Timoxi

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tymoxy® (Tymoxy®) Composition: Active ingredient: moxifloxacin; 1 film-coated tablet contains 400 mg moxifloxacin (as moxifloxacin hydrochloride); Excipients: Tablet core: microcrystalline cellulose, partially pregelatinized corn starch, low-substituted hydroxypropylcellulose, sodium lauryl sulfate, sodium stearyl fumarate; Coating: Opadry II Orange [polyvinyl alcohol; titanium dioxide (E 171); polyethylene glycol; talc; sunset yellow color (E 110)]. Pharmaceutical form. Film-coated tablets. Main physicochemical properties: elongated biconvex film-coated tablets, light orange in color with a score on one side. The score is not intended for dividing the tablet in half. Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterials of the quinolone group. ATC code J01MA14. Pharmacological properties. Pharmacodynamics. Mechanism of action Moxifloxacin is an 8-methoxyfluoroquinolone agent with a broad spectrum of bactericidal activity. In vitro, moxifloxacin is effective against many Gram-positive and Gram-negative microorganisms. Moxifloxacin has been shown to be effective against bacteria resistant to β-lactam and macrolide agents. The bactericidal activity of moxifloxacin is due to inhibition of both types of 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 in Gram-positive bacteria compared to C8-H substituent. The presence of a large dicycloamine substituent at the C-7 position prevents active efflux mediated by norA or pmrA genes found in some Gram-positive bacteria. Moxifloxacin exhibits concentration-dependent bactericidal activity. Minimum bactericidal concentrations (MBC) are usually equivalent to minimum inhibitory concentrations (MIC). Effect on intestinal flora in humans The following changes in intestinal flora were observed in volunteers after oral administration of moxifloxacin: reduction in 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 two weeks. Resistance Mechanisms of resistance that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not affect the antibacterial efficacy of moxifloxacin. Other resistance mechanisms, such as permeability barriers (common in Pseudomonas aeruginosa) and efflux mechanisms, may affect 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, since moxifloxacin inhibits both type II topoisomerases (DNA gyrase and topoisomerase IV) with similar potency in certain Gram-positive bacteria, these bacteria may be resistant to other quinolones but remain susceptible to moxifloxacin. Breakpoints Clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) Table 1

* Species-unspecific breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the MIC distribution of specific species. These data are used only for species for which no species-specific breakpoints have been defined, and are not used for species for which interpretive criteria are to be determined.

Microbiological susceptibility
The frequency of acquired resistance may vary depending on geographical location, region, and over time for specific microorganisms. It is desirable to have access to local information on microbial resistance, especially when treating severe infections. Consultation with an expert in antimicrobial resistance should be sought if local resistance prevalence is so high that the efficacy of a particular medicinal product against certain infectious agents becomes questionable.

Susceptible species
Aerobic Gram-positive microorganisms
Gardnerella vaginalis
Staphylococcus aureus* (methicillin-susceptible)
Streptococcus agalactiae (Group B)
Streptococcus milleri group* (S. anginosus, S. constellatus, and S. intermedius)
Streptococcus pneumoniae*
Streptococcus pyogenes* (Group A)
Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus)

Aerobic Gram-negative microorganisms
Acinetobacter baumannii
Haemophilus influenzae*
Haemophilus parainfluenzae*
Legionella pneumophila
Moraxella (Branhamella) catarrhalis*

Annaerobic 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*

Annaerobic microorganisms
Bacteroides fragilis*
Peptostreptococcus spp.*

Resistant species
Aerobic Gram-negative microorganisms
Pseudomonas aeruginosa

* Demonstrated adequate activity against susceptible strains in clinical trials within approved clinical indications.
#Strains producing extended-spectrum beta-lactamases (ESBL) are usually resistant to fluoroquinolones.
+Resistance rate > 50% in one or more countries.

