INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Moxifloxacin (MOXIFLOXACIN)

Composition:

Active substance: moxifloxacin (moxifloxacin);

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

Excipients: sodium croscarmellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, coating (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, iron oxide red (E 172), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped tablets, convex on both upper and lower surfaces, with a break line on one side, coated with a pink film coating.

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

ATC code J01MA14.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms. The bactericidal effect of moxifloxacin is due to inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for 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 C8-H substituents. The presence of a bulky dicyclic amino group at the C-7 position prevents active efflux mediated by the norA or pmrA genes found in some Gram-positive bacteria.

Pharmacodynamic studies indicate that moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are generally equivalent to minimal inhibitory concentrations (MIC).

Effect on intestinal flora in humans

In two studies involving healthy volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. Decreased numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes including Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, were noted. An increase in Bacteroides fragilis was observed. The numbers of the aforementioned microorganisms returned to normal 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 has been observed as a gradual process involving point mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux mechanisms in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones occurs. However, because moxifloxacin inhibits both 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 according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) (01.01.2024)

Species-specific breakpoints have been established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the distribution of MICs of specific species. The following breakpoints are defined: susceptible ≤ 0.25 mg/L; resistant > 0.25 mg/L. These breakpoints apply only to species for which species-specific breakpoints have not been established, and should not be used for species where interpretive criteria are yet to be determined.

Microbiological susceptibility

The frequency of acquired resistance in certain microbial species may vary with geographical location and over time. Local information on microbial resistance patterns should be consulted, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is so high that the efficacy of a particular antimicrobial agent against some infectious pathogens becomes questionable.

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

Strains producing extended-spectrum beta-lactamases are generally 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. Neurotoxicity (central nervous system [CNS] effects, including seizures) was observed in monkeys. These effects were observed only after administration of high doses of moxifloxacin or prolonged treatment.

Moxifloxacin, like other quinolones, showed genotoxicity in in vitro tests with bacteria or mammalian cells. Since this effect is explained by interaction with bacterial gyrase and, at higher concentrations, with mammalian topoisomerase II, a threshold concentration for genotoxicity can be assumed. No signs of genotoxicity were observed in in vivo tests, even with high doses of moxifloxacin. Thus, the drug demonstrates sufficient safety potential for humans when used at therapeutic doses. Moxifloxacin showed no carcinogenic effect 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 both in vitro and in vivo. Under the same conditions, other quinolones demonstrated such effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the delayed rectifier potassium current (I_Kr) in cardiomyocytes and thus may lead to QT interval prolongation. Toxicological studies in dogs receiving oral doses ≥ 90 mg/kg, achieving plasma concentrations ≥ 16 mg/L, revealed QT interval prolongation without arrhythmias. Reversible non-lethal ventricular arrhythmia was 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 higher than the therapeutic level).

It is known that quinolones cause cartilage damage in large diarthrodial joints in young animals. The lowest oral dose of moxifloxacin causing arthrotoxic effects in young dogs was four times higher than the maximum recommended therapeutic dose of 400 mg (based on a 50 kg body weight), when normalized to body weight (mg/kg), and resulted in 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) revealed no risk to ocular organs. 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 (administered moxifloxacin orally and intravenously) and monkeys (administered moxifloxacin orally) revealed no teratogenic effects 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 following administration of moxifloxacin at therapeutic doses. In rats, reduced fetal weight, increased abortion rates, slightly prolonged gestation period, and increased spontaneous activity in offspring were observed at moxifloxacin doses 63 times higher than the recommended doses.

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 600 mg daily for 10 days, pharmacokinetics are linear. Following a single 400 mg oral dose, peak plasma concentration is reached within 0.5–4 hours and amounts to 3.1 mg/L. Maximum and minimum plasma concentrations at steady state (400 mg once daily) are 3.2 mg/L and 0.6 mg/L, respectively. At steady state, exposure over the dosing interval is approximately 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. In vitro and ex vivo experiments indicate that 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

| Tissue/Fluid | Peak Concentration (mg/L or mg/kg) | Sampling Time (h) | |--------------|------------------------------------|-------------------| | Plasma | 3.1 | 1–2 | | Bronchial mucosa | 7.9 | 6 | | Lung tissue | 4.4 | 6 | | Alveolar macrophages | 22.0 | 6 | | Epithelial lining fluid | 2.8 | 6 | | Sinus mucosa | 4.6 | 6 | | Skin | 2.8 | 3–6 | | Abdominal tissue | 3.1 | 3–6 | | Female genital tract tissue | 3.1 | 3–6 | | Prostate | 2.5 | 6 | | Tonsils | 3.1 | 6 | | Cerebrospinal fluid^a | 0.26 | 4 |

^a Data from patients with inflamed meninges.

