinc)

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 medicinal products containing iron or zinc) and moxifloxacin.

Activated charcoal

When activated charcoal is administered orally concomitantly with moxifloxacin 400 mg, its systemic bioavailability is reduced by more than 80% due to inhibition of absorption. Therefore, concomitant use of these agents is not recommended (except in cases of overdose, see section “Overdose”).

Oral anticoagulants

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 infectious diseases (and associated inflammatory processes), age, and general patient condition. Due to these circumstances, it is difficult to assess whether the infection or the treatment causes deviations in INR. As a precautionary measure, more frequent INR monitoring may be considered. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

Digoxin

Following repeated administration of moxifloxacin in healthy volunteers, an increase in Cmax of digoxin by approximately 30% at steady state was observed, without affecting AUC (area under the concentration-time curve) or trough levels. Therefore, no precautionary measures are required when these agents are used concomitantly.

Glibenclamide

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glibenclamide resulted in a reduction of the latter’s maximum concentration by approximately 21%. Concomitant use of glibenclamide with moxifloxacin may theoretically lead to mild, short-term hyperglycemia. However, the observed changes in pharmacokinetics did not result in changes in pharmacodynamic parameters (blood glucose levels, insulin levels). Thus, no clinically relevant interaction between moxifloxacin and glibenclamide has been identified.

Medicinal products 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.

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

Effect on diagnostic tests

Treatment with moxifloxacin may interfere with microbiological culture testing for detection of Mycobacterium spp. due to suppression of microbial growth, which in turn may lead to false-negative results in samples from patients currently receiving moxifloxacin.

Special precautions for use.

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

Avoid using the medicinal product in patients with a history of serious adverse reactions to quinolones or fluoroquinolone-containing agents (see section "Adverse reactions"). Treatment of such patients should only be initiated if no alternative therapy is available and after careful benefit-risk assessment (see also section "Contraindications").

Long-term, disabling and potentially irreversible serious adverse reactions

Rare cases of long-term (months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, psychiatric and sensory organs), regardless of age or presence of risk factors, have been reported with the use of quinolones and fluoroquinolones. If any initial symptoms or signs of a serious adverse reaction occur, the medicinal product should be discontinued immediately and the patient should seek medical advice.

Aneurysm / aortic dissection and cardiac valve regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Rare 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 only be used after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions

• both for aortic aneurysm and dissection, and for cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, 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 cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection and their rupture may be increased in patients concurrently receiving systemic corticosteroids.

Patients should seek immediate medical attention at an emergency department if sudden abdominal, chest or back pain occurs.

Patients should be advised to seek immediate medical help if acute shortness of breath, new onset palpitations, or development of abdominal or lower limb swelling occurs.

Prolongation of QTc interval and clinical conditions potentially associated with QTc prolongation

With moxifloxacin use, some patients may experience QT interval prolongation on electrocardiogram (ECG). Analysis of ECG results 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.

The medicinal product should be used with caution in patients taking agents that may lead to decreased potassium levels (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

The medicinal product should be used with caution in patients with ongoing proarrhythmic conditions (particularly women and elderly patients), such as acute myocardial ischemia or QT prolongation, as this may increase the risk of ventricular arrhythmias, including torsade de pointes, and cardiac arrest (see section "Contraindications").

The degree of QT 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.

Hypersensitivity reactions

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

Severe hepatic impairment

Cases of fulminant hepatitis, potentially leading to liver failure (including fatal outcomes), have been reported with moxifloxacin use (see section "Adverse reactions"). If signs and symptoms of fulminant hepatitis such as rapidly progressing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy occur, patients should seek medical advice before continuing treatment. If symptoms of liver dysfunction occur, liver function tests/investigations should be performed.

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), 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 "Adverse reactions"). Before prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If symptoms or signs characteristic of such reactions occur, the medicinal product should be discontinued immediately and alternative treatment considered. If serious reactions such as SJS, TEN, AGEP or DRESS occur during moxifloxacin use, the drug must not be re-administered at any time in the future.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia or weakness, have been reported with quinolones, including moxifloxacin. To prevent potentially irreversible damage, patients should seek medical advice if symptoms of neuropathy such as pain, burning, tingling, numbness or weakness occur (see section "Adverse reactions").

Psychiatric reactions

Psychiatric reactions may occur with quinolones, including moxifloxacin, even after the first dose. In rare cases, depression or psychotic reactions have led to suicidal thoughts and self-harming behavior, including suicide attempts (see section "Adverse reactions"). If such reactions occur, the medicinal product should be discontinued and appropriate measures taken. The medicinal product should be used with caution in patients with psychosis or a history of psychiatric disorders.