Safety data
Effects on the hematopoietic system (mild reduction in erythrocyte and platelet counts) 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 (CNS effects – 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. In vivo tests showed no signs of genotoxicity despite administration of high doses of moxifloxacin. Thus, the drug demonstrated sufficient 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 from comprehensive in vitro and in vivo testing programs indicate the absence of phototoxic and photogenotoxic properties of moxifloxacin. Under the same conditions, other quinolones demonstrated these 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 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 arrhythmia was observed only after intravenous administration of a high cumulative dose more than 50 times higher than 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 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), and resulted in plasma concentrations two to three times higher than those expected with maximum therapeutic dosing.

Toxicity studies in rats and monkeys (repeated dosing for up to 6 months) revealed no signs of risk to the organs of vision. In studies in dogs, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L caused changes in electroretinograms and, in individual cases, retinal atrophy.

Studies on the effect of moxifloxacin on animal reproductive function have demonstrated that moxifloxacin crosses the placenta. Studies in rats (with oral and intravenous administration of moxifloxacin) and monkeys (with oral administration of moxifloxacin) showed no teratogenic effects of moxifloxacin or effects on fertility. Intravenous administration of moxifloxacin at 20 mg/kg in rabbits resulted in skeletal malformations. An increased incidence of abortions was observed in monkeys and rabbits at therapeutic doses of moxifloxacin. In rats, reduced fetal weight, increased incidence of abortions, slight prolongation of gestation period, and increased spontaneous activity in offspring were observed 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 to 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, 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 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 administration of 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 administration of 400 mg moxifloxacin:
Table 2

* Single intravenous dose of 400 mg. 1 10 hours after administration. 2 Free concentration. 3 From 3 hours to 36 hours after 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 unchanged and as inactive sulfated compounds (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro studies and Phase I clinical trials did not reveal any metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation mediated by cytochrome P450 enzymes. There is no evidence of oxidative metabolism. Elimination The elimination half-life of the drug is approximately 12 hours. The mean total clearance after administration of 400 mg ranges from 179 to 246 mL/min. Renal clearance is approximately 24–53 mL/min, indicating partial tubular reabsorption of the drug by the kidneys. After administration of a 400 mg dose, excretion in urine (approximately 19% unchanged drug, approximately 2.5% as M1, and approximately 14% as M2) and feces (approximately 25% unchanged drug, approximately 36% as M1, and absence of excretion as M2) totaled approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug. Pharmacokinetics in different patient groups. Elderly patients and patients with low body weight Higher plasma concentrations of the drug were observed in healthy volunteers with low body weight (particularly in women) and in healthy elderly volunteers. Renal impairment. No significant changes in moxifloxacin pharmacokinetics were 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, while exposure to the parent drug was comparable to that in healthy volunteers. There is insufficient clinical experience with the use of moxifloxacin for treating patients with hepatic impairment. Clinical characteristics. Indications. Treatment of the following bacterial infections caused by moxifloxacin-susceptible microorganisms (see sections "Pharmacological properties", "Special precautions for use", "Adverse reactions") in patients aged 18 years and older. Moxifloxacin should be prescribed only when antibacterial agents typically recommended for initial treatment of the following infections are inappropriate or when such treatment has been ineffective.

• Acute bacterial sinusitis (diagnosed with high probability).
• Acute exacerbation of chronic obstructive pulmonary disease, including bronchitis (diagnosed with high probability).
• 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 drug Timoxi is not recommended for use as monotherapy for moderate to severe pelvic inflammatory disease, but it 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 N. gonorrhoeae) (see sections "Pharmacological properties", "Special precautions for use").

Timoxi may be used to complete a course of treatment where initial therapy with intravenous moxifloxacin was effective and indicated for the following conditions:

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

Timoxi is not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia. Attention should be paid to official recommendations regarding 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").
• Patients with a 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 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;
• history of symptomatic arrhythmias.

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 drug use, the drug 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 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, difemelane).