*Intravenous administration of a single 400 mg dose.

1 10 hours after administration.

2 Free concentration.

3 From 3 hours to 36 hours after dose administration.

4 At the end of the infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both in unchanged form and as inactive sulfate conjugate (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 drugs 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 by the kidneys. After a 400 mg dose, excretion in urine (approximately 19% — unchanged drug, approximately 2.5% — M1, approximately 14% — M2) and feces (approximately 25% — unchanged drug, approximately 36% — M1, 0% — M2) totaled approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Elderly patients and patients with low body weight

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

Renal impairment.

No significant changes in moxifloxacin pharmacokinetics 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 for the treatment of patients with hepatic impairment.

Clinical characteristics.

Indications.

To be prescribed to adult patients (aged 18 years and older) for the treatment of the following bacterial infections caused by microorganisms sensitive to moxifloxacin (see sections "Special precautions for use", "Adverse reactions", "Pharmacological properties").

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

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

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

• Community-acquired pneumonia, excluding severe community-acquired pneumonia.
• Moderate to severe pelvic inflammatory diseases (including infectious involvement of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. In such cases, Moxifloxacin, film-coated tablets, are not recommended for use as monotherapy, but may be used (except in cases of infection with Neisseria gonorrhoeae strains resistant to moxifloxacin) in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin (see sections "Special precautions for use", "Pharmacological properties").

Moxifloxacin, film-coated tablets, may be used to complete a treatment course in which initial therapy with intravenous moxifloxacin has been effective for the following indications:

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

The medicinal product is not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia.

Official guidelines on appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to moxifloxacin or to other quinolones, or to any of the excipients of the medicinal product.
• Age under 18 years.
• Pregnancy or breastfeeding (see section "Use during pregnancy or lactation").
• History of tendon disorders related to quinolone therapy.

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;
• Electrolyte imbalances, particularly uncorrected hypokalemia;
• 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 drugs that prolong the QT interval (see section "Interaction with other medicinal products and other types of interactions").

Due to limited clinical data, the use of 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 types of interactions.

An additive effect between 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 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, difemanyl.

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

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

When activated charcoal and moxifloxacin are administered orally at a dose of 400 mg, the systemic bioavailability of moxifloxacin is reduced by more than 80% due to inhibition of its absorption. Therefore, concomitant use of these two agents is not recommended (except in cases of overdose; see also section "Overdose").

After repeated administration of moxifloxacin in healthy volunteers, an increase in digoxin Cmax by approximately 30% was observed, without affecting AUC (area under the concentration-time curve) or minimum concentrations. Therefore, no preventive measures are required when digoxin is co-administered.

In studies involving volunteers and patients with diabetes mellitus, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of peak glyburide concentration by approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to mild, transient hyperglycemia. However, the observed pharmacokinetic changes did not result in changes in pharmacodynamic parameters (blood glucose levels, insulin levels). Thus, no clinically relevant interaction between moxifloxacin and glyburide has been identified.

Change in international normalized ratio (INR)

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

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

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

Special precautions for use.

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

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

QTc interval prolongation and clinical conditions associated with QT interval prolongation

Use of moxifloxacin may result in QT interval prolongation on the electrocardiogram in some patients. Analysis of ECG data from clinical trials showed that QTc prolongation with moxifloxacin was 6 ms ± 26 ms (1.4%) compared to baseline. Since women 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 the drug's effect on the QT interval.

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

Moxifloxacin should be used with caution in patients with proarrhythmic conditions (particularly in women and elderly patients), such as acute myocardial ischemia or prolonged QT interval, 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 with moxifloxacin, treatment should be discontinued and an ECG should be performed.

Increased sensitivity / allergic reactions

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

Severe liver dysfunction

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

Liver function tests should be performed if signs of liver dysfunction appear.

Severe skin reactions

Cases of 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 syndrome), some of which were life-threatening or fatal, have been reported during moxifloxacin use (see section "Adverse reactions"). Patients should be warned about signs and symptoms of severe skin reactions, and closely monitored. If symptoms suggestive of such reactions occur, moxifloxacin should be immediately discontinued and alternative treatment considered. If a patient develops severe skin reactions such as SJS, TEN, AGEP, or DRESS syndrome during moxifloxacin therapy, re-administration of moxifloxacin to this patient is absolutely contraindicated.

