Trajectol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Traektol (Traektol)

Composition:

Active substance: moxifloxacin;

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

Excipients: microcrystalline cellulose, sodium croscarmellose, povidone, magnesium stearate, film coating: Opadry II 85F23452 (polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol, talc, FD&C Yellow #6 / Sunset Yellow FCF Aluminum Lake (E 110), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, light orange in color, capsule-shaped, biconvex.

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 replication, transcription, and repair of bacterial DNA.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to the C8-H substituent. The presence of a bulky dicycloamine substituent at position C-7 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. The minimum bactericidal concentration (MBC) usually corresponds to the minimum inhibitory concentration (MIC).

Effect on intestinal flora in humans

In two studies involving adult 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 of 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 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 may occur. However, since moxifloxacin inhibits both topoisomerases (II and 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 MICs and disk diffusion breakpoints for moxifloxacin (01.01.2012) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing)

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

Microbiological susceptibility

The frequency of acquired resistance may vary depending on the geographical region and over time, as defined for specific microorganisms. It is desirable to have access to local information on microbial resistance, especially when treating severe infections. When local resistance prevalence is so high that the efficacy of a particular medicinal product is at least questionable for some infectious agents, consultation with an expert in antibiotic resistance should be sought.

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)

Streptoc游戏副本 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

*Satisfactory activity against susceptible strains has been demonstrated in clinical studies within the 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 (slight decrease in red blood cells and platelets) were observed in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was observed in rats, monkeys, and dogs. Neurotoxicity (manifested as 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 topoisomerase II in mammalian cells, a threshold concentration for genotoxicity can be assumed. No signs of genotoxicity were observed in in vivo tests, despite administration of high doses of moxifloxacin. Thus, the drug demonstrated sufficient safety potential for humans at therapeutic doses. Moxifloxacin did not show carcinogenic effects in a study conducted in rats.

Many quinolones are photoreactive and may provoke phototoxic reactions and exhibit photomutagenic and photocarcinogenic effects. However, data indicate that moxifloxacin lacks phototoxic and photogenotoxic properties when tested within a comprehensive testing program in vitro and in vivo. Under similar conditions, other quinolones demonstrated these effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the delayed rectifier potassium current in cardiomyocytes and may therefore lead to QT interval prolongation. Toxicological studies in dogs, in which the drug was administered orally at doses ≥ 90 mg/kg, resulting in plasma concentrations ≥ 16 mg/L, revealed QT interval prolongation without arrhythmias. Reversible non-lethal ventricular arrhythmias were observed only after intravenous administration of a high cumulative dose exceeding the human dose by more than 50 times (> 300 mg/kg), resulting in plasma concentrations ≥ 200 mg/L (more than 40 times 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 arthrototoxic effects in young dogs was four times higher than the maximum recommended therapeutic dose of 400 mg (calculated for a body weight of 50 kg), 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 administration for up to six months) did not reveal risks to the organs of vision. In dog studies, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L led to 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 orally and intravenously) and monkeys (administered orally) 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, slightly prolonged gestation period, and increased spontaneous activity in offspring were observed when moxifloxacin was administered at doses 63 times higher than the recommended dose.

Pharmacokinetics.

Absorption and bioavailability

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

Within the dose range of 50–800 mg after single administration and at a dose of 600 mg daily for 10 days, pharmacokinetics are linear. After oral administration of a 400 mg dose, maximum plasma concentration (Cmax) 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 nearly 30% higher than after the first dose.

Distribution

Moxifloxacin rapidly distributes into the extravascular space. After administration of a 400 mg dose, the area under the plasma concentration-time curve (AUC) is 35 μg·h/mL. The volume of distribution at steady state is 2 L/kg. As determined in in vitro and ex vivo experiments, plasma protein binding is approximately 40–42% and is independent of drug concentration.

Table 2

Maximum concentration (geometric mean) after single oral administration of 400 mg moxifloxacin

*Intravenous administration of a single 400 mg dose.

110 hours after administration.

2Free concentration.

3From 3 hours to 36 hours after dose administration.

4At the end of the infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both as unchanged drug and as inactive sulfocompounds (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro studies and phase I clinical trials showed no evidence of metabolic pharmacokinetic interactions with other drugs 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% as unchanged drug, approximately 2.5% as M1, and approximately 14% as M2) and in feces (approximately 25% as unchanged drug, 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 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 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 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 following bacterial infections caused by microorganisms sensitive to moxifloxacin (see sections “Pharmacological properties”, “Special instructions”, “Adverse reactions”) in patients aged 18 years and older.

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

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

For the following indications, moxifloxacin should be prescribed only when the use of other antibacterial agents, which are usually recommended for initial treatment of the following 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 infection of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. The medicinal product Traektol is not recommended for use as monotherapy for moderate to severe pelvic inflammatory diseases, but may be used (except for moxifloxacin-resistant strains of Neisseria gonorrhoeae) in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of Neisseria gonorrhoeae to moxifloxacin (see sections “Pharmacological properties”, “Special instructions”).

The medicinal product Traektol may be used to complete a treatment course in which initial parenteral therapy with Traektol has been effective and was prescribed for the following indications:

• community-acquired pneumonia;
• complicated skin and soft tissue infections.

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

Attention should be paid to official guidelines on appropriate use of antibacterial agents.

Contraindications.

• Known hypersensitivity to moxifloxacin or to other quinolones or to any of the excipients of the drug.
• Age under 18 years.
• Pregnancy or breastfeeding (see section “Use during pregnancy or breastfeeding”).
• Tendon disorders related to treatment with quinolones in medical history.

