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

Composition:

Active substance: moxifloxacin;

One film-coated tablet contains moxifloxacin hydrochloride equivalent to 400 mg of moxifloxacin;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone (K 30), magnesium stearate; film coating: hypromellose 6 cP, titanium dioxide (E 171), macrogol 4000, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: matte red-colored modified capsule-shaped film-coated tablets, with "E 18" embossed on one side.

Pharmacotherapeutic group.

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

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to the C8-H substituent. The presence of a bulky diazabicyclic group at the C-7 position prevents active efflux mediated by norA or pmrA genes identified in some Gram-positive bacteria.

Pharmacodynamic studies indicate that moxifloxacin exhibits concentration-dependent bactericidal activity. Minimum bactericidal concentrations (MBC) are generally comparable to minimum inhibitory concentrations (MIC).

Effect on intestinal flora in humans.

In two studies involving volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. Decreased numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus. An increase in the number of Bacteroides fragilis was observed. The levels of the above-mentioned microorganisms returned to normal within 2 weeks.

Mechanism of resistance.

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

Development of resistance to moxifloxacin in vitro has been observed as a gradual process involving point mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux mechanisms in Gram-positive microorganisms.

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

Clinical breakpoints.

Clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing)

Microbiological susceptibility.

The frequency of acquired resistance may vary depending on geographical location and over time for specific microorganisms. It is advisable to have access to local information on microbial resistance, especially when treating severe infections.

Expert consultation regarding antibiotic resistance should be sought if local resistance prevalence is so high that the efficacy of a particular medicinal product against certain infectious agents is at least questionable.

Susceptible species

Aerobic Gram-positive microorganisms

Gardnerella vaginalis

Staphylococcus aureus* (methicillin-susceptible)

Streptococcus agalactiae (Group B)

Streptococcus milleri group* (S. anginosus, S. constellatus and S. intermedius)

Streptococcus pneumoniae*

Streptococcus pyogenes* (Group A)

Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus)

Aerobic Gram-negative microorganisms

Acinetobacter baumannii

Haemophilus influenzae*

Haemophilus parainfluenzae*

Legionella pneumophila

Moraxella (Branhamella) catarrhalis*

Anaerobic microorganisms

Fusobacterium spp.

Prevotella spp.

Other microorganisms

Chlamydophila (Chlamydia) pneumoniae*

Chlamydia trachomatis*

Coxiella burnetii

Mycoplasma genitalium

Mycoplasma hominis

Mycoplasma pneumoniae*

Species with possible acquired resistance

Aerobic Gram-positive microorganisms

Enterococcus faecalis*

Enterococcus faecium*

Staphylococcus aureus (methicillin-resistant)+

Aerobic Gram-negative microorganisms

Enterobacter cloacae*

Escherichia coli*#

Klebsiella pneumoniae*#

Klebsiella oxytoca

Neisseria gonorrhoeae*+

Proteus mirabilis*

Anaerobic microorganisms

Bacteroides fragilis*

Peptostreptococcus spp.*

Resistant species

Aerobic Gram-negative microorganisms

Pseudomonas aeruginosa

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

Strains producing ESBL are usually resistant to fluoroquinolones.

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

Preclinical 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 observed in rats, monkeys, and dogs. Cases of neurotoxicity (CNS effects manifested as seizures) were recorded 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 in vivo tests, no signs of genotoxicity were detected 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 studies conducted in rats.

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

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the delayed rectifier potassium current in cardiomyocytes and thus may lead to QT interval prolongation. Toxicological studies in dogs, where the drug was administered orally at doses ≥ 90 mg/kg, resulting in plasma concentrations ≥ 16 mg/L, revealed QT 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 damage to cartilage in large diarthrodial joints in young animals. The lowest oral dose of moxifloxacin causing arthrototoxic effects in young dogs was four times higher than the maximum recommended therapeutic dose of 400 mg (for a 50 kg body weight), calculated on the basis of dose/body weight ratio (mg/kg), resulting 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 6 months) did not reveal any risk to vision organs. In dog studies, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L led to changes in electroretinograms and, in some cases, retinal atrophy.