Antibiotic-associated diarrhea (AAD), 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, 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 treatment. If AAD or AAC is suspected or confirmed, antibacterial therapy, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. In addition, appropriate sanitary and epidemiological measures should be taken to reduce the risk of disease transmission. Antiperistaltic agents are contraindicated in patients with severe diarrhea.

Tendon inflammation and rupture

Tendon inflammation and rupture (particularly of the Achilles tendon), sometimes bilateral, may occur with quinolones, including moxifloxacin, even within the first 48 hours of administration. Cases have also been reported months after discontinuation of treatment (see sections "Contraindications" and "Adverse reactions"). The risk of tendon inflammation and rupture is increased during therapy with quinolones, including moxifloxacin, particularly in elderly patients, patients with renal impairment, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. The medicinal product should be avoided in such patients.

If symptoms of tendinitis (painful swelling, inflammation) occur, the medicinal product should be discontinued and alternative treatment considered. Appropriate management of the affected limb(s) (e.g., immobilization) should be initiated (see sections "Contraindications", "Adverse reactions"). Corticosteroids should not be used if symptoms of tendinopathy occur.

Visual disturbances

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

Dysglycemia

As with other fluoroquinolones, deviations in plasma glucose levels, including hypoglycemia and hyperglycemia, have been observed with moxifloxacin use (see section "Adverse reactions"). 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. Careful monitoring of plasma glucose levels is recommended in diabetic patients during treatment.

Photosensitivity reactions

Photosensitivity reactions may occur with quinolones. However, studies have shown that moxifloxacin has a lower risk of such reactions. Nevertheless, during treatment, exposure to both ultraviolet radiation and prolonged and/or intense sunlight should be avoided (see section "Adverse reactions").

Use in patients predisposed to seizures

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

Use in patients with severe myasthenia gravis

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

Use in patients with renal impairment

The medicinal product should be used with caution in elderly patients with renal dysfunction who are unable to maintain adequate fluid intake, as dehydration may increase the risk of renal failure.

Use in patients with glucose-6-phosphate dehydrogenase deficiency

Patients with a family or personal history of glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions during quinolone therapy. The medicinal product should be used with caution in such patients.

Use in patients with pelvic inflammatory disease

The medicinal product 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 completely ruled out. If there is no clinical improvement after 3 days of treatment, therapy should be re-evaluated.

Use in patients with severe skin and soft tissue infections

The clinical efficacy of intravenous moxifloxacin in the treatment of severe infections associated with burns, fasciitis, and diabetic foot complicated by osteomyelitis has not been established.

Use in 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").

Use in 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").

Precautions related to excipients

The medicinal product contains less than 1 mmol/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

The safety of moxifloxacin use during pregnancy has not been established. Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk in humans is not known. Due to the risk of fluoroquinolone-induced joint damage in young animals (based on experimental data) and reversible joint lesions described in children treated with certain fluoroquinolones, the medicinal product is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, causes damage to the cartilage of joints 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 medicinal product in breastfeeding women. The medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Animal studies did not reveal impaired fertility (see section "Pharmacological properties").

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

The medicinal product is intended for oral administration. The tablets should be taken whole, with sufficient water. The medicinal product can be taken independently of food intake.

Adults

The recommended dose is 400 mg (1 tablet) once daily.

Duration of Treatment

The duration of therapy with Moksykum 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 inflammatory diseases of the pelvic organs – 14 days.

According to clinical studies, the treatment duration with oral moxifloxacin formulation was up to 14 days.

Sequential (intravenous, oral) therapy

During 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 oral and parenteral treatment is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

It is not recommended to exceed the specified dose (400 mg once daily) or the treatment duration for each indication.

Elderly patients / patients with low body weight

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

Patients with hepatic impairment

There is no reliable information regarding patients with impaired liver function (see section "Contraindications").

Patients with renal 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").

Children

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

Overdose

In case of accidental overdose, no specific measures are recommended. Management should be based on clinical presentation and include symptomatic and supportive therapy, as well as ECG monitoring due to the potential for QT interval prolongation. Administration of activated charcoal at the early stage of absorption may be effective in preventing increased systemic exposure to moxifloxacin: co-administration of activated charcoal with a 400 mg oral dose of moxifloxacin reduces systemic availability of the drug by more than 80%.

Side effects

The following adverse reactions have been observed during clinical trials following administration of moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, step-down [intravenous/oral] and oral) and in the post-marketing period. Adverse reactions are classified according to their frequency. All adverse reactions occurred with a frequency of less than 3%, except for nausea and diarrhea. Within each group, adverse reactions are listed in order of decreasing severity. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Infections and infestations:

common – superinfection due to bacterial or fungal resistance (e.g. oral or vaginal candidiasis).

Blood and lymphatic system disorders:

uncommon – anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time / increased INR (International Normalized Ratio); very rare – elevated prothrombin levels / decreased INR, agranulocytosis, pancytopenia.