Patients predisposed to seizures

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

Prolonged, disabling, and potentially irreversible serious adverse reactions

Rare cases of prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of patient age or presence of risk factors. Moxifloxacin should be immediately discontinued at the first signs of any serious adverse reaction, and patients should be advised to consult a physician.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients receiving moxifloxacin should be advised to inform their physician about 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 therapy should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with psychiatric disorders or a history thereof.

Antibiotic-associated diarrhea, including colitis

Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-induced diarrhea, have been observed during treatment 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 therapy, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. 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 gravis

Moxifloxacin should be used with caution in patients with severe 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 or even 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 of the affected limb(s) (e.g., immobilization) should be initiated. Corticosteroids should not be used if symptoms of tendinopathy develop.

Aortic aneurysm and aortic dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, and development of regurgitation on aortic and mitral valves following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal), and regurgitation/insufficiency of any cardiac 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. Factors predisposing to aortic aneurysm, aortic dissection, and valvular regurgitation/insufficiency include connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis; risk factors for aortic aneurysm and dissection include vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome; risk factors for valvular regurgitation/insufficiency include infective endocarditis.

The risk of aortic aneurysm and dissection, as well as rupture, is increased in patients receiving concomitant systemic corticosteroid therapy.

In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention.

Patients are advised to seek immediate medical help if acute dyspnea, tachycardia, or development of abdominal or lower limb edema 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 deterioration or any effect on the eyes, immediate consultation with an ophthalmologist is required (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").

Dysglycemia

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

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase 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 these patients.

Patients with pelvic inflammatory disease

Moxifloxacin 400 mg film-coated tablets are 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, when empirically using moxifloxacin, another appropriate antibiotic (e.g., a cephalosporin) should be co-administered 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.

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.

Effect on biological tests

Moxifloxacin use may interfere with microbiological testing for Mycobacterium spp. due to inhibition of mycobacterial growth, potentially leading to false-negative results.

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

Due to the presence of lactose, this medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

The safety of moxifloxacin use during pregnancy has not been established.

Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk for humans has not been established.

Since fluoroquinolones are known to damage weight-bearing joints in young animals (based on experimental data) and cases of reversible joint damage in children treated with certain fluoroquinolones have been reported, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, is known to cause cartilage damage in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on 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 influence reaction rate when driving or operating machinery.

No studies on the effect of moxifloxacin on the ability to drive or operate machinery have been conducted. However, fluoroquinolones, including moxifloxacin, may impair the ability to drive or operate machinery due to central nervous system reactions such as dizziness, acute transient visual loss, or acute short-term loss of consciousness (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 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 section "Contraindications").

Elderly Patients / Patients with Low Body Weight

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

Method of Administration

Tablets should be swallowed whole with plenty of water. The medicinal product can be taken regardless of food intake.

Duration of Therapy

The duration of therapy depends on the type of infection and is as follows:

• for acute exacerbation of chronic obstructive pulmonary disease, including bronchitis — 5–10 days;
• for community-acquired pneumonia — 10 days;
• for acute bacterial sinusitis — 7 days;
• for moderate to severe pelvic inflammatory disease — 14 days.

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

Step-down (Intravenous/Oral) Therapy

In clinical trials of step-down therapy, most patients switched from intravenous to oral administration of moxifloxacin within 4 days (for community-acquired pneumonia) or 6 days (for complicated skin and skin structure infections). The recommended total duration of treatment with moxifloxacin tablets and infusion solution is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and skin structure infections.

The recommended dose (400 mg once daily) and treatment duration for each indication should not be exceeded.

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

Overdose.

In case of accidental overdose, no specific measures are recommended. Management should be based on clinical presentation and include symptomatic and supportive therapy, along with ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin reduces systemic availability of the drug by more than 80%. In cases 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 diarrhea. 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, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Table 3

Description of individual adverse reactions

* Rare cases of prolonged (lasting for several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, difficulty walking, neuropathy associated with paresthesia, neuralgia, depression, suicidal thoughts, anxiety, panic attacks, fatigue, memory impairment, difficulty concentrating, sleep disorders, and disturbances of hearing, vision, taste, and smell) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age or presence of risk factors (see section "Special precautions for use").

** Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal outcomes), as well as regurgitation/insufficiency of any cardiac valve have been reported in patients treated with fluoroquinolones (see section "Special precautions for use").

Rare adverse reactions reported after treatment with other fluoroquinolones (these adverse reactions may also potentially occur with moxifloxacin) include: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, and hemolytic anemia.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 5 or 10 tablets in a blister pack, 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Lubnifarm".

Manufacturer's address and location of its business activity. 16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.