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

Pharmacokinetics.

Absorption and bioavailability.

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

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 a single 400 mg oral dose, peak blood concentration is reached within 0.5–4 hours and amounts to 3.1 mg/L. Maximum and minimum plasma concentrations at steady state (400 mg once daily) are 3.2 and 0.6 mg/L, respectively. At steady state, exposure over the dosing interval is nearly 30% higher than after the first dose.

Distribution.

Moxifloxacin rapidly distributes into the extravascular space. After a 400 mg dose, AUC is 35 µg·h/mL. The volume of distribution at steady state is 2 L/kg. In vitro and ex vivo experiments have shown that plasma protein binding is approximately 40–42% and independent of drug concentration.

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

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 sulfated metabolite (M1) and glucuronides (M2). M1 and M2 are the only metabolites relevant in humans, both being microbiologically inactive. In vitro studies and phase I clinical trials showed no evidence of metabolic pharmacokinetic interactions with other medicinal products 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) accounted for approximately 96% overall. 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 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 in patients with hepatic impairment.

Clinical characteristics.

Indications.

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

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

• Community-acquired pneumonia, excluding community-acquired pneumonia with severe course.
• Moderate to severe pelvic inflammatory disease (including infectious involvement of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses.

Moxivar is not recommended for use as monotherapy in moderate to severe pelvic inflammatory disease, 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 "Special precautions for use", "Pharmacological properties").

Moxivar may be used to complete a treatment course in which initial parenteral moxifloxacin therapy was effective and indicated for:

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

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

Attention should be paid to official guidelines for 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").
• History of tendon disorders related to quinolone therapy. In preclinical and clinical studies, moxifloxacin administration was associated with changes in cardiac electrophysiology, including QT interval prolongation. Therefore, for safety reasons, the drug is contraindicated in patients with:
• Congenital or diagnosed acquired QT interval prolongation;
• Electrolyte imbalances, particularly uncorrected hypokalemia;
• Clinically significant bradycardia;
• Clinically significant heart failure with reduced left ventricular ejection fraction;
• 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 forms of interaction").

Due to limited clinical data, 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 forms of interaction.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may increase the risk of ventricular arrhythmias, including torsades de pointes. For this reason, the concomitant use of moxifloxacin 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 in patients receiving 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 bivalent 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 400 mg reduces systemic bioavailability of the drug 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% at steady state was observed, without affecting AUC (area under the concentration–time curve) or trough concentrations. Therefore, no precautionary 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 decrease in peak glyburide concentration by approximately 21%. The combination of glyburide with moxifloxacin may theoretically lead to minor, short-term 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, co-trimoxazole, and certain cephalosporins. Risk factors include infection (and associated inflammatory process), age, and general patient condition. Due to these circumstances, it is difficult to determine whether the infection or its treatment causes INR deviations. As a precaution, more frequent monitoring of INR may be advisable. Dose adjustment of the oral anticoagulant should be performed as necessary.

For the following substances, 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. Considering 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.

The use of moxifloxacin should be avoided in patients with a history of serious adverse reactions after treatment with drugs containing quinolones or 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 assessment of the benefit-risk ratio (see also section "Contraindications").

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

QTc interval prolongation and clinical conditions associated with QT interval prolongation
Moxifloxacin may cause an increase in the QT interval on the electrocardiogram (ECG) in some patients.

Analysis of ECG results obtained within clinical trial programs showed that QTc interval prolongation with moxifloxacin was 6 ms ± 26 ms (1.4%) compared to baseline levels. 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-associated 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 administered with caution to 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 should be performed.

Increased sensitivity/allergic reactions

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

Severe hepatic impairment

Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported during moxifloxacin therapy (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 reactions

Severe skin reactions, including toxic epidermal necrolysis (also known as Lyell’s syndrome), Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be 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 signs or symptoms suggestive of such reactions occur, moxifloxacin should be discontinued immediately and alternative therapy considered. Moxifloxacin must never be re-administered to patients who have developed severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or DRESS during previous treatment.