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 is required between administration of drugs containing divalent or trivalent cations (such as antacids containing magnesium or aluminum, didanosine tablets, sucralfate, and iron or zinc-containing products) and moxifloxacin. Concomitant administration of activated charcoal and oral moxifloxacin 400 mg reduces systemic bioavailability 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 multiple doses of moxifloxacin in healthy volunteers, an increase in digoxin Cmax of approximately 30% at steady state was observed without affecting AUC (area under the concentration-time curve) or trough levels. Therefore, no precautions are needed when co-administering digoxin. In studies involving volunteers and diabetic patients, concomitant administration of oral moxifloxacin and glyburide resulted in a decrease in peak glyburide concentration of approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to mild transient hyperglycemia. However, the observed changes in pharmacokinetics did not lead to changes in pharmacodynamic parameters (blood glucose level, insulin level). Thus, no clinically relevant interaction between moxifloxacin and glyburide was observed. 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 infection (and associated inflammatory process), age, and the patient's general condition. Due to these circumstances, it is difficult to assess whether infection or treatment causes INR deviations. As a precaution, more frequent monitoring of INR may be considered. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed. 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. Given these results, metabolic interaction via cytochrome P450 enzymes is unlikely. Moxifloxacin absorption is independent of food intake (including dairy products), therefore moxifloxacin can be administered regardless of food intake. Special precautions for use. Avoid use of moxifloxacin in patients who have previously experienced serious adverse reactions to quinolones or products containing fluoroquinolones (see section "Adverse reactions"). Treatment of these patients with moxifloxacin should be initiated only if there are no alternative treatment options and after careful benefit/risk assessment (see section "Contraindications"). Benefits of moxifloxacin treatment, especially in mild infections, should be evaluated considering the information contained in this section. Prolonged, disabling, and potentially irreversible serious adverse reactions In patients receiving quinolones and fluoroquinolones, regardless of age, very rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported, along with risk factors. Moxifloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a physician. QTc interval prolongation and clinical conditions associated with QT interval prolongation QT interval prolongation on electrocardiogram may occur in some patients during moxifloxacin use. Analysis of ECG results from clinical trial programs showed that QTc interval 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 drug-related effects on the QT interval. Patients taking moxifloxacin should use drugs that may lead to decreased potassium levels with caution (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions"). Moxifloxacin should be prescribed with caution in patients with prolonged proarrhythmic conditions (especially 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 increasing drug concentration. Therefore, the recommended dose should not be exceeded. If arrhythmia symptoms occur during treatment, therapy should be discontinued and an ECG performed. Hypersensitivity/allergic reactions Cases of hypersensitivity and allergic reactions after first administration of fluoroquinolones, including moxifloxacin, have been reported. Anaphylactic reactions may manifest as life-threatening shock even after first administration of the drug. In cases of clinically significant hypersensitivity reactions, moxifloxacin use should be discontinued and appropriate therapy initiated (e.g., anti-shock). Severe hepatic impairment Cases of fulminant hepatitis, which may lead to hepatic failure (including fatal cases), have been reported with moxifloxacin use (see section "Adverse reactions"). If symptoms of fulminant hepatitis such as rapidly developing fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy occur, patients are advised to consult a physician before continuing treatment. Liver function tests should be performed if signs of hepatic dysfunction appear. Severe skin adverse reactions Severe skin adverse reactions (SCARs), 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 fatal, have been reported (see section "Adverse reactions"). Patients should be warned about signs and symptoms of severe skin reactions and closely monitored. If signs and symptoms indicating these reactions appear, moxifloxacin should be discontinued immediately, and alternative treatment should be considered. If a patient develops a serious reaction such as SJS, TEN, AGEP, or DRESS during moxifloxacin use, moxifloxacin treatment should never be