During preclinical and clinical studies, changes in cardiac electrophysiology in the form of QT interval prolongation were observed after administration of moxifloxacin. 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 drugs that prolong the QT interval (see section “Interaction with other medicinal products and other types of interactions”).

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 types of interactions.

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, 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 (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, including halofantrine);
• certain antihistamines (terfenadine, astemizole, mizolastine);
• others (cisapride, vinca alkaloids IV, bepridil, difemanil).

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

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

Concomitant administration of activated charcoal and oral moxifloxacin at a dose of 400 mg reduces systemic bioavailability of the drug by more than 80% due to inhibition of its absorption. Therefore, concomitant use of these two drugs 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 or minimum concentration (Cmin). Therefore, no precautionary measures are required when co-administering digoxin.

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

Change in international normalized ratio (INR)

Numerous cases of increased anticoagulant activity have been 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 infection or treatment causes INR deviations. 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 confirmed the above. Given these results, metabolic interaction via cytochrome P450 enzymes is unlikely.

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

Special precautions for use.

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

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

QTc interval prolongation and clinical conditions in which QT interval prolongation may occur

Prolongation of the QT interval on electrocardiogram (ECG) may occur in some patients receiving moxifloxacin. 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 generally have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients may also be more susceptible to drug-related effects on the QT interval.

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

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

Hypersensitivity/allergic reactions

Cases of hypersensitivity and allergic reactions have been reported after the first dose 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 initiated (e.g., anti-shock treatment).

Severe hepatic dysfunction

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

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

Severe skin adverse reactions

Severe skin adverse reactions (SSARs), including toxic epidermal necrolysis (TEN; also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or result in death, have been reported with moxifloxacin use (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, moxifloxacin should be immediately discontinued and alternative therapy considered. Moxifloxacin therapy must never be resumed in patients who have experienced a serious reaction such as SJS, TEN, AGEP, or DRESS.

Patients predisposed to seizures

Quinolones are known to induce seizures. Quinolones 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 (months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems (musculoskeletal, nervous, psychiatric, and sensory organs), sometimes multiple systems, have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or existing 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 taking moxifloxacin should be advised to inform their physician if they develop neuropathic symptoms 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 ideation 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 is required when prescribing moxifloxacin to patients with psychiatric disorders or a history thereof.

Diarrhea associated with antibiotic use, including colitis

Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been observed with broad-spectrum antibiotics, including moxifloxacin. The severity of these events may range from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin therapy. If suspected or confirmed AAD or AAC, antimicrobial therapy including moxifloxacin should be discontinued and appropriate therapeutic measures initiated immediately. Additionally, appropriate infection control measures should be implemented to reduce transmission risk. 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 and possibly occurring months after discontinuation (see sections "Contraindications" and "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use with corticosteroids should be avoided.

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

Aortic aneurysm and aortic dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, and development of aortic and mitral valve regurgitation following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal), and valvular regurgitation/insufficiency 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 therapies in patients with a history of aneurysm or congenital heart valve defect, diagnosed aortic aneurysm and/or aortic dissection, valvular heart disease, or other risk factors or conditions predisposing to aortic aneurysm and dissection and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, arterial hypertension, rheumatoid arthritis), or conditions associated with aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or valvular regurgitation/insufficiency (e.g., infective endocarditis).

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

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

Patients should be 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 disorders

In case of visual impairment or any effect on the eyes, patients should immediately consult an ophthalmologist (see sections "Ability to affect 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. 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 or a family history of this condition are prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in such patients.

Patients with pelvic inflammatory disease

Oral administration of moxifloxacin tablets 400 mg (e.g., Trajectol) is not recommended in patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess) who require intravenous therapy.

Pelvic inflammatory disease may be caused by Neisseria gonorrhoeae resistant to fluoroquinolones. Therefore, empirical use of moxifloxacin in such cases should be combined with another appropriate antibiotic (e.g., a cephalosporin) if Neisseria gonorrhoeae resistant to moxifloxacin cannot be fully excluded. If there is no clinical improvement after 3 days of treatment, therapy should be re-evaluated.

Patients with specific complicated skin and soft tissue infections

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

Effect on biological tests

Moxifloxacin therapy may interfere with microbiological testing for Mycobacterium spp. due to inhibition of mycobacterial growth, potentially leading to false-negative results in samples from patients currently taking moxifloxacin.

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

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

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

The product contains sunset yellow (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk in humans is not established.

Due to the risk of fluoroquinolone-induced joint damage in young animals (based on experimental data) and reversible joint lesions described in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, causes 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 did not reveal any effect on fertility (see section "Pharmacological properties").

Ability to affect reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Dosage (adults)

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

Renal or hepatic impairment

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

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

Elderly patients / patients with low body weight

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

Method of administration

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

Duration of therapy

The duration of treatment with Trajectol 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 Trajectol tablets 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 treatment with Trajectol tablets 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 treatment duration for each indication should not be exceeded.

Children.

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

Overdose.

In case of accidental overdose, no specific antidote is recommended. Management should be based on clinical symptoms and include symptomatic and supportive therapy, as well as ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin reduces systemic availability by more than 80%. In 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], and oral) 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 reactions are listed in decreasing order of severity. Frequency is defined as follows: common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), infrequent (≥ 1/10,000, <1/1000), rare (<1/10,000), frequency not known (cannot be estimated based on available data).

Table 3

*Rare cases of prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age and existing risk factors (see section "Special 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 heart valve have been reported in patients receiving fluoroquinolones (see section "Special precautions for use").

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. 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 Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life.

5 years.

Storage conditions.

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

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Rivopharm S.A.

Manufacturer's address and location of its business operations.

Centro Insema, 6928 Manno, Switzerland.