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 months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients treated with quinolones and fluoroquinolones, regardless of patient age or existing risk factors. Moxifloxacin should be discontinued immediately upon the first symptoms 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, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones or fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients undergoing treatment should inform their physician before continuing therapy to prevent the development of potentially irreversible conditions (see section "Adverse reactions").

Psychiatric reactions

Psychiatric reactions may develop even after the first dose of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychotic reactions have led to suicidal thoughts and self-harming behaviors, including suicide attempts (see section "Adverse reactions"). If such reactions occur, moxifloxacin should be discontinued and appropriate measures taken. Moxifloxacin should be prescribed with caution 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-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 therapy. If AAD or AAC is suspected or confirmed, 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. Patients who develop severe diarrhea should not receive peristalsis-inhibiting agents.

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 (particularly of the Achilles tendon), sometimes bilateral, may occur during therapy with quinolones and fluoroquinolones, developing within 48 hours of starting treatment and possibly occurring 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 (e.g., immobilization) should be initiated for the affected limb(s). Corticosteroids should not be used in cases of tendonopathy.

Aortic aneurysm and aortic dissection, valvular regurgitation / insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, as well as valvular regurgitation at the aortic and mitral valves following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal), and valvular regurgitation/insufficiency of any cardiac valve have been reported in patients treated with 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, diagnosed aortic aneurysm and/or aortic dissection, or valvular heart disease, as well as in the presence of 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 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 developing aortic aneurysm, dissection, and rupture may be increased in patients receiving concomitant systemic corticosteroid therapy.

Patients should seek immediate medical attention in case of sudden abdominal, chest, or back pain.

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

Patients with renal impairment

Moxifloxacin should be administered with caution to elderly patients with renal disorders who are unable to maintain adequate fluid volume, as dehydration increases the risk of renal failure.

Visual disorders

If visual disturbances or other effects on the visual organs occur, patients should seek immediate consultation with an ophthalmologist (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose deviations, 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 treated with 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 this patient population.

Patients with pelvic inflammatory disease

Moxivar 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, empirical use of moxifloxacin in such cases should be combined with another appropriate antibiotic (e.g., a cephalosporin) if resistance to moxifloxacin cannot be fully excluded.

If there is no clinical improvement after 3 days of treatment, the 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 related to burns, fasciitis, and infected diabetic foot with associated osteomyelitis has not been established.

Effect on biological tests

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

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

Moxifloxacin is not recommended for the treatment of infections caused by 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 is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp 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 determined.

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

Breastfeeding.

Moxifloxacin, like other quinolones, has been shown to cause damage to the cartilage of joints in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on the use of the 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.

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 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 / 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 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 regardless of food intake.

Duration of therapy.

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

• 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.

According to clinical studies, the treatment duration with the tablet form of Moxivar was up to 14 days.

Step-down (intravenous to oral) therapy.

During clinical studies 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 soft tissue infections). The recommended total duration of step-down (intravenous/oral) therapy 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 in children have not been established (see also section "Contraindications").

Overdose.

In case of accidental overdose, no specific measures are recommended. In the event of overdose, management should be based on clinical presentation and include symptomatic and supportive therapy, as well as ECG monitoring due to the potential for QT interval prolongation. Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin results in more than 80% reduction in systemic drug availability.

In cases of overdose following oral administration of the drug, early administration of activated charcoal during the initial absorption phase 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 listed in the "frequent" column 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: frequent (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000).

* Rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple, organ systems and sensory organs (including such reactions as tendon inflammation, tendon rupture, arthralgia, limb pain, difficulty walking, neuropathy associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration disturbances, 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 Warnings and 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 Warnings and Precautions for Use").

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 5 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 5 tablets per blister, 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit VII, India.

Manufacturer's address and location of business operations.

Special Economic Zone, TSIIC, Plot No. S1, Sy. No. 411/R, 425/R, 434/R, 435/R, and 458/R, Green Industrial Park, Polepally Village, Jadcherla Mandal, Mahbubnagar District, Telangana State, 509302, India.