resumed for this patient. Patients predisposed to seizures Quinolones are known to induce seizures. They should be prescribed with caution in patients with CNS disorders or other risk factors that may provoke seizures or lower the seizure threshold. If seizures occur, moxifloxacin use should be discontinued and appropriate measures taken. Peripheral neuropathy Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones, including moxifloxacin. Patients taking moxifloxacin are advised to inform their physician if they develop 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 administration of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions progressed to suicidal thoughts and self-harm behaviors such as suicide attempts (see section "Adverse reactions"). If such reactions develop in a patient, moxifloxacin treatment should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with a history or current psychiatric disorders. Antibiotic-associated diarrhea, 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 the use of 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 administration. If suspected or confirmed AAD or AAC, treatment with antimicrobial agents, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. Additionally, appropriate measures should be taken to control infection to reduce transmission risk. Drugs that inhibit peristalsis are contraindicated in patients who develop severe diarrhea. Patients with severe myasthenia Moxifloxacin should be used with caution in patients with severe myasthenia gravis, as symptoms may be exacerbated. Tendon inflammation, tendon rupture Tendon inflammation and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, including moxifloxacin, even within 48 hours of starting treatment, and have been reported to occur up to several months after discontinuation of treatment. The risk of developing tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplants, and those receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. If signs of tendinitis (e.g., painful swelling, inflammation) appear, moxifloxacin treatment should be discontinued and alternative treatment considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear. Patients with renal impairment Elderly patients with renal disorders should be prescribed moxifloxacin with caution if they are unable to maintain adequate fluid volume, as dehydration increases the risk of renal failure. Ocular disorders If visual impairment or any effect on the eyes occurs, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction speed when driving or operating machinery", "Adverse reactions"). Dysglycemia As with all fluoroquinolones, cases of blood glucose level abnormalities, both hypoglycemia and hyperglycemia, have been reported during moxifloxacin treatment. Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin with moxifloxacin treatment. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels (see section "Adverse reactions"). Prevention of photosensitization reactions Photosensitization reactions have been reported in patients receiving quinolones. However, studies have shown that moxifloxacin has a lower risk of photosensitization. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense sunlight exposure during moxifloxacin treatment (see section "Adverse reactions"). Patients with glucose-6-phosphate dehydrogenase deficiency Patients with glucose-6-phosphate dehydrogenase deficiency, as well as patients with a family history of this condition, are predisposed to hemolytic reactions during quinolone treatment. Therefore, moxifloxacin should be used with caution in this patient group. Patients with pelvic inflammatory disease Patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess), for whom intravenous therapy is considered necessary, should not be treated with Timoxi 400 mg coated tablets. Pelvic inflammatory disease may be caused by Neisseria gonorrhoeae resistant to fluoroquinolones. Therefore, empirical use of moxifloxacin in such cases should be prescribed concomitantly with another appropriate antibiotic (e.g., a cephalosporin) if the presence of moxifloxacin-resistant Neisseria gonorrhoeae 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 for treating severe infections associated with burns, fasciitis, and diabetic foot with osteomyelitis has not been established. Effect on biological tests Moxifloxacin treatment may interfere with culture testing for detection of Mycobacterium spp. due to inhibition of microbial growth, which may lead 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 treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In case of suspected or confirmed MRSA infection, appropriate antibacterial treatment 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"). Aortic aneurysm and dissection and cardiac valve regurgitation/insufficiency Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation after fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), 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 other therapeutic treatment 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