Immune system disorders:

uncommon – hypersensitivity reactions (see section "Special precautions"); rare – anaphylaxis (including rare cases of life-threatening shock), angioedema / allergic oedema (including potentially life-threatening laryngeal oedema) (see section "Special precautions").

Endocrine disorders:

very rare – syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Metabolism and nutrition disorders:

uncommon – hyperlipidaemia; rare – hyperglycaemia, hyperuricaemia; very rare – hypoglycaemia, hypoglycaemic coma.

Psychiatric disorders*:

uncommon – anxiety reactions, increased psychomotor activity / agitation; rare – mood lability, depression (in rare cases with possible self-harm such as suicidal ideation / thoughts or suicide attempts) (see section "Special precautions"), hallucinations, delirium; very rare – depersonalization, psychotic reactions (with possible self-harm such as suicidal ideation / thoughts or suicide attempts) (see section "Special precautions").

Nervous system disorders*:

common – headache, dizziness; uncommon – paraesthesia / dysaesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence; rare – hypoaesthesia, smell disturbances (including loss of smell), pathological dreams, coordination disorders (including gait disturbance due to dizziness or vertigo), seizures with various clinical presentations (including grand mal seizures) (see section "Special precautions"), attention disorders, speech disorders, amnesia, peripheral neuropathy and polyneuropathy; very rare – hyperaesthesia.

Eye disorders*:

uncommon – visual disturbances, including diplopia and blurred vision (particularly during CNS-related reactions) (see section "Special precautions"); rare – photophobia; very rare – transient loss of vision (particularly during CNS-related reactions) (see sections "Special precautions", "Effect on ability to drive and use machines"), uveitis, bilateral acute transient mydriasis (see section "Special precautions").

Ear and labyrinth disorders*:

rare – tinnitus, hearing disturbances (including deafness, usually reversible).

Cardiac disorders**:

common – QT interval prolongation in patients with hypokalaemia (see sections "Special precautions", "Contraindications"); uncommon – QT interval prolongation (see section "Special precautions"), palpitations, tachycardia, atrial fibrillation, angina pectoris; rare – ventricular tachyarrhythmias, syncope (i.e. acute and transient loss of consciousness); very rare – non-specific arrhythmias, torsade de pointes (see section "Special precautions"), cardiac arrest (see section "Special precautions").

Vascular disorders**:

uncommon – vasodilation; rare – arterial hypertension, arterial hypotension; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders:

uncommon – dyspnoea (including asthmatic condition).

Gastrointestinal disorders:

common – nausea, vomiting, gastrointestinal pain, abdominal pain, diarrhoea; uncommon – decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels; rare – dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, in rare cases associated with life-threatening complications) (see section "Special precautions").

Hepatobiliary disorders:

common – increased transaminase levels; uncommon – liver function abnormalities (including increased LDH [lactate dehydrogenase]), increased bilirubin levels, increased GGT (gamma-glutamyl transferase), increased alkaline phosphatase levels in blood; rare – jaundice, hepatitis (predominantly cholestatic); very rare – fulminant hepatitis potentially leading to life-threatening hepatic failure (including fatal outcomes) (see section "Special precautions").

Skin and subcutaneous tissue disorders:

uncommon – pruritus, rash, urticaria, dry skin; very rare – bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening) (see section "Special precautions"); not known – acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions"), fixed drug eruption, photosensitization reactions (see section "Special precautions").

Musculoskeletal and connective tissue disorders*:

uncommon – arthralgia, myalgia; rare – tendinitis (see section "Special precautions"), muscle twitching, muscle cramps, muscle weakness; very rare – tendon rupture (see section "Special precautions"), arthritis, muscle rigidity, exacerbation of symptoms of myasthenia gravis (see section "Special precautions"); not known – rhabdomyolysis.

Renal and urinary disorders:

uncommon – dehydration; rare – renal function impairment (including increased blood urea nitrogen and plasma creatinine), renal failure (see section "Special precautions").

General disorders*:

uncommon – general weakness (mainly asthenia or fatigue), pain (including back pain, chest pain, limb pain, pelvic pain), hyperhidrosis; rare – oedema.

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

* Very rare reports of prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple, organ systems (tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, anxiety, suicidal thoughts, panic attacks, neuralgia, difficulty concentrating, neuropathies with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, smell and taste) associated with quinolone and fluoroquinolone use, in some cases regardless of pre-existing risk factors (see section "Special precautions").

** In patients receiving fluoroquinolones, cases of aneurysm and dissection of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported (see section "Special precautions").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 25°C, in the original packaging and out of reach of children.

Packaging.

7 film-coated tablets in a blister. 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLDMEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.