• for both aortic aneurysm and dissection and 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, or known atherosclerosis, or Sjögren's syndrome) or additionally

• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving systemic corticosteroids concomitantly.

If sudden abdominal, chest, or back pain occurs, patients should immediately seek medical attention at an emergency department. Patients should be advised to seek immediate medical help if acute shortness of breath, new onset palpitations, or development of abdominal or lower limb edema occurs. The product contains the colorant 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 study results indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk for humans has not been established. Due to the risk of fluoroquinolone-induced damage to weight-bearing joints in young animals (based on experimental data) and reversible joint damage described in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications"). Breastfeeding Period Moxifloxacin, like other quinolones, has been shown to cause damage to joint cartilage in young animals. Preclinical study results 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 use 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 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 reactions (e.g., dizziness, acute transient vision loss, see section "Adverse reactions") or acute brief loss of consciousness (syncope, see section "Adverse reactions"). Patients should be advised to monitor their reaction 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/hepatic impairment No dose adjustment is required for patients with moderate to severe renal impairment, as well as for patients undergoing continuous hemodialysis and long-term ambulatory peritoneal dialysis (see section "Pharmacological properties"). No dose adjustment is required for patients with hepatic impairment (see also section "Contraindications"). Elderly patients/low body weight patients No dose adjustment is required for elderly patients/low body weight patients. Method of administration Tablets should be swallowed whole with sufficient water. The drug can be taken regardless of food intake. Duration of therapy The duration of Timoxi therapy depends on the type of infection and is:

• acute 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.

Clinical trial data indicate that the duration of moxifloxacin (tablet) treatment was up to 14 days. Step-down therapy (intravenous administration followed by transition to oral administration) In clinical studies of sequential therapy, most patients transitioned from intravenous to oral moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (complicated skin and soft tissue infections). The recommended total duration of treatment with tablets and infusion solution of moxifloxacin is 7-14 days for community-acquired pneumonia and 7-21 days for complicated skin and soft tissue infections. Exceeding the specified dose (400 mg once daily) and treatment duration for each indication is not recommended. Children. Moxifloxacin is contraindicated in children (under 18 years of age). The efficacy and safety of moxifloxacin use in children have not been established (see also section "Contraindications"). Overdose. In case of accidental overdose, no specific measures are recommended. In case of overdose, treatment should be based on clinical presentation and include symptomatic supportive therapy and ECG monitoring due to the potential for QT interval prolongation. Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin will reduce systemic availability of the drug by more than 80%. In case of overdose due to oral intake of the drug, administration of activated charcoal at the initial stage of absorption may be effective in preventing increased systemic effects of moxifloxacin. Adverse reactions. The adverse effects listed below were obtained from clinical trials and post-marketing reports of moxifloxacin 400 mg (oral and step-down therapy) and their frequency. All adverse reactions were observed 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 (≥1/10000, <1/1000), very rare (<1/10000), frequency not known. Table 3

* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions to medicinal products affecting several, sometimes multiple, organ system classes and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance; in some cases, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances in hearing, vision, taste, and smell have been reported), which are associated with the use of quinolones and fluoroquinolones, regardless of pre-existing risk factors (see section "Special precautions for use"), as well as anxiety, suicidal thoughts, panic attacks, neuralgia, and concentration difficulties as potential aspects of prolonged and disabling adverse reactions induced by fluoroquinolones. ** In patients receiving fluoroquinolones, cases of aneurysms and aortic dissections, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported (see section "Special precautions for use"). In rare cases following treatment with other fluoroquinolones, adverse reactions such as increased intracranial pressure (including idiopathic intracranial hypertension), hypernatraemia, hypercalcaemia, and haemolytic anaemia have been observed, which might possibly also occur during moxifloxacin use. Reporting of adverse reactions after drug authorization is highly important. It enables ongoing 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 of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua.
Shelf life: 3 years. Do not use after the expiry date stated on the packaging.
Storage conditions: This medicinal product does not require special storage temperature conditions. Store in the original packaging to protect from light. Keep out of reach of children.
Packaging: Film-coated tablets in aluminum foil blisters. 5 or 7 tablets per blister. 1 blister (containing 5 tablets) or 1 blister (containing 7 tablets) in a cardboard box.
Prescription status: Prescription only.
Manufacturer: ALKALOID AD Skopje. ALKALOID AD Skopje.
Manufacturer's address and location of operations: Bulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia. Bulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.